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75 results on '"MESH: Immune Tolerance"'

1. Trained immunity, tolerance, priming and differentiation: distinct immunological processes

Author

Boris Novakovic, Andreas Schlitzer, Giuseppe Matarese, Zahi A. Fayad, Willem J. M. Mulder, Henk Stunnenberg, Andrew R. DiNardo, Niels P. Riksen, Joachim L. Schultze, Christine Stabell Benn, Joseph C. Sun, Eva Kaufmann, Shabaana A. Khader, Michael H. Sieweke, Siroon Bekkering, Stephanie Fanucchi, Luis B. Barreiro, Maziar Divangahi, Mihai G. Netea, Reinout van Crevel, Jordi Ochando, Peter Aaby, Shruti Naik, Leo A. B. Joosten, Triantafyllos Chavakis, Musa M. Mhlanga, Eicke Latz, David L. Williams, Jos W. M. van der Meer, Luke A. J. O'Neill, Ramnik J. Xavier, Nigel Curtis, Robert W. Sauerwein, Kate L. Jeffrey, Edward R. Sherwood, Elaine Fuchs, Sebastian Weis, Nargis Khan, Melanie Hamon, Raphael Duivenwoorden, Keiko Ozato, Simone J.C.F.M. Moorlag, Jorge Domínguez-Andrés, Frank L. van de Veerdonk, Precision Medicine, ICMS Core, McGill University Health Center [Montreal] (MUHC), Bandim Health Project, International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH Network), Washington University in Saint Louis (WUSTL), The University of Chicago Medicine [Chicago], Radboud University Medical Center [Nijmegen], Technische Universität Dresden = Dresden University of Technology (TU Dresden), University of Melbourne, Baylor College of Medicine (BCM), Baylor University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Eindhoven University of Technology [Eindhoven] (TU/e), University of Cape Town, Rockefeller University [New York], Chromatine et Infection - Chromatin and Infection, Institut Pasteur [Paris] (IP), Harvard Medical School [Boston] (HMS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Trinity Biomedical Sciences Institute, School of Biochemistry & Immunology, National Institute of Child Health and Human Development [Bethesda], National Institutes of Health, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Universität Bonn = University of Bonn, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biotechnology Center, and Center for Regenerative Therapies Dresden (CRTD), Max Delbrück Centrum für Molekulare Medizin (MDC), University of Southern Denmark (SDU), Radboud University [Nijmegen], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Jena University Hospital [Jena], East Tennessee State University (ETSU), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts Institute of Technology (MIT), Divangahi, M., Aaby, P., Khader, S. A., Barreiro, L. B., Bekkering, S., Chavakis, T., van Crevel, R., Curtis, N., Dinardo, A. R., Dominguez-Andres, J., Duivenwoorden, R., Fanucchi, S., Fayad, Z., Fuchs, E., Hamon, M., Jeffrey, K. L., Khan, N., Joosten, L. A. B., Kaufmann, E., Latz, E., Matarese, G., van der Meer, J. W. M., Mhlanga, M., Moorlag, S. J. C. F. M., Mulder, W. J. M., Naik, S., Novakovic, B., O'Neill, L., Ochando, J., Ozato, K., Riksen, N. P., Sauerwein, R., Sherwood, E. R., Schlitzer, A., Schultze, J. L., Sieweke, M. H., Benn, C. S., Stunnenberg, H., Sun, J., van de Veerdonk, F. L., Weis, S., Williams, D. L., Xavier, R., Netea, M. G., Institut Pasteur [Paris], Consiglio Nazionale delle Ricerche (CNR), University of Bonn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft, Radboud university [Nijmegen], Hamon, Melanie, and ACS - Atherosclerosis & ischemic syndromes

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], animal diseases, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Priming (immunology), Adaptive Immunity, 0302 clinical medicine, Immunology and Allergy, MESH: Animals, ComputingMilieux_MISCELLANEOUS, immunology [BCG Vaccine], Vaccination, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Cell Differentiation, Common framework, [SDV] Life Sciences [q-bio], MESH: BCG Vaccine, BCG Vaccine, MESH: Immunologic Memory, MESH: Immunity, Innate, MESH: Cell Differentiation, MESH: Immune Tolerance, Immunology, education, immunology [Adaptive Immunity], chemical and pharmacologic phenomena, Biology, Article, 03 medical and health sciences, Immune system, Immunity, Immune Tolerance, Animals, Humans, ddc:610, Molecular Biology, MESH: Humans, immunology [Immune Tolerance], Cell Biology, MESH: Vaccination, biochemical phenomena, metabolism, and nutrition, Immunity, Innate, immunology [Immunologic Memory], immunology [Immunity, Innate], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030104 developmental biology, bacteria, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Neuroscience, Immunologic Memory, MESH: Adaptive Immunity, 030215 immunology
Abstract

The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.

Published
2021

2. PD-1 is expressed by and regulates human group 3 innate lymphoid cells in human decidua

Author

Emanuela Marcenaro, Marco Greppi, Enrico Munari, Paola Vacca, Maria Cristina Mingari, Alessandro Moretta, Silvia Pesce, Lorenzo Moretta, Ezio Fulcheri, Daniel Olive, Department of Experimental Medicine - DIMES [Genoa, Italy] (DIMES), University of Genoa (UNIGE), Department of Experimental Medicine, University of Genoa, D.I.C.M.I., Universita degli studi di Genova, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istituto Nazionale per la Ricerca sul Cancro, Genova, Immunologia, Università di Genova, Dipartimento di Medicina Sperimentale, IRCCS Istituto Giannina Gaslini, Genova, and Università degli studi di Genova = University of Genoa (UniGe)

Subjects
MESH: Signal Transduction, 0301 basic medicine, MESH: Trophoblasts, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, B7-H1 Antigen, MESH: Decidua, Immune tolerance, MESH: Pregnancy, 0302 clinical medicine, Pregnancy, MESH: B7-H1 Antigen, Homeostasis, Innate, Immunology and Allergy, Lymphocytes, Receptor, Hepatitis A Virus Cellular Receptor 2, MESH: Cytokines, Innate lymphoid cell, Decidua, MESH: Programmed Cell Death 1 Receptor, Trophoblasts, MESH: Placental Circulation, 3. Good health, Cell biology, medicine.anatomical_structure, MESH: Homeostasis, Cytokines, Female, MESH: Immunity, Innate, Signal transduction, Signal Transduction, Programmed cell death, MESH: Immune Tolerance, T cell, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Immune system, Immune Tolerance, medicine, Humans, Placental Circulation, MESH: Humans, Immunity, Immunity, Innate, MESH: Hepatitis A Virus Cellular Receptor 2, 030104 developmental biology, MESH: Lymphocytes, MESH: Female, 030215 immunology
Abstract

International audience; Group 3 innate lymphoid cells (ILC3) have been detected in both murine and human decidual tissues where they are thought to play a relevant role in the induction and maintenance of pregnancy. However, limited information exists on the molecular mechanisms that regulate these cells, including immune checkpoints. Here, we show that ILC3 express the inhibitory checkpoints programmed cell death (PD-1) and T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) during the first trimester of pregnancy and that these receptors could regulate production of cytokines, including IL-22, IL-8, and TNF-α, induced by IL-23. We also show that the intermediate extravillous trophoblast (iEVT) expresses high levels of the PD-1-ligand PD-L1, suggesting that PD-1/PD-L1 interaction may regulate ILC3 function at the feto-maternal interface. Our present data provide the first evidence that human decidual ILC3 express a functional PD-1. It is possible that an altered expression or function of PD-1 may break the immune-tolerance resulting in pregnancy failure.

Published
2019

3. Tumor immunosurveillance and immunotherapies: a fresh look from intravital imaging

Author

Morgane Boulch, Capucine L. Grandjean, Philippe Bousso, Marine Cazaux, Dynamiques des Réponses immunes - Dynamics of Immune Responses, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), The work was supported by Institut Pasteur, Inserm, and an Advanced grant (ENLIGHTEN) from the European Research Council (P.B.)., We thank Mikael Pittet, Thorsten Mempel, and Thomas Gebhardt for kindly providing images., European Project: 741167,ERC-2016-ADG,ENLIGHTEN(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and École normale supérieure - Lyon (ENS Lyon)

Subjects
0301 basic medicine, Intravital Microscopy, Computer science, MESH: Immunotherapy, medicine.medical_treatment, immunosurveillance, 0302 clinical medicine, Cell Movement, Neoplasms, MESH: Tumor Microenvironment, Tumor Microenvironment, Immunology and Allergy, MESH: Monitoring, Immunologic, MESH: Animals, MESH: Neoplasms, Immunologic Surveillance, MESH: Cell Movement, Cell migration, Intravital Imaging, 3. Good health, Immunosurveillance, MESH: Tumor Escape, [SDV.IMM]Life Sciences [q-bio]/Immunology, immunotherapy, MESH: Immune Tolerance, Immunology, Tumor immunity, 03 medical and health sciences, MESH: Intravital Microscopy, Immune system, Monitoring, Immunologic, Immune Tolerance, medicine, Animals, Humans, two-photon microscopy, MESH: Immunologic Surveillance, Tumor microenvironment, two- photon microscopy, MESH: Humans, Tumor immunosurveillance, Immunotherapy, tumor immunity, Disease Models, Animal, 030104 developmental biology, Tumor Escape, intravital imaging, MESH: Disease Models, Animal, Neuroscience, 030215 immunology
Abstract

International audience; Understanding complex interactions between the immune system and the tumor microenvironment is an essential step towards the rational development and optimization of immunotherapies. Several experimental approaches are available to tackle this complexity but most are not designed to address the dynamic features of immune reactions, including cell migration, cellular interactions, and transient signaling events. By providing a unique means to access these precious parameters, intravital imaging offers a fresh look at intratumoral immune responses at the single-cell level. Here, we discuss how in vivo imaging sheds light on fundamental aspects of tumor immunity and helps elucidate modes of action of immunotherapies. We conclude by discussing future developments that may consolidate the unique contribution of intravital imaging for our understanding of tumor immunity.

Published
2019

4. Shigella -mediated immunosuppression in the human gut: subversion extends from innate to adaptive immune responses

Author

Philippe J. Sansonetti, Fatoumata Samassa, Armelle Phalipon, Katja Brunner, Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire Microbiologie et Maladies infectieuses, and Phalipon, Armelle

Subjects
medicine.medical_treatment, bacterial mucosal, mucosal, Review, MESH: Virulence, medicine.disease_cause, immunomodulation, MESH: Shigella, Type three secretion system, 0302 clinical medicine, Immunology and Allergy, Shigella, MESH: Animals, MESH: Immunity, Humoral, enteropathogen, 0303 health sciences, Immunosuppression, Acquired immune system, 3. Good health, MESH: Immunity, Innate, MESH: Intestines, type three secretion system, MESH: Immune Tolerance, MESH: Dysentery, Bacillary, infectious disease, Immunology, Adaptive immunity, T cells, Virulence, immune modulators, Biology, Microbiology, 03 medical and health sciences, dysentery, MESH: Type III Secretion Systems, Immune system, Human gut, parasitic diseases, medicine, bacterial, MESH: Mice, 030304 developmental biology, Pharmacology, MESH: Humans, MESH: Host-Pathogen Interactions, biochemical phenomena, metabolism, and nutrition, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, virulence, Infectious disease (medical specialty), bacteria, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Adaptive Immunity, 030215 immunology
Abstract

International audience; The enteropathogen, Shigella, is highly virulent and remarkably adjusted to the intestinal environment of its almost exclusive human host. Key for Shigella pathogenicity is the injection of virulence effectors into the host cell via its type three secretion system (T3SS), initiating disease onset and progression by the vast diversity of the secreted T3SS effectors and their respective cellular targets. The multifaceted modulation of host signaling pathways exerted by Shigella T3SS effectors, which include the subversion of host innate immune defenses and the promotion of intracellular bacterial survival and dissemination, have been extensively reviewed in the recent past. This review focuses on the human species specificity of Shigella by discussing some possible evasion mechanisms towards the human, but not non-human or rodent gut innate defense barrier, leading to the lack of a relevant animal infection model. In addition, subversion mechanisms of the adaptive immune response are highlighted summarizing research advances of the recent years. In particular, the new paradigm of Shigella pathogenicity constituted of invasion-independent T3SS effector-mediated targeting of activated, human lymphocytes is discussed. Along with consequences on vaccine development, these findings offer new directions for future research endeavors towards a better understanding of immunity to Shigella infection.

Published
2018

5. Liver macrophages: Friend or foe during hepatitis B infection?

Author

Julie Lucifora, Suzanne Faure-Dupuy, David Durantel, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lucifora, Julie, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Hepatitis B virus, MESH: Immune Tolerance, Kupffer Cells, medicine.disease_cause, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Pathogenesis, 03 medical and health sciences, Immune system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Parenchyma, Immune Tolerance, Medicine, Humans, innate immunity inhibition, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Hepatitis, tolerance, MESH: Humans, MESH: Hepatitis B, Hepatology, business.industry, Macrophages, MESH: Host-Pathogen Interactions, MESH: Macrophages, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Hepatitis B, Phenotype, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Immunity, Innate, 3. Good health, Hepatitis B infection, MESH: Hepatitis B virus, MESH: Kupffer Cells, 030104 developmental biology, Liver, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunology, Host-Pathogen Interactions, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Hepatic stellate cell, MESH: Immunity, Innate, business, MESH: Liver
Abstract

International audience; The Hepatitis B virus chronically infects the liver of 250 million people worldwide. Over the past decades, major advances have been made in the understanding of Hepatitis B virus life cycle in hepatocytes. Beside these parenchymal cells, the liver also contains resident and infiltrating myeloid cells involved in immune responses to pathogens and much less is known about their interplay with Hepatitis B virus. In this review, we summarized and discussed the current knowledge of the role of liver macrophages (including Kupffer cells and liver monocyte-derived macrophages), in HBV infection. While it is still unclear if liver macrophages play a role in the establishment and persistence of HBV infection, several studies disclosed data suggesting that HBV would favour liver macrophage anti-inflammatory phenotypes and thereby increase liver tolerance. In addition, alternatively activated liver macrophages might also play in the long term a key role in hepatitis B-associated pathogenesis, especially through the activation of hepatic stellate cells. Therapies aiming at a transient activation of pro-inflammatory liver macrophages should therefore be considered for the treatment of chronic HBV infection.

Published
2018

6. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in septic patients

Author

Uhel, Fabrice, Azzaoui, Imane, Grégoire, Murielle, Pangault, Céline, Dulong, Joelle, Tadié, Jean-Marc, Gacouin, Arnaud, Camus, Christophe, Cynober, Luc, Fest, Thierry, Le Tulzo, Yves, Roussel, Mikael, Tarte, Karin, Service des Maladies Infectieuses et Réanimation Médicale, Hôpital Pontchaillou, Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Microenvironment, Cell Differentiation, Immunology and Cancer ( MICMAC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] ( EFS Bretagne ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d’immunologie, de thérapie cellulaire et d’hématopoïèse, Prévention et traitement de la perte protéique musculaire en situation de résistance à l'anabolisme ( PRETRRAM - EA 4466 ), Université Paris Descartes - Paris 5 ( UPD5 ), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Research grant from the French Intensive Care Society / Société de Réanimation de Langue Française (FICS/SRLF), Research grant from the National Institute of Cancer and Direction Générale de l'Organisation des Soins Ministère de la Santé (Projet Recherche Translationnelle 2010), Research grant from the Comité de la Recherche Translationnelle (CORECT), Rennes University Hospital, UHEL, Fabrice, Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes], CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] (EFS Bretagne), Prévention et traitement de la perte protéique musculaire en situation de résistance à l'anabolisme (PRETRRAM - EA 4466), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
immune tolerance, MESH : monocytes, [SDV.IMM] Life Sciences [q-bio]/Immunology, MDSC, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, infections nosocomiales, choc septique, [ SDV.BC.IC ] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], sepsis, MESH: immune tolerance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], nosocomial infections, polynucléaires neutrophiles, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : granulocytes, MESH: granulocytes, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Sepsis, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: monocytes, cytométrie en flux, flow cytometry, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, granulocytes, myeloid-derived suppressor cells, cross infection, MESH: cross infection, MESH : immune tolerance, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, septic shock, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH : Sepsis, MESH : cross infection, monocytes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Rationale - Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression, but their clinical impact remains poorly defined.Objectives - To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in patients with sepsis.Methods - Peripheral blood transcriptomic analysis was performed on 29 patients with sepsis and 15 healthy donors. A second cohort of 94 consecutive patients with sepsis, 11 severity-matched intensive care patients, and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments.Measurements and main results - Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8, and ARG1, were up-regulated in the peripheral blood of patients with sepsis. CD14HLA-DR monocytic (M)-MDSCs were expanded in intensive care unit patients with and without sepsis and CD14CD15 low-density granulocytes/granulocytic (G)-MDSCs were more specifically expanded in patients with sepsis (P Conclusions - M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in patients with sepsis. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and seem to be major actors of sepsis-induced immune suppression.

Published
2017

7. Trained Immunity or Tolerance: Opposing Functional Programs Induced in Human Monocytes after Engagement of Various Pattern Recognition Receptors

Author

Leo A. B. Joosten, David L. Williams, Trees Jansen, Daniela C. Ifrim, Cor Jacobs, Liesbeth Jacobs, Jos W. M. van der Meer, Mihai G. Netea, Neil A. R. Gow, Jessica Quintin, Radboud University Medical Center [Nijmegen], University of Aberdeen, Swansea University, and East Tennessee State University (ETSU)

Subjects
Microbiology (medical), MAPK/ERK pathway, MESH: Immune Tolerance, Lipopolysaccharide, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Immunology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology, MESH: Monocytes, Monocytes, Immune tolerance, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], MESH: Receptors, Pattern Recognition, MESH: Viruses, chemistry.chemical_compound, Histone methylation, Candida albicans, Immune Tolerance, Immunology and Allergy, Humans, Protein kinase A, Antigens, Viral, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Cytokines, Antigens, Bacterial, MESH: Humans, Bacteria, MESH: Candida albicans, Pattern recognition receptor, MESH: Bacteria, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Receptors, Pattern Recognition, Viruses, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin 19, Cytokines, Clinical Immunology, MESH: Antigens, Viral, Reprogramming, MESH: Antigens, Bacterial
Abstract

Upon priming with Candida albicans or with the fungal cell wall component β-glucan, monocytes respond with an increased cytokine production upon restimulation, a phenomenon termed “trained immunity.” In contrast, the prestimulation of monocytes with lipopolysaccharide has long been known to induce tolerance. Because the vast majority of commensal microorganisms belong to bacterial or viral phyla, we sought to systematically investigate the functional reprogramming of monocytes induced by the stimulation of pattern recognition receptors (PRRs) with various bacterial or viral ligands. Monocytes were functionally programmed for either enhanced (training) or decreased (tolerance) cytokine production, depending on the type and concentration of ligand they encountered. The functional reprogramming of monocytes was also associated with cell shape, granulocity, and cell surface marker modifications. The training effect required p38- and Jun N-terminal protein kinase (JNK)-mediated mitogen-activated protein kinase (MAPK) signaling, with specific signaling patterns directing the functional fate of the cell. The long-term effects on the function of monocytes were mediated by epigenetic events, with both histone methylation and acetylation inhibitors blocking the training effects. In conclusion, our experiments identify the ability of monocytes to acquire adaptive characteristics after prior activation with a wide variety of ligands. Trained immunity and tolerance are two distinct and opposing functional programs induced by the specific microbial ligands engaging the monocytes.

Published
2014

8. Intensification of Antiretroviral Therapy through Addition of Enfuvirtide in Naive HIV-1-Infected Patients with Severe Immunosuppression Does Not Improve Immunological Response: Results of a Randomized Multicenter Trial (ANRS 130 Apollo)

Author

Charlotte Charpentier, Véronique Joly, Carine Grondin, Sophie Tabuteau, Yazdan Yazdanpanah, François Raffi, André Cabié, Catherine Fagard, Patrick Yeni, Geneviève Chêne, Nathalie Colin de Verdiere, Diane Descamps, Service de maladies infectieuses et tropicales, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Modélisation, Aide à la Décision, et Coût-Efficacité en Maladies Infectieuses (ATIP-Avenir Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies Infectieuses et Tropicales, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Maladies infectieuses et tropicales, Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), ANRS (French National Agency for Research on AIDS and Viral Hepatitis), ANRS 130 Apollo Trial Group, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Le Corre, Morgane, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université Bordeaux Segalen - Bordeaux 2

Subjects
CD4-Positive T-Lymphocytes, Cyclopropanes, Male, Enfuvirtide, MESH: CD4 Lymphocyte Count, MESH: HIV Envelope Protein gp41, HIV Infections, Deoxycytidine, MESH: Antiretroviral Therapy, Highly Active, Lopinavir, MESH: HIV-1, chemistry.chemical_compound, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Emtricitabine, Pharmacology (medical), 030212 general & internal medicine, MESH: Anti-HIV Agents, MESH: Peptide Fragments, MESH: Treatment Outcome, 0303 health sciences, MESH: Lopinavir, MESH: CD4-Positive T-Lymphocytes, virus diseases, MESH: HIV Infections, Viral Load, HIV Envelope Protein gp41, 3. Good health, Drug Combinations, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Treatment Outcome, Infectious Diseases, MESH: RNA, Viral, MESH: Benzoxazines, Alkynes, RNA, Viral, Female, medicine.symptom, MESH: Viral Load, MESH: Organophosphonates, Viral load, medicine.drug, Adult, medicine.medical_specialty, MESH: Adenine, MESH: Immune Tolerance, Efavirenz, Anti-HIV Agents, Organophosphonates, Antiviral Agents, Asymptomatic, 03 medical and health sciences, Multicenter trial, Internal medicine, Immune Tolerance, medicine, Humans, Tenofovir, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Drug Combinations, Pharmacology, MESH: Humans, Ritonavir, 030306 microbiology, business.industry, Adenine, MESH: Deoxycytidine, MESH: Adult, MESH: Male, Peptide Fragments, Benzoxazines, CD4 Lymphocyte Count, Surgery, chemistry, HIV-1, MESH: Ritonavir, business, MESH: Female
Abstract

We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of 3 or stage B/C disease with CD4 counts of 3 . Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥200/mm 3 at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm 3 , and the median HIV-1 RNA load was 5.4 log 10 copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥200/mm 3 at week 24 were 34% and 38% in the ENF and control arms, respectively ( P = 0.53). The proportions of patients with HIV-1 RNA loads of P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up ( P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression.

Published
2013

9. Prolonged Gene Expression in Muscle Is Achieved Without Active Immune Tolerance Using MicrorRNA 142.3p-Regulated rAAV Gene Transfer

Author

Razzak, A, al Samarrai, A, Al Samarrai, Razzak, Boisgérault, Florence, Gross, David-Alexandre, Ferrand, Maxime, Poupiot, Jérôme, Darocha, Sylvie, Richard, Isabelle, Galy, Anne, Immunologie moléculaire et biothérapies innovantes (IMBI), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Généthon, Tolérance immunitaire et présentation antigénique: impact en auto-immunité et en transplantation, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), Généthon, Evry, Association française contre les myopathies (AFM-Téléthon), and École pratique des hautes études (EPHE)

Subjects
CD4-Positive T-Lymphocytes, Male, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Gene Expression, MESH: Dependovirus, CD8-Positive T-Lymphocytes, MESH: Muscular Dystrophy, Animal, Immune tolerance, Transduction (genetics), Mice, 0302 clinical medicine, MESH: Genetic Vectors, Gene expression, MESH: Animals, Transgenes, 0303 health sciences, MESH: Muscle, Skeletal, Gene Transfer Techniques, MESH: CD4-Positive T-Lymphocytes, Dependovirus, MESH: CD8-Positive T-Lymphocytes, Cell biology, Sarcoglycan, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Expression cassette, MESH: Gene Expression, MESH: Immune Tolerance, Transgene, Genetic Vectors, MESH: Transgenes, MESH: Gene Transfer Techniques, Gene delivery, Biology, Viral vector, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Sarcoglycans, Genetics, Immune Tolerance, Animals, MESH: Sarcoglycans, Muscle, Skeletal, Molecular Biology, MESH: Mice, 030304 developmental biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Muscular Dystrophy, Animal, Molecular biology, MESH: Male, Mice, Inbred C57BL, MicroRNAs, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: MicroRNAs, MESH: Female
Abstract

International audience; Gene transfer efficacy is limited by unwanted immunization against transgene products. In some models, immunization may be avoided by regulating transgene expression with mir142.3p target sequences. Yet, it is unclear if such a strategy controls T-cell responses following recombinant adeno-associated viral vector (rAAV)-mediated gene transfer, particularly in muscle. In mice, intramuscular rAAV1 gene delivery of a tagged human sarcoglycan muscle protein is robustly immunogenic and leads to muscle destruction. In this model, the simple insertion of mir142.3p-target sequences in the transgene expression cassette modifies the outcome of gene transfer, providing high and persistent levels of muscle transduction in C57Bl/6 mice. Such regulated vector fails to prime specific CD4 and CD8 T cells; although, transgene tolerance seems to result from ignorance and could be broken by a robust antigenic challenge. While effective in normal mice, the mir142.3p-regulated transgene remains immunogenic in sarcoglycan-deficient dystrophic mice. In these mice, transgene expression is only prolonged but does not persist as effector CD4 and CD8 T-cell responses develop. Thus, using a mir142.3p-regulated transgene can improve rAAV muscle gene transfer results, but the level of efficacy depends on the context of application. In normal muscle, this strategy is sufficient to prevent immunization and functions even more effectively than tissue-specific promoters. In dystrophic models, additional strategies are required to fully control T-cell responses.

Published
2013
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10. Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

Author

S. Brunelle, Mélanie Bentobji, Alessandro Moretta, Samuel Granjeaud, Gwenaelle Gravis, Flora Poizat, N. Salem, Palma Rocchi, Daniel Olive, Mathilde Guerin, Jeanne Thomassin-Piana, Francine Azario-Cheillan, Jochen Walz, Christine Pasero, Maria Paciencia-Gros, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Genova [Genova, Italy], Rocchi, Palma, and Università degli studi di Genova = University of Genoa (UniGe)

Subjects
0301 basic medicine, Cytotoxicity, Immunologic, Male, MESH: Killer Cells, Natural, Cancer Research, MESH: Cell Line, Tumor, MESH: Immune Tolerance, Oncology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biology, Immune tolerance, Natural killer cell, 03 medical and health sciences, Interleukin 21, Prostate cancer, 0302 clinical medicine, Cell Line, Tumor, MESH: Tumor Microenvironment, medicine, Immune Tolerance, Tumor Microenvironment, Humans, Prospective Studies, MESH: Cytotoxicity, Immunologic, Neoplasm Metastasis, Tumor microenvironment, MESH: Cytokines, Lymphokine-activated killer cell, MESH: Humans, Prostatic Neoplasms, Immunotherapy, medicine.disease, NKG2D, MESH: Neoplasm Metastasis, MESH: Male, MESH: Prospective Studies, [SDV] Life Sciences [q-bio], Killer Cells, Natural, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Prostatic Neoplasms, Immunology, Cytokines
Abstract

The field of immunotherapy for solid tumors, such as prostate cancer, has been recently focusing on therapies that can counter tumor-mediated immunosuppression. Precise quantification and characterization of the immune infiltrates in tumors is crucial to improve treatment efficacy. Natural killer (NK) cells, major components of the antitumor immune system, have never been isolated from prostate tumors, despite their suspected role in disease progression. Here, we examined the frequency, phenotype, and functions of NK cells infiltrating control and tumor prostate tissues. NK cell infiltrates in prostate tissues were mainly CD56 (NCAM1)-positive and displayed an unexpected immature, but activated, phenotype with low or no cytotoxic potential. Furthermore, we show that TGFβ1 (TGFB1) is highly secreted into the prostate environment and partly mediates the immunosuppressive effects on NK cells. In addition to this basal level of immunotolerance to NK cells, the prostate environment became further resistant to NK cell–mediated immunity upon cancer cell infiltration. Coculture experiments revealed that prostate cancer cells induced the expression of inhibitory receptor (ILT2/LILRB1) and downregulated the expression of activating receptors NKp46 (NCR1), NKG2D (KLRK1), and CD16 (FCGR3) by NK cells, thus preventing their recognition of tumor cells. Notably, blood levels of NKp46 were also decreased in prostate cancer patients and were inversely correlated with levels of prostate-specific antigen, the main prognostic factor in prostate cancer. Our study shows that a strong immunosuppressive environment impairs NK cell function at multiple levels in prostate cancer and provides a rationale for the design of therapies that restore NK cell efficiency in the prostate tumor microenvironment. Cancer Res; 76(8); 2153–65. ©2016 AACR.

Published
2016

11. Maternal exposure to GOS/inulin mixture prevents food allergies and promotes tolerance in offspring in mice

Author

Michel Neunlist, Philippe Aubert, Laure Castan, Faouzi Braza, Julie Chesné, Antoine Magnan, Marie Bodinier, Grégory Bouchaud, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no 624910, European Project: 267196,EC:FP7:PEOPLE,FP7-PEOPLE-2010-COFUND,AGREENSKILLS(2012), Unité de recherche de l'institut du thorax (ITX-lab), The Enteric Nervous System in gut and brain disorders [U1235] (TENS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE)

Subjects
0301 basic medicine, Allergy, [SDV]Life Sciences [q-bio], Oligosaccharides, MESH: Dietary Supplements, MESH: Inulin, medicine.disease_cause, Mice, chemistry.chemical_compound, Allergen, MESH: Pregnancy, Pregnancy, wheat, Immunology and Allergy, Medicine, MESH: Animals, Intestinal Mucosa, MESH: Maternal Exposure, 2. Zero hunger, Inulin, 3. Good health, Maternal Exposure, Prenatal Exposure Delayed Effects, MESH: Permeability, Allergic response, MESH: Intestinal Mucosa, gut, Female, Food Hypersensitivity, MESH: Lactation, MESH: Immune Tolerance, Offspring, Immunology, Permeability, MESH: Prenatal Exposure Delayed Effects, 03 medical and health sciences, Th2 Cells, Food allergy, MESH: Th2 Cells, Immune Tolerance, microbiota, Animals, Lactation, Weaning, MESH: Microbiota, MESH: Mice, business.industry, medicine.disease, immunity, Disease Models, Animal, 030104 developmental biology, chemistry, Dietary Supplements, MESH: Food Hypersensitivity, symptoms, MESH: Disease Models, Animal, business, MESH: Oligosaccharides, MESH: Female
Abstract

International audience; BACKGROUND: Food allergies affect 4-8% of children and are constantly on the rise, thus making allergies a timely issue. Most importantly, prevention strategies are nonexistent, and current therapeutic strategies have limited efficacy and need to be improved. One alternative to prevent or reduce allergies, particularly during infancy, could consist of modulating maternal immunity and microbiota using nondigestible food ingredients, such as prebiotics. For this purpose, we studied the preventive effects of prebiotics in Balb/c mothers during pregnancy and breastfeeding on food allergy development in offspring mice. METHODS: After weaning, the offspring from mothers that were exposed to GOS/inulin mixture or fed a control diet were intraperitoneally sensitized to wheat proteins to induce a systemic allergic response and orally exposed to the same allergen. Immunological, physiological, and microbial parameters were analyzed. RESULTS: GOS/inulin mixture diet modified the microbiota of mothers and their offspring. Offspring from mothers that received GOS/inulin prebiotics were protected against food allergies and displayed lower clinical scores, specifically of IgE and histamine levels, compared to offspring from mothers fed a control diet. Moreover, GOS/inulin supplementation for the mother resulted in stronger intestinal permeability in the offspring. Enhancement of the regulatory response to allergic inflammation and changes in the Th2/Th1 balance toward a dampened Th2 response were observed in mice from GOS/inulin mixture-exposed mothers. CONCLUSION: The treatment of pregnant and lactating mice with nondigestible GOS/inulin prebiotics promotes a long-term protective effect against food allergies in the offspring.

Published
2016

12. Peptidoglycan Sensing by the Receptor PGRP-LE in the Drosophila Gut Induces Immune Responses to Infectious Bacteria and Tolerance to Microbiota

Author

Julien Royet, Bernard Charroux, Mickael Poidevin, Karine Narbonne-Reveau, Ivo G. Boneca, Virginie Bosco-Drayon, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris] (IP), National Institute of Child Health and Human Development [Bethesda], National Institutes of Health, Réponse immunitaire et developpement chez les insectes (RIDI - UPR 9002), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MRC Centre for Developmental Neurobiology, and Institut Pasteur [Paris]

Subjects
Cancer Research, MESH: Drosophila, Segmented filamentous bacteria, medicine.disease_cause, Immune tolerance, chemistry.chemical_compound, 0302 clinical medicine, MESH: Animals, 0303 health sciences, biology, MESH: Peptidoglycan, Bacterial Infections, 3. Good health, Intestines, MESH: Lactobacillus plantarum, Drosophila, Female, MESH: Erwinia, MESH: Immunity, Innate, MESH: Intestines, MESH: Immune Tolerance, MESH: Bacterial Infections, MESH: Carrier Proteins, Peptidoglycan, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microbiology, 03 medical and health sciences, Immune system, Downregulation and upregulation, Immunity, Immunology and Microbiology(all), Virology, Immune Tolerance, medicine, Animals, Humans, Molecular Biology, 030304 developmental biology, MESH: Humans, Pathogenic bacteria, MESH: Metagenome, biology.organism_classification, Immunity, Innate, Disease Models, Animal, chemistry, Erwinia, Metagenome, Parasitology, MESH: Disease Models, Animal, Carrier Proteins, MESH: Female, 030217 neurology & neurosurgery, Bacteria, Lactobacillus plantarum
Abstract

International audience; Gut epithelial cells contact both commensal and pathogenic bacteria, and proper responses to these bacteria require a balance of positive and negative regulatory signals. In the Drosophila intestine, peptidoglycan-recognition proteins (PGRPs), including PGRP-LE, play central roles in bacterial recognition and activation of immune responses, including induction of the IMD-NF-κB pathway. We show that bacteria recognition is regionalized in the Drosophila gut with various functional regions requiring different PGRPs. Specifically, peptidoglycan recognition by PGRP-LE in the gut induces NF-κB-dependent responses to infectious bacteria but also immune tolerance to microbiota through upregulation of pirk and PGRP-LB, which negatively regulate IMD pathway activation. Loss of PGRP-LE-mediated detection of bacteria in the gut results in systemic immune activation, which can be rescued by overexpressing PGRP-LB in the gut. Together these data indicate that PGRP-LE functions as a master gut bacterial sensor that induces balanced responses to infectious bacteria and tolerance to microbiota.

Published
2012

13. Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymph node dendritic cells in the generation of antigen-specific CD4+Foxp3+ regulatory T cells in the establishment of oral tolerance

Author

Hideaki Takagi, Hideo Yagita, Katsuaki Sato, Kawori Eizumi, Yumiko Sato, Honami Taya, Miyuki Azuma, Tomohiro Fukaya, Bernard Malissen, Tahiro Shin, Lieping Chen, Chen Dong, Kaori Sato, RIKEN Research Center for Allergy and Immunology, Yokohama (RCAI), Research Unit for Immune Homeostasis, The University of Texas Health Science Center (uthscsa), Department of Medicine, Division of Medical Oncology, Cancer Therapy and Research Center, Department of Dermatology and Oncology, Johns Hopkins University School of Medicine, M. D. Anderson Cancer Center, Department of Immunology, Tokyo Medical and Dental University (TMDU), Department of Molecular Immunology, Juntendo University School of Medicine, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Membrane Glycoproteins, Administration, Oral, MESH: Lymph Nodes, MESH: Mice, Knockout, T-Lymphocytes, Regulatory, Biochemistry, B7-H1 Antigen, Immune tolerance, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, MESH: Animals, Mesentery, MESH: Immunoglobulin G, Mice, Knockout, Antigen Presentation, Mice, Inbred BALB C, 0303 health sciences, Membrane Glycoproteins, MESH: Dendritic Cells, MESH: Peptides, FOXP3, MESH: Receptors, Antigen, T-Cell, Forkhead Transcription Factors, hemic and immune systems, Hematology, Recombinant Proteins, MESH: Administration, Oral, B7-1 Antigen, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Antigens, MESH: Immune Tolerance, MESH: Mice, Transgenic, Ovalbumin, Immunology, Antigen presentation, MESH: Mice, Inbred BALB C, Receptors, Antigen, T-Cell, Mice, Transgenic, chemical and pharmacologic phenomena, In Vitro Techniques, Biology, 03 medical and health sciences, MESH: Antigens, CD80, Antigen, MESH: Mice, Inbred C57BL, MESH: Forkhead Transcription Factors, Immune Tolerance, Animals, Antigens, Antigen-presenting cell, MESH: Mesentery, MESH: Mice, Immunobiology, 030304 developmental biology, CD86, MESH: Ovalbumin, MESH: T-Lymphocytes, Regulatory, Dendritic Cells, Cell Biology, Dendritic cell, Programmed Cell Death 1 Ligand 2 Protein, Mice, Inbred C57BL, Immunoglobulin G, MESH: Antigen Presentation, Lymph Nodes, Peptides, CD80, 030215 immunology
Abstract

Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to fed antigens. However, the molecular mechanism mediating oral tolerance remains unclear. In this study, we examined the role of the B7 family members of costimulatory molecules in the establishment of oral tolerance. Deficiencies of B7-H1 and B7-DC abrogated the oral tolerance, accompanied by enhanced antigen-specific CD4+ T-cell response and IgG1 production. Mesenteric lymph node (MLN) dendritic cells (DCs) displayed higher levels of B7-H1 and B7-DC than systemic DCs, whereas they showed similar levels of CD80, CD86, and B7-H2. MLN DCs enhanced the antigen-specific generation of CD4+Foxp3+ inducible regulatory T cells (iTregs) from CD4+Foxp3− T cells rather than CD4+ effector T cells (Teff) relative to systemic DCs, owing to the dominant expression of B7-H1 and B7-DC. Furthermore, the antigen-specific conversion of CD4+Foxp3− T cells into CD4+Foxp3+ iTregs occurred in MLNs greater than in peripheral organs during oral tolerance under steady-state conditions, and such conversion required B7-H1 and B7-DC more than other B7 family members, whereas it was severely impaired under inflammatory conditions. In conclusion, our findings suggest that B7-H1 and B7-DC expressed on MLN DCs are essential for establishing oral tolerance through the de novo generation of antigen-specific CD4+Foxp3+ iTregs.

Published
2010

14. Dichotomy between factors inducing the immunosuppressive enzyme IL-4-induced gene 1 (IL4I1) in B lymphocytes and mononuclear phagocytes

Author

Nadine Martin-Garcia, Marie-Line Puiffe, Véronique Baud, Jean-Pierre Farcet, Céline Cousin, Fanny Chereau, Valérie Molinier-Frenkel, Fanette Lasoudris, Jeanine Marquet, Flavia Castellano, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Guellaen, Georges, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR10 - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
MESH: Inflammation, MESH: NF-kappa B, Immune tolerance, 0302 clinical medicine, MESH: RNA, Small Interfering, Immunology and Allergy, RNA, Small Interfering, MESH: Flavoproteins, granuloma, Mononuclear Phagocyte System, Tissue homeostasis, STAT6, B-Lymphocytes, 0303 health sciences, STAT, NF-kappa B, 3. Good health, Cell biology, STAT1 Transcription Factor, MESH: STAT6 Transcription Factor, 030220 oncology & carcinogenesis, medicine.symptom, immunosuppressive enzyme, MESH: Immune Tolerance, MESH: Interferon-gamma, CD40 Ligand, Immunology, Inflammation, Biology, L-Amino Acid Oxidase, Article, NFkB, Cell Line, Proinflammatory cytokine, MESH: Coculture Techniques, Interferon-gamma, 03 medical and health sciences, Th2 Cells, MESH: Th2 Cells, MESH: B-Lymphocytes, MESH: Cell Proliferation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Immune Tolerance, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Interleukin 4, Cell Proliferation, MESH: CD40 Ligand, 030304 developmental biology, MESH: Mononuclear Phagocyte System, MESH: Humans, CD40, Flavoproteins, Th1 Cells, MESH: Interleukin-4, Coculture Techniques, MESH: Cell Line, MESH: Th1 Cells, inflammation, Cell culture, biology.protein, Interleukin-4, MESH: STAT1 Transcription Factor, STAT6 Transcription Factor
Abstract

International audience; MPhi and DC are key elements in the control of tissue homeostasis and response to insult. In this work, we demonstrate that MPhi and DC are the major producers of the phenylalanine catabolizing enzyme IL-4-induced gene 1 (IL4I1) under inflammatory conditions. IL4I1 was first described in B cells, which indeed can produce IL4I1 in vitro, although at much lower levels. In vivo, IL4I1 is highly expressed by MPhi and DC of Th1 granulomas (sarcoidosis, tuberculosis) but poorly detected in Th2 granulomas (schistosomiasis). In vitro, expression of the enzyme is induced in mononuclear phagocytes by various pro-inflammatory stimuli through the activation of the transcription factors NF-kappaB and/or STAT1. B cells also express IL4I1 in response to NF-kappaB-activating stimuli such as CD40L; however, in contrast to myeloid cells, B cells are insensitive to IFN-gamma but respond to stimulation of the IL-4/STAT6 axis. As we show that the expression of IL4I1 by a monocytic cell line inhibits T-cell proliferation and production of IFN-gamma and inflammatory cytokines, we propose that IL4I1 participates in the downregulation of Th1 inflammation in vivo.

Published
2010

15. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy

Author

A. Sarah Walker, Osamah Hamouda, Virginie Rondeau, Maria Dorrucci, Heiner C. Bucher, Maria Prins, Geneviève Chêne, Kholoud Porter, Caroline A. Sabin, Rodolphe Thiébaut, Benoît Marin, Dominique Costagliola, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Basel Institute for Clinical Epidemiology, University Hospital Basel [Basel], Epidémiologie Clinique et Traitement de l'Infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Malattie Infettive, Reparto di Epidemiologia, Istituto Superiore di Sanita [Rome], Department of Infectious Disease Epidemiology, Robert Koch Institute [Berlin] (RKI), Cluster Infectious Diseases, Amsterdam BioMed Cluster, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Research Department of Infection and Population Health [London], CASCADE has been funded through grants from the European Union BMH4-CT97-2550, QLK2-2000-01431, QLRT-2001-01708 and LSHP-CT-2006-018949., Istituto Superiore di Sanità (ISS), AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, and Infectious diseases

Subjects
Male, MESH: CD4 Lymphocyte Count, medicine.medical_treatment, CD4 cell count, Disease, MESH: Epidemiologic Methods, MESH: Antiretroviral Therapy, Highly Active, Hepatitis, Liver disease, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Neoplasms, Immunology and Allergy, MESH: Neoplasms, 030212 general & internal medicine, Causes of death, Immunodeficiency, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: AIDS-Related Opportunistic Infections, Liver Diseases, Immunosuppression, Middle Aged, Human Immunodeficiency Virus/AIDS, Antiretroviral therapy, 3. Good health, Infectious Diseases, Cardiovascular Diseases, MESH: Young Adult, Female, Viral disease, Adult, medicine.medical_specialty, MESH: Immune Tolerance, MESH: Liver Diseases, Adolescent, Immunology, Article, Young Adult, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Internal medicine, Immune Tolerance, medicine, Humans, Seroconversion, highly active, Aged, MESH: Acquired Immunodeficiency Syndrome, MESH: Adolescent, Acquired Immunodeficiency Syndrome, MESH: Humans, AIDS-Related Opportunistic Infections, 030306 microbiology, business.industry, MESH: Cardiovascular Diseases, MESH: Adult, medicine.disease, MESH: Male, CD4 Lymphocyte Count, Neoplasm, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Bacterial infection, Epidemiologic Methods, business, MESH: Female
Abstract

International audience; OBJECTIVE: To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death in the era of combination antiretroviral therapy (cART). DESIGN: Observational multicentre cohorts. METHODS: Twenty-three cohorts of adults with estimated dates of human immunodeficiency virus (HIV) seroconversion were considered. Patients were seroconverters followed within the cART era. Measurements were latest CD4, nadir CD4 and time spent with CD4 cell count less than 350 cells/microl. Outcomes were specific causes of death using a standardized classification. RESULTS: Among 9858 patients (71 230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease accounted for 53% of non-AIDS deaths. For each 100 cells/microl increment in the latest CD4 cell count, we found a 64% (95% confidence interval 58-69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18-44%), end-stage liver disease (33, 18-46%) and non-AIDS malignancies (34, 21-45%). Non-AIDS-defining causes of death were also associated with nadir CD4 while being cART-naive or duration of exposure to immunosuppression. No relationship between risk of death from cardiovascular disease and CD4 cell count was found though there was a raised risk associated with elevated HIV RNA. CONCLUSION: In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only cardiovascular disease was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV-infected patients.

Published
2009

16. Regulatory T-cell expansion and function do not account for the impaired alloreactivity ofex vivo-expanded T cells

Author

Eric Robinet, Mélanie Couturier, Christophe Ferrand, Nicolas Montcuquet, Patricia Mercier-Letondal, Sylvain Perruche, Abdelghani Bouchekioua, Pierre Tiberghien, Anne Duperrier, Mark Bonyhadi, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Invitrogen Corporation, Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
T-Lymphocytes, Regulatory, Receptors, Tumor Necrosis Factor, Interleukin 21, 0302 clinical medicine, Immunology and Allergy, Cytotoxic T cell, CTLA-4 Antigen, IL-2 receptor, MESH: Antigens, CD, Cells, Cultured, 0303 health sciences, CD28, FOXP3, Forkhead Transcription Factors, hemic and immune systems, medicine.anatomical_structure, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Cells, Cultured, MESH: Immune Tolerance, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Immunophenotyping, MESH: Interferon-gamma, Regulatory T cell, Immunology, chemical and pharmacologic phenomena, Receptors, Nerve Growth Factor, Biology, Immunophenotyping, Interferon-gamma, MESH: Receptors, Nerve Growth Factor, 03 medical and health sciences, Antigens, CD, MESH: Forkhead Transcription Factors, MESH: Lymphocyte Culture Test, Mixed, Glucocorticoid-Induced TNFR-Related Protein, MESH: Cell Proliferation, Immune Tolerance, medicine, Humans, Cell Proliferation, 030304 developmental biology, MESH: Humans, MESH: T-Lymphocytes, Regulatory, MESH: Interleukin-2, Original Articles, MESH: Receptors, Tumor Necrosis Factor, Molecular biology, Interleukin-2, Lymphocyte Culture Test, Mixed, Ex vivo, 030215 immunology
Abstract

International audience; CD3- and CD28-activated T cells expanded for 12 days ex vivo to produce suicide gene-modified T cells are hyporesponsive to alloantigens. To investigate whether this impaired alloreactivity is a result of preferential expansion of regulatory T (Treg) cells, we compared peripheral blood mononuclear cells (PBMC) activated with CD3 and CD28 antibodies co-immobilized on beads and expanded for 12 days with interleukin (IL)-2 (Co(CD3/CD28) cells) to the respective unactivated PBMC in terms of proliferation, cytokine production, and expression of Treg markers [cytotoxic T-lymphocyte antigen 4 (CTLA4), glucocorticoid-induced tumour necrosis factor receptor (GITR) and forkhead box P3 (FoxP3)] after allostimulation. Alloreactive cells were identified by carboxyfluoresceine succinimidyl ester staining dilution. Alloreactive cells in Co(CD3/CD28) cells had a lower proliferative response and a lower potential for IL-2 and interferon-gamma secretion than did those in PBMC, demonstrating a functional impairment of alloreactive cells during ex vivo expansion. Expression of Treg markers transiently increased during ex vivo expansion and was unaffected by depletion of CD25(+) cells (containing Treg cells) before ex vivo PBMC expansion. Such prior CD25(+) depletion did not restore the alloreactivity of Co(CD3/CD28) cells. After allostimulation, expression of Treg markers was restricted to proliferative (alloreactive) cells among PBMC or Co(CD3/CD28) cells. Lastly, CD4(+) CD25(+) cells purified from Co(CD3/CD28) cells lacked suppressive activity when used as a third party, in contrast to CD4(+) CD25(+) cells purified from PBMC. In conclusion, the impaired alloreactivity of T cells expanded ex vivo is not a result of preferential Treg cell expansion and/or enhanced suppressive Treg activity.

Published
2008

17. Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways

Author

Frédéric Gros, Leonardo Scarpellino, Jérôme D. Coudert, Werner Held, Eric Vivier, Laboratory of experimental immunology, Frederick National Laboratory for Cancer Research (FNLCR), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Ligands, Lymphocyte Activation, Biochemistry, Mice, Interleukin 21, 0302 clinical medicine, MESH: Ligands, Antigens, Ly, MESH: Animals, Receptors, Immunologic, Receptor, 0303 health sciences, Janus kinase 3, MESH: Antigens, Ly, hemic and immune systems, Hematology, 3. Good health, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, NK Cell Lectin-Like Receptor Subfamily K, Interleukin 12, Receptors, Natural Killer Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Membrane Proteins, NK Cell Lectin-Like Receptor Subfamily A, Receptors, NK Cell Lectin-Like, MESH: Killer Cells, Natural, MESH: Immune Tolerance, Immunology, chemical and pharmacologic phenomena, Biology, Natural killer cell, 03 medical and health sciences, Immune Tolerance, MESH: Antibody-Dependent Cell Cytotoxicity, medicine, Animals, Lectins, C-Type, MESH: Lymphocyte Activation, MESH: Mice, MESH: Receptors, Immunologic, Adaptor Proteins, Signal Transducing, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, Lymphokine-activated killer cell, Antibody-Dependent Cell Cytotoxicity, Membrane Proteins, Cell Biology, NKG2D, MESH: Lectins, C-Type, 030215 immunology
Abstract

NKG2D is a multisubunit activation receptor that allows natural killer (NK) cells to detect and eliminate stressed, infected, and transformed host cells. However, the chronic exposure of NK cells to cell-bound NKG2D ligands has been shown to impair NKG2D function both in vitro and in vivo. Here we have tested whether continuous NKG2D engagement selectively impacted NKG2D function or whether heterologous NK cell activation pathways were also affected. We found that sustained NKG2D engagement induced cross-tolerization of several unrelated NK cell activation receptors. We show that receptors that activate NK cells via the DAP12/KARAP and DAP10 signaling adaptors, such as murine NKG2D and Ly49D, cross-tolerize preferentially NK cell activation pathways that function independent of DAP10/12, such as antibody-dependent cell-mediated cytotoxicity and missing-self recognition. Conversely, DAP10/12-independent pathways are unable to cross-tolerize unrelated NK cell activation receptors such as NKG2D or Ly49D. These data define a class of NK cell activation receptors that can tolerize mature NK cells. The reversible suppression of the NK cells' cytolytic function probably reduces the NK cells' efficacy to control endogenous and exogenous stress yet may be needed to limit tissue damage.

Published
2008

18. Leukemia inhibitory factor: Role in human mesenchymal stem cells mediated immunosuppression

Author

Dominique Thierry, Sandrine Bouchet, Sabine François, Norbert-Claude Gorin, Aisha Nasef, Loic Fouillard, Christelle Mazurier, Alain Chapel, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Saas, Philippe

Subjects
endocrine system, MESH: Immune Tolerance, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Bone Marrow Cells, chemical and pharmacologic phenomena, Cell Separation, Lymphocyte proliferation, Biology, Leukemia Inhibitory Factor, MESH: Cell Separation, Antibodies, MESH: Histocompatibility Antigens Class I, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, MESH: Forkhead Transcription Factors, HLA-G, Immune Tolerance, Humans, Neutralizing antibody, MESH: HLA Antigens, Cells, Cultured, reproductive and urinary physiology, 030304 developmental biology, HLA-G Antigens, Immunosuppression Therapy, 0303 health sciences, MESH: Humans, MESH: Antibodies, MESH: Bone Marrow Cells, Histocompatibility Antigens Class I, Mesenchymal stem cell, MESH: Immunosuppression, FOXP3, Forkhead Transcription Factors, Mesenchymal Stem Cells, MESH: Leukemia Inhibitory Factor, Mixed lymphocyte reaction, Molecular biology, 3. Good health, Transplantation, MESH: Mesenchymal Stem Cells, 030220 oncology & carcinogenesis, embryonic structures, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Leukemia inhibitory factor, MESH: Cells, Cultured
Abstract

International audience; The interactions between mesenchymal stem cells (MSCs) and immune system are currently being explored. Leukemia inhibitory factor (LIF) is linked to regulatory transplantation tolerance. Our aim was to study the expression of LIF on human MSCs at both gene and protein level in mixed lymphocyte reaction (MSC/MLR), and its implication in MSC immunosuppressive effect. There was a 7-fold increase (611pg/ml) in LIF in MSC/MLR as compared to MSCs alone. Using LIF neutralizing antibody, a significant restoration of up to 91% of CD3+ lymphocyte proliferation in MSC/MLR was observed (p=0.021). LIF was implicated in the generation of regulatory lymphocytes, as demonstrated by decrease of Foxp3+ regulatory cells after using LIF neutralizing antibody in MSC/MLR (p=0.06) by flow cytometry. A positive correlation between LIF and human leukocyte antigen (HLA-G) gene expression by MSCs was found (R(2)=0.74). Our findings provide evidence supporting the immunomodulatory effect of MSCs.

Published
2008

19. Influenza Virus-Induced Type I Interferon Leads to Polyclonal B-Cell Activation but Does Not Break Down B-Cell Tolerance

Author

Sylviane Muller, Anne-Sophie Korganow, Thierry Martin, Jean-Louis Pasquali, Anne Woods, Pauline Soulas-Sprauel, Fanny Monneaux, Tolérance lymphocytaire B et autoimmunité, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et chimie thérapeutiques (ICT), and Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Interferon Type I, Autoimmunity, Lymphocyte Activation, medicine.disease_cause, Autoantigens, Immune tolerance, Mice, Interferon, Influenza A virus, MESH: Autoantibodies, MESH: Animals, B-Lymphocytes, MESH: Antibody Formation, MESH: Immunoglobulin M, medicine.anatomical_structure, MESH: Autoantigens, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Interferon Type I, medicine.drug, MESH: Rheumatoid Factor, MESH: Immune Tolerance, MESH: Mice, Transgenic, MESH: Influenza A virus, Immunology, Orthomyxoviridae, Mice, Inbred Strains, Mice, Transgenic, Biology, MESH: Mice, Inbred Strains, Microbiology, Virus, Rheumatoid Factor, MESH: B-Lymphocytes, Virology, MESH: Autoimmunity, Immune Tolerance, medicine, Animals, Humans, MESH: Lymphocyte Activation, MESH: Mice, B cell, Autoantibodies, MESH: Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Type I interferon production, biology.organism_classification, Immunoglobulin M, Insect Science, Antibody Formation, Pathogenesis and Immunity, Interferon type I
Abstract

The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB × NZW)F 1 ] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB × NZW)F 1 mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.

Published
2007

20. Mediators Involved in the Immunomodulatory Effects of Apoptotic Cells

Author

Stéphanie Kury-Paulin, Philippe Saas, François Kleinclauss, Sylvain Perruche, Francis Bonnefoy, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Mucosal Immunology Unit, National Institute of Dental and Craniofacial Research-National Institutes of Health, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Saas, Philippe

Subjects
TGF-β, MESH: Immune Tolerance, [SDV.IMM] Life Sciences [q-bio]/Immunology, Transcription, Genetic, Cell Transplantation, Regulatory T cell, Cell, Apoptosis, Biology, Article, regulatory T cells, Immune tolerance, 03 medical and health sciences, 0302 clinical medicine, Immune system, Transforming Growth Factor beta, Immune Tolerance, medicine, Animals, MESH: Animals, Secretion, dendritic cells, MESH: Transforming Growth Factor beta, 030304 developmental biology, 0303 health sciences, Transplantation, MESH: Apoptosis, MESH: Transcription, Genetic, apoptotic cells, Transforming growth factor beta, macrophages, 3. Good health, MESH: Cell Transplantation, surgical procedures, operative, medicine.anatomical_structure, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030215 immunology
Abstract

International audience; Immunomodulatory properties are attributed to apoptotic cells. These properties have been used to modulate allogeneic immune responses in experimental transplantation settings. In independent studies, apoptotic cell infusion has been shown to favor hematopoietic cell engraftment, to increase heart graft survival, and to delay the lethal onset of graft-versus-host disease (GVHD). The goal of this review was to discuss how apoptotic cell infusion interferes with graft rejection or host rejection (i.e., GVHD) and to focus on the potential mediators or "perpetuators" involved in apoptotic cell-induced immunomodulation. Particular emphasis on apoptotic cell phagocytosis, transforming growth factor (TGF)-beta secretion, and regulatory T cell induction was performed. Stimulating "naturally" immunosuppressive molecules (i.e., TGF-beta) or immunomodulatory cells ("alternatively-activated" macrophages, certain dendritic cell subsets, or regulatory T cells) in a physiological manner by using apoptotic cell infusion can be a promising way to induce tolerance.

Published
2007

21. Natural Regulation of Immunity to Minor Histocompatibility Antigens

Author

Emily Manktelow, Nathan J Robertson, Fazila Hashim, Julian Dyson, François A. Lemonnier, Diane Scott, Jian-Guo Chai, Maggie Millrain, Elizabeth Simpson, Transplantation Biology Group, Imperial College London, Division of Virology, University of Cambridge [UK] (CAM), Immunité Cellulaire Antivirale, Institut Pasteur [Paris], and Institut Pasteur [Paris] (IP)

Subjects
MESH: Minor Histocompatibility Antigens, T-Lymphocytes, Graft vs Host Disease, MESH: Mice, Knockout, MESH: Hematopoietic Stem Cells, MESH: Histocompatibility Antigens Class I, Mice, 0302 clinical medicine, Minor histocompatibility antigen, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, IL-2 receptor, Receptors, Immunologic, Mice, Knockout, Mice, Inbred BALB C, 0303 health sciences, Leukemia, Hematopoietic Stem Cell Transplantation, Skin Transplantation, MESH: Antigens, CD94, 3. Good health, Haematopoiesis, Receptors, Natural Killer Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, NK Cell Lectin-Like Receptor Subfamily C, NK Cell Lectin-Like Receptor Subfamily D, MESH: Immune Tolerance, Immunology, MESH: Mice, Inbred BALB C, MESH: Graft vs Host Disease, Graft vs Leukemia Effect, Biology, MESH: H-2 Antigens, Minor Histocompatibility Antigens, 03 medical and health sciences, MESH: Leukemia, MHC class I, Immune Tolerance, Animals, Humans, MESH: Mice, MESH: Receptors, Immunologic, MESH: Hematopoietic Stem Cell Transplantation, 030304 developmental biology, MESH: Humans, Histocompatibility Antigens Class I, H-2 Antigens, MESH: Graft vs Leukemia Effect, Hematopoietic Stem Cells, Histocompatibility, Transplantation, MESH: T-Lymphocytes, MESH: Skin Transplantation, biology.protein, CD8, 030215 immunology
Abstract

MHC-matched hemopoietic stem cell transplantation is commonly used for the treatment of some forms of leukemia. Conditioning regimens before transplant act to reduce the burden of leukemic cells and the graft-vs-leukemia (GvL) effect can eliminate residual disease. The GvL effect results largely from the recognition of minor histocompatibility Ags by donor T cells on recipient tissues. These Ags are generally widely expressed and also provoke graft-vs-host (GvH) disease. Manipulation of immunity to promote GvL while curtailing GvH would greatly improve clinical outcome. To develop strategies that may achieve this, the parameters which control immunity to minor histocompatibility Ags need to be defined. In this study, we have analyzed responses to the mouse HY minor histocompatibility Ag using hemopoietic cell and skin grafts as surrogate GvL and GvH targets, respectively. We show that natural regulation of CD8 T cell responses to HY operates at multiple levels. First, CD4 T cell help is required for primary CD8 responses directed at hemopoietic cells. However, although CD4 T cells of H2k mouse strains recognize HY, they provide ineffective help associated with a proportion of recipients developing tolerance. This was further investigated using TCR-transgenic mice which revealed H2k-restricted HY-specific CD4 T cells are highly susceptible to regulation by CD25+ regulatory T cells which expand in tolerant recipients. A second level of regulation, operating in the context of skin grafts, involves direct inhibition of CD8 T cell responses by CD94/NKG2 engagement of the nonclassical MHC class I molecule Qa1.

Published
2007

22. Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes

Author

Nathalie Gorsse, Joost P. M. van Meerwijk, Olivier Joffre, Denis Hudrisier, Paola Romagnoli, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), and Van Meerwijk, Joost

Subjects
CD4-Positive T-Lymphocytes, Graft Rejection, CD8-Positive T-Lymphocytes, Biochemistry, Immune tolerance, Epitopes, Mice, Interleukin 21, 0302 clinical medicine, Histocompatibility Antigens, MESH: Animals, IL-2 receptor, MESH: Bone Marrow Transplantation, Cells, Cultured, Bone Marrow Transplantation, 0303 health sciences, MESH: Bone Marrow Cells, MESH: CD4-Positive T-Lymphocytes, Hematology, MESH: CD8-Positive T-Lymphocytes, 3. Good health, medicine.anatomical_structure, Mice, Inbred DBA, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Cells, Cultured, MESH: Immune Tolerance, MESH: Epitopes, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Bone Marrow Cells, MESH: Graft Rejection, Biology, Major histocompatibility complex, Article, TCIRG1, 03 medical and health sciences, MESH: Mice, Inbred, Antigen, MESH: Mice, Inbred C57BL, Immune Tolerance, medicine, Animals, Transplantation, Homologous, MESH: Mice, 030304 developmental biology, MESH: Histocompatibility Antigens, Receptors, Interleukin-2, MESH: Haplotypes, Cell Biology, T lymphocyte, Mice, Inbred C57BL, Haplotypes, biology.protein, Bone marrow, Spleen, 030215 immunology
Abstract

Thymus-derived regulatory T lymphocytes of CD4+CD25+ phenotype regulate a large variety of beneficial and deleterious immune responses and can inhibit lethal graft-versus-host disease in rodents. In vitro, CD4+CD25+ T cells require specific major histocompatibility complex (MHC)/peptide ligands for their activation, but once activated they act in an antigen-nonspecific manner. In vivo, regulatory T cells are also activated in an antigen-specific fashion, but nothing is known about antigen specificity of their suppressor-effector function. Here we show that CD4+CD25+ regulatory T lymphocytes isolated from naive mice and activated in vitro with allogeneic antigen-presenting cells (APCs) induced specific long-term tolerance to bone marrow grafts disparate for major and minor histocompatibility antigens; whereas “target” bone marrow was protected, third-party bone marrow was rejected. Importantly, in mice injected with a mix of target and third-party bone marrows, protection and rejection processes took place simultaneously. These results indicate that CD4+CD25+ regulatory T cells can act in an antigen-specific manner in vivo. Our results suggest that CD4+CD25+ regulatory T cells could in the future be used in clinical settings to induce specific immunosuppression. (Blood. 2004;103:4216-4221)

Published
2004

23. Direct and indirect immunosuppression by a malaria parasite in its mosquito vector

Author

Christophe Boëte, Jacob C. Koella, Richard Paul, Parasitologie évolutive (PE), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Biochimie et Biologie Moléculaire des Insectes, Institut Pasteur [Paris] (IP), and C.B. received financial support from the Fondation pour la Recherche Médicale and F. Lacoste. R.E.L.P. was supported by the Institut Pasteur.

Subjects
efficacy, gallinaceum, Plasmodium gallinaceum, Immune tolerance, sephadex beads, Aedes aegypti, Aedes, Parasite hosting, MESH: Animals, Laboratory of Entomology, General Environmental Science, insect immunity, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, immunosuppression, biology, MESH: Chickens, transmission, General Medicine, MESH: Aedes, PE&RC, Microspheres, MESH: Malaria, Avian, General Agricultural and Biological Sciences, susceptible strains, MESH: Oocysts, Research Article, MESH: Immune Tolerance, Malaria, Avian, malaria, MESH: Microspheres, General Biochemistry, Genetics and Molecular Biology, Immune system, Immunity, MESH: Analysis of Variance, parasitic diseases, medicine, Immune Tolerance, Animals, infected anopheles-gambiae, Analysis of Variance, General Immunology and Microbiology, MESH: Plasmodium gallinaceum, stephensi, fungi, Oocysts, Plasmodium falciparum, medicine.disease, biology.organism_classification, Laboratorium voor Entomologie, Virology, immunity, melanization response, plasmodium-falciparum, Chickens, Malaria
Abstract

International audience; Malaria parasites develop as oocysts within the haemocoel of their mosquito vector during a period that is longer than the average lifespan of many of their vectors. How can they escape from the mosquito's immune responses during their long development? Whereas older oocysts might camouflage themselves by incorporating mosquito-derived proteins into their surface capsule, younger stages are susceptible to the mosquito's immune response and must rely on other methods of immune evasion. We show that the malaria parasite Plasmodium gallinaceum suppresses the encapsulation immune response of its mosquito vector, Aedes aegypti, and in particular that the parasite uses both an indirect and a direct strategy for immunosuppression. Thus, when we fed mosquitoes with the plasma of infected chickens, the efficacy of the mosquitoes to encapsulate negatively charged Sephadex beads was considerably reduced, whether the parasite was present in the blood meal or not. In addition, zygotes that were created ex vivo and added to the blood of uninfected chickens reduced the efficacy of the encapsulation response. As dead zygotes had no effect on encapsulation, this result demonstrates active suppression of the mosquito's immune response by malaria parasites.

Published
2004

24. Immune tolerance induction with multiepitope peptide derived from citrullinated autoantigens attenuates arthritis manifestations in adjuvant arthritis rats

Author

Howard Amital, Yehuda Shoenfeld, Smadar Gertel, Guy Serre, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CARBILLET, Véronique, and Tel Aviv University (TAU)

Subjects
Arthritis, MESH: Autoantigens / immunology, Apoptosis, Filaggrin Proteins, Autoantigens, Severity of Illness Index, T-Lymphocytes, Regulatory, Immune tolerance, Arthritis, Rheumatoid, Epitopes, 0302 clinical medicine, MESH: Arthritis, Rheumatoid / immunology, MESH: Citrulline / metabolism, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, T-Lymphocyte Subsets, MESH: Arthritis, Rheumatoid / pathology, Immunology and Allergy, MESH: Animals, MESH: T-Lymphocyte Subsets / metabolism, 0303 health sciences, MESH: Epitopes / metabolism, 3. Good health, Tolerance induction, medicine.anatomical_structure, Phenotype, MESH: Peptides / administration & dosage, MESH: Epitopes / immunology, Rheumatoid arthritis, MESH: T-Lymphocyte Subsets / immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Filaggrin, MESH: Immune Tolerance, MESH: Immunophenotyping, MESH: Rats, Regulatory T cell, MESH: T-Lymphocytes, Regulatory / metabolism, T cell, Immunology, MESH: Autoantibodies / immunology, MESH: Peptides / immunology, MESH: Phenotype, MESH: Autoantigens / metabolism, MESH: Apoptosis / immunology, Immunophenotyping, 03 medical and health sciences, MESH: Severity of Illness Index, medicine, Immune Tolerance, Animals, 030304 developmental biology, Autoantibodies, 030203 arthritis & rheumatology, MESH: Arthritis, Experimental / immunology, business.industry, Autoantibody, medicine.disease, Arthritis, Experimental, Rats, MESH: T-Lymphocytes, Regulatory / immunology, Disease Models, Animal, MESH: Peptides / metabolism, MESH: Epitopes / administration & dosage, MESH: Arthritis, Experimental / pathology, Citrulline, MESH: Disease Models, Animal, business, Peptides, MESH: Female
Abstract

Citrullinated peptides are major targets of disease-specific autoantibodies in rheumatoid arthritis. Currently, citrullinated peptides are used as biomarkers for diagnosing rheumatoid arthritis by measuring anti-citrullinated protein Ab (ACPA) titers in patients’ sera. The accumulation of citrullinated proteins at synovial inflammation sites suggests that they are possible targets for tolerance induction. The objective of the present study was to determine whether citrullinated peptides could induce tolerance in an experimental arthritis model in rats. In view of the multiplicity of target citrullinated autoantigens described for ACPA, we generated a multiepitope citrullinated peptide (Cit-ME), derived from major prevalent citrullinated autoantigens (citrullinated filaggrin, fibrinogen, vimentin, and collagen type II), and studied its effects on arthritic rats. Adjuvant-induced arthritis was induced in Lewis rats. Beginning at day 7 after disease induction, the rats received eight s.c. injections of Cit-ME on alternate days. Differences in clinical status and modulation of T cell populations were analyzed. In adjuvant-induced arthritis rats treated with Cit-ME, disease severity was significantly reduced compared with that of untreated rats. Moreover, amelioration of disease manifestations was related to an increased regulatory T cell subset and an elevated apoptosis rate of T cells associated with reduced Th17 cells. Thus, the use of citrullinated peptides–based immunotherapy may be a promising approach for tolerance induction in experimental arthritis and perhaps even in susceptible individuals that are ACPA-seropositive in human arthritis.

Published
2014

25. Allo-Immune Membranous Nephropathy and Recombinant Aryl Sulfatase Replacement Therapy: A Need for Tolerance Induction Therapy

Author

Laure-Hélène Noël, Vassili Valayannopoulos, Pierre Ronco, Niaudet P, Olivia Boyer, Patrice Callard, Pascale de Lonlay, Hanna Debiec, Hélène Sarda, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence pour les maladies métaboliques héréditaires [CHU Necker Enfants Malades - AP-HP], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pédiatrie [CH René Dubos, Pontoise], Centre Hospitalier René Dubos [Pontoise], Research is supported by European Research Council Grant ERC-2012-ADG_20120314 (Grant Agreement 322947), Agence Nationale pour la Recherche Programme Blanc SVSE1 (2012) Decision ANR-12-BSE1-0002-01, Fondation pour la Recherche Médicale Equipe FRM 2012 grant, and 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases)., European Project: 322947,EC:FP7:ERC,ERC-2012-ADG_20120314,OSAI(2013), European Project: 305608,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EURENOMICS(2012), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie pathologique [CHU Necker], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie, Hopital Réné Dubos-CH Pontoise, European Research Council Grant ERC-2012-ADG_20120314 (Grant Agreement 322947), Agence Nationale pour la Recherche Programme Blanc SVSE1 (2012) Decision ANR-12-BSE1-0002-01, Fondation pour la Recherche Médicale Equipe FRM 2012 grant, and 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare KidneyDiseases)., Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [CHU Tenon], RONCO, Pierre, Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI) - OSAI - - EC:FP7:ERC2013-05-01 - 2018-04-30 - 322947 - VALID, European Consortium for High-Throughput Research in Rare Kidney Diseases - EURENOMICS - - EC:FP7:HEALTH2012-10-01 - 2017-09-30 - 305608 - VALID, Service de Département de Néphrologie = Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service de néphrologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, N-Acetylgalactosamine-4-Sulfatase, Mucopolysaccharidosis type VI, MESH: Glomerulonephritis, Membranous, MESH : Child, Preschool, MESH : N-Acetylgalactosamine-4-Sulfatase, Gastroenterology, Glomerulonephritis, Membranous, MESH: Recombinant Proteins, 0302 clinical medicine, Isoantibodies, Medicine, MESH : Glomerulonephritis, Membranous, MESH: Enzyme Replacement Therapy, 0303 health sciences, Proteinuria, Mucopolysaccharidosis VI, MESH : Enzyme Replacement Therapy, MESH : Immune Tolerance, Glomerulonephritis, General Medicine, Enzyme replacement therapy, Recombinant Proteins, 3. Good health, Tolerance induction, Nephrology, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine.symptom, Brief Communications, medicine.medical_specialty, MESH: Immune Tolerance, MESH: Mucopolysaccharidosis VI, MESH : Recombinant Proteins, MESH : Male, MESH : Isoantibodies, MESH: N-Acetylgalactosamine-4-Sulfatase, Nephropathy, 03 medical and health sciences, Membranous nephropathy, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Immune Tolerance, Humans, Enzyme Replacement Therapy, 030304 developmental biology, MESH: Humans, business.industry, MESH : Humans, MESH: Child, Preschool, medicine.disease, MESH: Isoantibodies, MESH: Male, MESH : Mucopolysaccharidosis VI, Immunology, business, Nephrotic syndrome, 030217 neurology & neurosurgery
Abstract

International audience; Nephrotic syndrome was reported in a highly-sensitized patient receiving enzyme replacement therapy (ERT) for Pompe disease, but the prevalence of ERT-induced renal complications and mechanisms to facilitate readministration of ERT in these patients remain unexplored. This work identifies a new antigen responsible for secondary membranous nephropathy (MN) in a patient with mucopolysaccharidosis type VI caused by aryl sulfatase B (ASB) deficiency. ERT (recombinant human ASB [rhASB]; 1 mg/kg per week) started at the age of 4 years led to a high anti-rhASB titer and dramatically improved clinical manifestations. However, 16 months later, the patient suddenly developed nephrotic syndrome resistant to steroid therapy 1 week after orthopedic surgery. Examination of the kidney biopsy specimen revealed glomerular deposition of IgG (mostly IgG4, C3, and C5b-9) in a granular pattern typical of MN. Double immunofluorescence staining showed that subepithelial granular deposits contained rhASB colocalized with IgG. Ig eluted from the patient's biopsy specimen reacted specifically with rhASB. On discontinuation of ERT, proteinuria progressively decreased, but the patient's clinical condition markedly deteriorated. Induction of tolerance to rhASB was initiated by coadministration of low-dose corticosteroids, rituximab, intravenous Igs, and oral methotrexate. ERT was resumed 8 weeks after starting immunosuppressive therapy without inducing a rebound of antibody titer or an increase in proteinuria. We conclude that the allo-immune response to the recombinant rhASB caused the nephropathy. Considering the critical requirement for ERT in patients with such enzyme deficiencies, immune tolerance induction should be advocated in the patients with allo-immune MN.

Published
2014

26. L14. Immunomodulatory properties of apoptotic cells

Author

Philippe Saas, Sylvain Perruche, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Université de Franche-Comté (UFC), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Saas, Philippe, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), and Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Inflammation, MESH: Signal Transduction, Cell Transplantation, Neutrophils, medicine.medical_treatment, Apoptosis, MESH: T-Lymphocyte Subsets, Pharmacology, MESH: Neutrophils, T-Lymphocytes, Regulatory, MESH : Neutrophils, MESH : T-Lymphocytes, Regulatory, 0302 clinical medicine, T-Lymphocyte Subsets, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH : Antigen-Presenting Cells, MESH: Desensitization, Immunologic, MESH: Phagocytosis, ComputingMilieux_MISCELLANEOUS, Desensitization (medicine), MESH : Macrophages, 0303 health sciences, Phagocytes, tolerance, MESH: Dendritic Cells, MESH: Antigen-Presenting Cells, MESH : Immune Tolerance, General Medicine, MESH: Chemokines, MESH: Cell Transplantation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Chemokines, Inflammation Mediators, medicine.symptom, Signal Transduction, TGF-β, MESH: Immune Tolerance, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Inflammation Mediators, MESH: Immunomodulation, Antigen-Presenting Cells, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Inflammation, Immunomodulation, MESH : Inflammation Mediators, 03 medical and health sciences, MESH: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Cell transplantation, Text mining, Phagocytosis, MESH : Phagocytosis, Immune Tolerance, medicine, Animals, Humans, MESH : Chemokines, 030304 developmental biology, MESH : Immunomodulation, MESH : Signal Transduction, MESH: Humans, MESH : Inflammation, business.industry, Macrophages, MESH: T-Lymphocytes, Regulatory, MESH: Apoptosis, MESH : Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, MESH : Humans, MESH: Macrophages, Dendritic Cells, MESH : T-Lymphocyte Subsets, MESH : Cell Transplantation, Desensitization, Immunologic, inflammation, MESH : Dendritic Cells, MESH : Desensitization, Immunologic, MESH : Animals, business, MESH : Apoptosis, 030215 immunology
Abstract

International audience

Published
2013

27. Candida albicans Primes TLR Cytokine Responses through a Dectin-1/Raf-1–Mediated Pathway

Author

Bart Jan Kullberg, Jessica Quintin, Daniela C. Ifrim, Trees Jansen, Leo A. B. Joosten, Neil A. R. Gow, Liesbeth Jacobs, Mihai G. Netea, David L. Williams, Jos W. M. van der Meer, Radboud University Medical Center [Nijmegen], East Tennessee State University (ETSU), and University of Aberdeen

Subjects
MESH: Signal Transduction, MESH: Inflammation, Infectious Disease and Host Response, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Priming (immunology), Ligands, Immune tolerance, Bacteroides fragilis, 0302 clinical medicine, Candida albicans, MESH: Staphylococcus aureus, MESH: Ligands, Immunology and Allergy, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Skin, 0303 health sciences, MESH: Cytokines, biology, MESH: Escherichia coli, [SDV.BA]Life Sciences [q-bio]/Animal biology, Toll-Like Receptors, Health aging / healthy living Pathogenesis and modulation of inflammation [IGMD 5], Corpus albicans, 3. Good health, Pathogenesis and modulation of inflammation [N4i 1], Cytokine, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, medicine.symptom, MESH: Toll-Like Receptors, Signal Transduction, Staphylococcus aureus, MESH: Immune Tolerance, Immunology, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Invasive mycoses and compromised host Infection and autoimmunity [N4i 2], Microbiology, 03 medical and health sciences, Immune system, MESH: Skin, Immunity, medicine, Escherichia coli, Immune Tolerance, Humans, Lectins, C-Type, 030304 developmental biology, MESH: Humans, Mucous Membrane, MESH: Candida albicans, MESH: Bacteroides fragilis, MESH: Mucous Membrane, Pathogenesis and modulation of inflammation Infection and autoimmunity [N4i 1], biology.organism_classification, Proto-Oncogene Proteins c-raf, MESH: Proto-Oncogene Proteins c-raf, MESH: Lectins, C-Type, 030215 immunology
Abstract

The immune system is essential to maintain homeostasis with resident microbial populations, ensuring that the symbiotic host–microbial relationship is maintained. In parallel, commensal microbes significantly shape mammalian immunity at the host mucosal surface, as well as systemically. Candida albicans is an opportunistic pathogen that lives as a commensal on skin and mucosa of healthy individuals. Little is known about its capacity to modulate responses toward other microorganisms, such as colonizing bacteria (e.g., intestinal microorganisms). The aim of this study was to assess the cytokine production of PBMCs induced by commensal bacteria when these cells were primed by C. albicans. We show that C. albicans and β-1,3-glucan induce priming of human primary mononuclear cells and this leads to enhanced cytokine production upon in vitro stimulation with TLR ligands and bacterial commensals. This priming requires the β-1,3-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. In addition, although purified mannans cannot solely mediate the priming, the presence of mannosyl residues in the cell wall of C. albicans is nevertheless required. In conclusion, C. albicans is able to modify cytokine responses to TLR ligands and colonizing bacteria, which is likely to impact the inflammatory reaction during mucosal diseases.

Published
2013

28. NKp30 enables NK cells to act naturally with fungi

Author

Stuart M. Levitz, Jessica Quintin, Radboud University Medical Center [Nijmegen], University of Massachusetts Medical School [Worcester] (UMASS), and University of Massachusetts System (UMASS)

Subjects
Antifungal, MESH: Killer Cells, Natural, Cancer Research, MESH: Immune Tolerance, medicine.drug_class, [SDV]Life Sciences [q-bio], HIV Infections, Biology, Microbiology, MESH: Candida, Virology, Immunology and Microbiology(all), Immune Tolerance, medicine, Humans, Receptor, Molecular Biology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Candida, Natural Cytotoxicity Triggering Receptor 3, MESH: Humans, MESH: Host-Pathogen Interactions, MESH: HIV Infections, Cell biology, Pathogenesis and modulation of inflammation [N4i 1], Killer Cells, Natural, Cryptococcus, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Host-Pathogen Interactions, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Parasitology, MESH: Natural Cytotoxicity Triggering Receptor 3, MESH: Cryptococcus
Abstract

Item does not contain fulltext NK cells have direct activity against fungal pathogens. Using an unbiased systematic approach, Li et al. (2013) find that NKp30 is a major NK cell receptor responsible for fungal recognition. Moreover, diminished NKp30 expression is associated with reduced antifungal activity in NK cells isolated from HIV-infected persons.

Published
2013

29. Loss of central and peripheral CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis

Author

Boucherma, Rachid, Kridane-Miledi, Hédia, Vives, Francina Langa, Vauchy, Charline, Borg, Christophe, Kleinclauss, François, Fiette, Laurence, Tiberghien, Pierre, Lemonnier, François, Rohrlich, Pierre, Huetz, François, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Immunité Cellulaire Antivirale, Institut Pasteur [Paris], Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'urologie, andrologie et transplantation rénale, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Histopathologie humaine et Modèles animaux, Département de pédiatrie, Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Institut Pasteur [Paris] (IP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC)

Subjects
MESH: Hemochromatosis, MESH: Genetic Diseases, Inborn, MESH: Immune Tolerance, [SDV.IMM] Life Sciences [q-bio]/Immunology, Mutation, Missense, Graft vs Host Disease, MESH: Graft vs Host Disease, Thymus Gland, CD8-Positive T-Lymphocytes, MESH: Mice, Knockout, MESH: Histocompatibility Antigens Class I, Mice, MESH: Skin, Immune Tolerance, MESH: Transplantation, Homologous, Animals, Humans, Transplantation, Homologous, MESH: Animals, Hemochromatosis Protein, MESH: Mice, Skin, Mice, Knockout, MESH: Mutation, Missense, MESH: Humans, MESH: Mice, Inbred DBA, Histocompatibility Antigens Class I, Genetic Diseases, Inborn, Membrane Proteins, MESH: Thymus Gland, MESH: Amino Acid Substitution, MESH: CD8-Positive T-Lymphocytes, Disease Models, Animal, Amino Acid Substitution, Mice, Inbred DBA, [SDV.IMM]Life Sciences [q-bio]/Immunology, Hemochromatosis, MESH: Membrane Proteins, MESH: Disease Models, Animal
Abstract

International audience; HFE, an MHC class Ib molecule that controls iron metabolism, can be directly targeted by cytotoxic TCR αβ T lymphocytes. Transgenic DBA/2 mice expressing, in a Rag 2 KO context, an αβ TCR that directly recognizes mouse HFE (mHFE) were created to further explore the interface of HFE with the immune system. TCR-transgenic mHfe WT mice deleted mHFE-reactive T cells in the thymus, but a fraction of reprogrammed cells were able to escape deletion. In contrast, TCR-transgenic mice deprived of mHFE molecules (mHfe KO mice) or expressing a C282→Y mutated mHFE molecule - the most frequent mutation associated with human hereditary hemochromatosis - positively selected mHFE-reactive CD8(+) T lymphocytes and were not tolerant toward mHFE. By engrafting these mice with DBA/2 WT (mHFE(+)) skin, it was established, as suspected on the basis of similar engraftments performed on DBA/2 mHfe KO mice, that mHFE behaves as an autonomous skin-associated histocompatibility antigen, even for mHFE-C282→Y mutated mice. By contrast, infusion of DBA/2 mHFE(+) mice with naïve mHFE-reactive transgenic CD8(+) T lymphocytes did not induce GVHD. Thus, tolerance toward HFE in mHfe WT mice can be acquired at either thymic or peripheral levels but is disrupted in mice reproducing human familial hemochromatosis.

Published
2012

30. Maturation and function of human dendritic cells are regulated by B lymphocytes

Author

Pierre Youinou, Ahsen Morva, Sébastien Lemoine, Christophe Jamin, Achouak Achour, Jacques-Olivier Pers, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Laboratoire d'Immunologie et Immunothérapie, and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)

Subjects
MESH: Interleukin-12, Cellular differentiation, T-Lymphocytes, Palatine Tonsil, MESH: Flow Cytometry, MESH: Monocytes, Lymphocyte Activation, Biochemistry, T-Lymphocytes, Regulatory, Monocytes, Immune tolerance, Arthritis, Rheumatoid, Mice, 0302 clinical medicine, Lupus Erythematosus, Systemic, MESH: Animals, Cells, Cultured, 0303 health sciences, MESH: Arthritis, Rheumatoid, Antigen Presentation, B-Lymphocytes, biology, MESH: Dendritic Cells, MESH: Enzyme-Linked Immunosorbent Assay, hemic and immune systems, Cell Differentiation, Hematology, Flow Cytometry, MESH: Case-Control Studies, Interleukin-12, Cell biology, Tolerance induction, MESH: Leukocytes, Mononuclear, Interleukin 12, MESH: Palatine Tonsil, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Cells, Cultured, MESH: Cell Differentiation, MESH: Immune Tolerance, Immunology, Antigen presentation, chemical and pharmacologic phenomena, Enzyme-Linked Immunosorbent Assay, CD19, MESH: Coculture Techniques, 03 medical and health sciences, MESH: B-Lymphocytes, Immune Tolerance, Animals, Humans, MESH: Lupus Erythematosus, Systemic, MESH: Lymphocyte Activation, MESH: Mice, 030304 developmental biology, MESH: Humans, Follicular dendritic cells, MESH: T-Lymphocytes, Regulatory, Cell Biology, Dendritic Cells, HLA-DR Antigens, MESH: HLA-DR Antigens, Coculture Techniques, MESH: T-Lymphocytes, Case-Control Studies, MESH: Antigen Presentation, biology.protein, Leukocytes, Mononuclear, CD80, 030215 immunology
Abstract

Mature dendritic cells (DCs) are stimulators of T-cell immune response, whereas immature DCs support T-cell tolerance. Murine B cells can inhibit the production of IL-12 by DCs and thereby hinder the inflammatory response. Notwithstanding the importance of this modulation, only a few studies are available in humans. Here, we have developed an in vitro model of cocultures to assess its significance. We establish that human activated B cells restrained the development of monocytes into immature DCs and their differentiation into mature DCs. In addition, they decreased the density of HLA-DR from mature DCs, the expression of CD80 and CD86 coactivation molecules, the production of IL-12p70 required for antigen presentation and Th1 differentiation, and inhibited the DC-induced T-cell proliferation. These modulations were mediated by CD19+IgDlowCD38+CD24lowCD27− B cells and needed direct cell-to-cell contacts that involved CD62L for the control of CD80 and CD86 expression and a soluble factor for the control of IL-12 production. Moreover, mature DCs from patients with systemic lupus erythematosus displayed insensitivity to the regulation of IL-12. Overall, it appears that human B cells can regulate DC maturation and function and that inefficient B-cell regulation may influence an improper balance between an effector inflammatory response and tolerance induction.

Published
2011

31. Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer

Author

Michael Gobert, Julien Faget, Alexandre Cassignol, Sana Intidhar Labidi-Galy, Nathalie Bendriss-Vermare, Jean-Yves Blay, Agathe Bajard, Christophe Caux, Vanja Sisirak, Isabelle Durand, Isabelle Treilleux, Jean-Damien Combes, François Mithieux, Olivier Tredan, Pierre Meeus, Isabelle Ray-Coquard, Christine Ménétrier-Caux, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Centre Léon Bérard [Lyon], Service d'Oncologie Chirurgicale, Equipe 9, Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biopathologie, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Unité de Biostatistique et d'Evaluation des Thérapeutiques (UBET), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Applications des ultrasons à la thérapie, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Infirmerie protestante, Departement de chirurgie, Département de Médecine Nucléaire, Service d'Oncologie Médicale, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biopathologie

Subjects
Cancer Research, MESH: Immune Tolerance, MESH: Immunophenotyping, Enzyme-Linked Immunosorbent Assay, MESH: Flow Cytometry, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Biology, Immunophenotyping, Immune tolerance, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Immune system, MESH: Lymphocyte Culture Test, Mixed, Immune Tolerance, medicine, Humans, Macrophage, MESH: Cohort Studies, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Tumor microenvironment, MESH: Cytokines, MESH: Humans, MESH: Dendritic Cells, MESH: Enzyme-Linked Immunosorbent Assay, hemic and immune systems, Dendritic Cells, Dendritic cell, Flow Cytometry, medicine.disease, 3. Good health, MESH: Ovarian Neoplasms, Oncology, Immunology, Cytokines, Female, Interleukin-3 receptor, Lymphocyte Culture Test, Mixed, Ovarian cancer, MESH: Female, 030215 immunology
Abstract

In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4+CD123+BDCA2+ pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-α, TNF-α, IL-6, macrophage inflammatory protein-1β, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-α and TGF-β. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4+ T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance. Cancer Res; 71(16); 5423–34. ©2011 AACR.

Published
2011

32. M-ficolin interacts with the long pentraxin PTX3: a novel case of cross-talk between soluble pattern-recognition molecules

Author

Gérard J. Arlaud, Christine Moriscot, Andrea Doni, Guy Schoehn, Chantal Dumestre-Pérard, Nicole M. Thielens, Monique Lacroix, Evelyne Gout, Julien Pérard, Alberto Mantovani, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité de Biochimie des Cancers et Biothérapies, CHU Grenoble, Unité Mixte de Thérapie Cellulaire et Tissulaire, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Humanitas Clinical and Research Institute, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
MESH: Signal Transduction, MESH: Serum Amyloid P-Component, Ligands, chemistry.chemical_compound, MESH: Protein Structure, Tertiary, MESH: Mutant Proteins, 0302 clinical medicine, MESH: Lectins, Lectins, MESH: Ligands, Immunology and Allergy, MESH: Immunity, Humoral, 0303 health sciences, biology, MESH: Acetylglucosamine, PTX3, Cell biology, MESH: Surface Plasmon Resonance, Serum Amyloid P-Component, C-Reactive Protein, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Biochemistry, MESH: Calcium, MESH: N-Acetylneuraminic Acid, Ficolin, Protein Binding, Signal Transduction, MESH: Immune Tolerance, Immunology, MESH: Microscopy, Electron, Acetylglucosamine, 03 medical and health sciences, Tetramer, MESH: C-Reactive Protein, Immune Tolerance, Humans, MESH: Protein Binding, 030304 developmental biology, Innate immune system, MESH: Humans, Pentraxins, Lectin, Surface Plasmon Resonance, N-Acetylneuraminic Acid, Immunity, Humoral, Protein Structure, Tertiary, Sialic acid, Complement system, Microscopy, Electron, chemistry, biology.protein, Calcium, Mutant Proteins, 030215 immunology
Abstract

Ficolins and pentraxins are soluble oligomeric pattern-recognition molecules that sense danger signals from pathogens and altered self-cells and might act synergistically in innate immune defense and maintenance of immune tolerance. The interaction of M-ficolin with the long pentraxin pentraxin 3 (PTX3) has been characterized using surface plasmon resonance spectroscopy and electron microscopy. M-ficolin was shown to bind PTX3 with high affinity in the presence of calcium ions. The interaction was abolished in the presence of EDTA and inhibited by N-acetyl-D-glucosamine, indicating involvement of the fibrinogen-like domain of M-ficolin. Removal of sialic acid from the single N-linked carbohydrate of the C-terminal domain of PTX3 abolished the interaction. Likewise, an M-ficolin mutant with impaired sialic acid-binding ability did not interact with PTX3. Interaction was also impaired when using the isolated recognition domain of M-ficolin or the monomeric C-terminal domain of PTX3, indicating requirement for oligomerization of both proteins. Electron microscopy analysis of the M-ficolin–PTX3 complexes revealed that the M-ficolin tetramer bound up to four PTX3 molecules. From a functional point of view, immobilized PTX3 was able to trigger M-ficolin–dependent activation of the lectin complement pathway. These data indicate that interaction of M-ficolin with PTX3 arises from its ability to bind sialylated ligands and thus differs from the binding to the short pentraxin C-reactive protein and from the binding of L-ficolin to PTX3. The M-ficolin–PTX3 interaction described in this study represents a novel case of cross-talk between soluble pattern-recognition molecules, lending further credit to the integrated view of humoral innate immunity that emerged recently.

Published
2011

33. Evidence for Ebola virus superantigen activity

Author

Nadia Wauquier, Pierre Becquart, Sylvain Baize, Eric M. Leroy, Zoonoses virales et MTN (MIVEGEC-VIROZ), Biologie des infections virales: Emergence, DIFfusion, Impact, Contrôle, Elimination (EDIFICE), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Centre International de Recherches Médicales de Franceville (CIRMF), Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This work was funded by a grant from the Agence Nationale pour la Recherche (appel MIME 2006, ANR-06-MIME-022-01) and a Fonds de Solidarité Prioritaire grant from the Ministère des Affaires Etrangères de la France (FSP 2002005700). The Centre International de Recherches Médicales de Franceville is supported by the Government of Gabon, Total-Fina-Elf Gabon, and the Ministère des Affaires Etrangères, France., Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], MATEO, MATHIEU, Génétique et évolution des maladies infectieuses (GEMI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Génétique et évolution des maladies infectieuses (GEMI), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)

Subjects
MESH: Immune Tolerance, Virulence Factors, T-Lymphocytes, Immunology, Apoptosis, Filoviridae, medicine.disease_cause, Microbiology, Herpesviridae, Immune tolerance, 03 medical and health sciences, 0302 clinical medicine, MESH: Superantigens, Virology, MESH: B-Lymphocytes, Immune Tolerance, medicine, Superantigen, Humans, MESH: Immune Evasion, MESH: Ebolavirus, Letter to the Editor, Antigens, Viral, ComputingMilieux_MISCELLANEOUS, Immune Evasion, 030304 developmental biology, MESH: Virulence Factors, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, B-Lymphocytes, 0303 health sciences, Superantigens, Ebola virus, MESH: Humans, biology, MESH: Apoptosis, T-cell receptor, Rhabdoviridae, Ebolavirus, biology.organism_classification, Acquired immune system, 3. Good health, MESH: T-Lymphocytes, Insect Science, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Antigens, Viral, 030215 immunology
Abstract

Zaire Ebola virus (ZEBOV) is the most lethal Ebola virus species and one of the most virulent human pathogens, causing a severe hemorrhagic fever syndrome that ends in the death of 90% of symptomatic patients within a few days (11). ZEBOV caused numerous human outbreaks in Central Africa between 1976 and 2008 and also devastated wild populations of nonhuman primates (2, 10, 13). Recent studies show that ZEBOV infection induces profound suppression of adaptive immunity, characterized by massive B- and T-lymphocyte apoptosis both in humans and in experimentally infected animals (1, 3, 5–6, 14). Lymphocytes are not infected by ZEBOV, and the mechanisms leading to this massive lymphocyte apoptosis are unclear. As the final shock-like syndrome associated with fatal ZEBOV infection resembles the toxic shock syndrome observed during infections with Gram-positive bacteria with superantigen (SAg) activity, we wondered if ZEBOV might also exhibit SAg activity. SAgs are microbial proteins that bind simultaneously to major histocompatibility complex class II molecules and to the T-cell receptor (TCR) Vβ region. This “bridge” skews the T-cell repertoire by amplifying specific T-cell Vβ subsets, which then are either rapidly deleted by activated cell death or become anergic (4, 7). Thus, we examined the TCR Vβ repertoire of peripheral blood mononuclear cells isolated from acutely infected patients by using PCR-based methods. Surprisingly, TCR Vβ12, Vβ13.2, and Vβ17 mRNA expression was undetectable throughout the symptomatic phase in ZEBOV victims, in survivors but also in three of seven asymptomatic individuals identified during the 1996 Booue outbreak in Gabon (9) (Fig. 1). Furthermore, expression of the other TCR-Vβ chains in deceased patients diminished as the disease progressed, reaching very low levels the day before death. In contrast, mRNA expression of the other Vβ chains was normally upregulated to the same level as β-actin mRNA in asymptomatic individuals but also at the beginning and end of the symptomatic phase and after recovery in survivors. Fig. 1. Reverse transcription (RT)-PCR analysis of the TCR Vβ repertoire during human Ebola virus infection. Agarose gel electrophoresis of PCR products obtained with various (n = 20) combinations of Vβ gene family-specific and Cβ oligonucleotide ... Together, these data show that, whatever the clinical outcome, human ZEBOV infection is associated with mRNA downregulation of three TCR Vβ subsets, indicating either anergy or deletion of the three corresponding T-lymphocyte populations. These results are consistent with ZEBOV SAg activity, the first time that it is suggested in the Filoviridae family. Whereas a large number of bacterial SAgs have been identified, only two families of viruses have SAg activity in humans, namely, Herpesviridae and Rhabdoviridae (8, 12). These findings may represent the “missing link” in our understanding of ZEBOV pathogenicity. The SAg activity of ZEBOV might contribute to the extraordinarily rapid and profound T-lymphocyte depletion observed during fatal infection. The high viral load observed during fatal ZEBOV infection, together with the simultaneous targeting of three Vβ T-cell subsets observed here, would elicit massive lymphocyte activation, rapidly resulting in the deletion of large populations of Vβ12-, Vβ13.2-, and Vβ17-bearing T cells. The loss of mRNA expression of the other Vβ T cells would be due to the proportionally small decline in these subsets.

Published
2011

34. Immunosuppression et cellules souches mésenchymateuses Mieux comprendre une propriété thérapeutique majeure

Author

Karin Tarte, Cédric Ménard, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), programmes européens CASCADE et REBORNE du 7e Programme cadre de recherche et développement, Établissement français du sang, Agence de la biomédecine, Ligue contre le cancer, programme hospitalier de recherche clinique (PHRC 2005)., Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
MESH: Forecasting, 0303 health sciences, MESH: Humans, MESH: Immune Tolerance, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, Biology, Molecular biology, MESH: Adaptation, Physiological, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, MESH: Mesenchymal Stem Cells, 030220 oncology & carcinogenesis, MESH: Animals, MESH: Mesenchymal Stem Cell Transplantation, 030304 developmental biology
Abstract

International audience; Since their efficiency to treat graft versus host disease has been proven, mesenchymal stem cells (MSC) represent a promising cell therapy approach for the treatment of immune disorders. In this context, much attention has focused on their mechanisms of action, in particular once the fact that their immune properties are also crucial for their efficiency in regenerative medicine was demonstrated. By their production of various and redundant soluble factors, MSC exert powerful anti-inflammatory and immunosuppressive effects targeting the main immune cell subsets. These immunoregulatory properties are essentially inducible by inflammatory mediators. In addition, it is now clear that allogeneic MSC are not immunoprivileged in immunocompetent recipient in agreement with their low persistence in vivo. They should thus display an early "touch-and-go" effect involving both direct interactions with recruited immune effectors and further amplification of this immunosuppression process through activation or conditioning of other regulatory immune cells. A better understanding of immunological properties of MSC will clearly improve their use in clinical settings.; Les cellules souches mésenchymateuses (CSM) possèdent des propriétés immunosuppressives très vastes liées à la production de facteurs solubles inductibles qui inhibent l'activation des principaux effecteurs de l'immunité. L'intérêt de ces propriétés a été confirmé dans des essais cliniques spectaculaires chez des patients atteints de la maladie du greffon contre l'hôte, une complication fréquente et grave des allogreffes de cellules souches hématopoïétiques. Depuis, les applications de ce potentiel anti-inflammatoire et immunosuppresseur des CSM ont été étendues à la médecine régénératrice puisque les capacités de réparation des CSM semblent étroitement liées à leurs propriétés immunologiques, démontrant tout l'intérêt d'une compréhension fine des interactions entre les CSM et les cellules immunitaires.

Published
2011

35. Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention?

Author

Barbara Seliger, Hans Grosse-Wilde, Laurence Amiot, Soldano Ferrone, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service d'hématologie clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Institute for Transfusion Medicine, University Hospital Essen, Université de Rennes (UR), and Université de Rennes (UR)-Hôpital Pontchaillou

Subjects
MESH: Immune Tolerance, HLA-G, Medizin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, Biology, MESH: HLA-G Antigens, Article, MESH: Prognosis, Immune tolerance, MESH: Histocompatibility Antigens Class I, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Immune system, Antigen, HLA Antigens, Neoplasms, medicine, Immune Tolerance, Animals, Humans, MESH: Animals, MESH: Neoplasms, Molecular Biology, Immunologic Surveillance, MESH: HLA Antigens, Tumors, MESH: Immunologic Surveillance, Pharmacology, Regulation of gene expression, HLA-G Antigens, MESH: Humans, Immune escape, Histocompatibility Antigens Class I, Cancer, Cell Biology, MESH: Gene Expression Regulation, Neoplastic, medicine.disease, Prognosis, 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Immunology, Molecular Medicine, 030215 immunology
Abstract

International audience; Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal-maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer.

Published
2011

36. Systems biology of infectious diseases: a focus on fungal infections

Author

Michael Bromley, Philippe Pierre, Ivo Gut, Lisa Rizzetto, Rodrigo Santamaría, Wanseon Lee, Duccio Cavalieri, Brian Miller, Misha Kapushesky, Teresa Zelante, Luigina Romani, Manuel A. S. Santos, Paul Bowyer, University of Salamanca - Spain, University of Salamanca, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Manchester [Manchester], Università degli Studi di Perugia (UNIPG), European Bioinforrmatics Institute (UK) (EBI), École de biologie industrielle (EBI), AlerGenetica (UK), AlerGenetica, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universidade de Aveiro, Universidad de Salamanca, Università degli Studi di Firenze = University of Florence (UniFI), and Università degli Studi di Perugia = University of Perugia (UNIPG)

Subjects
Proteomics, Antifungal Agents, MESH: Th17 Cells, Disease, MESH: Drug Design, Bioinformatics, MESH: Receptors, Pattern Recognition, MESH: Molecular Targeted Therapy, Candida albicans, Immunology and Allergy, MESH: Animals, MESH: Immune Evasion, MESH: Genetic Variation, Molecular Targeted Therapy, Organism, MESH: Cytokines, 0303 health sciences, MESH: Proteomics, Systems Biology, Hematology, 3. Good health, Drug development, MESH: Systems Biology, Receptors, Pattern Recognition, MESH: Genome, Fungal, Host-Pathogen Interactions, MESH: Communicable Diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, MESH: Aspergillus fumigatus, Genome, Fungal, MESH: Immune Tolerance, Systems biology, Host–pathogen interaction, Immunology, Computational biology, Biology, Communicable Diseases, Underlying infection, 03 medical and health sciences, MESH: Mycoses, Immune Tolerance, Animals, Humans, Immune Evasion, 030304 developmental biology, MESH: Humans, 030306 microbiology, MESH: Candida albicans, Aspergillus fumigatus, MESH: Host-Pathogen Interactions, MESH: Biological Markers, Genetic Variation, Th1 Cells, MESH: Antifungal Agents, Microarray Analysis, MESH: Microarray Analysis, MESH: Th1 Cells, Mycoses, Infectious disease (medical specialty), Drug Design, Th17 Cells, Biomarkers
Abstract

International audience; The study of infectious disease concerns the interaction between the host species and a pathogen organism. The analysis of such complex systems is improving with the evolution of high-throughput technologies and advanced computational resources. This article reviews integrative, systems-oriented approaches to understanding mechanisms underlying infection, immune response and inflammation to find biomarkers of disease and design new drugs. We focus on the systems biology process, especially the data gathering and analysis techniques rather than the experimental technologies or latest computational resources.

Published
2011

37. [The use of passive rabies immunotherapy: from the past to the future]

Author

Bourhy, Hervé, Dacheux, Laurent, Ribadeau-Dumas, Florence, Centre National de Référence de la Rage-Dynamique des Lyssavirus et adaptation à l'hôte (CNR), Institut Pasteur [Paris], and Centre Collaborateur de l'OMS pour la Rage - Dynamique des lyssavirus et adaptation à l'hôte (CC-OMS)

Subjects
History, MESH: Immune Tolerance, Rabies, Passive, History, 21st Century, MESH: Rabies, Immune Tolerance, Animals, Humans, MESH: Animals, Horses, MESH: Horses, MESH: Developing Countries, Developing Countries, 19th Century, MESH: Humans, Immunization, Passive, MESH: Rabies Vaccines, History, 19th Century, History, 20th Century, 21st Century, MESH: Rabies virus, 20th Century, Rabies Vaccines, Rabies virus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: History, 19th Century, Immunization, MESH: Immunization, Passive, MESH: History, 20th Century, Horse Diseases, MESH: History, 21st Century, MESH: Horse Diseases
Abstract

International audience; Rabies is a fatal disease transmitted by infected animals by bite, scratch, licking on broken skin or contamination of mucosis by saliva. The regimen of post-exposure prophylaxis for people not previously vaccinated, that is currently recommended by WHO, consists of a combination of wound cleaning, active immunization and passive immunization when the exposure is of category 3. Most of the products available on the market, in particular human rabies immunoglobulins, highly purified equine rabies immunoglobulins and the derived F(ab')(2) fragments, are now characterized by high potency and safety. Although the interest of passive anti-rabies immunization was first demonstrated in the first half of the 20th century, there is still an inadequate supply of these products to the target populations mostly in developing countries. Therefore, it is urgent to set-up training and information actions for healthcare personnel on the need to use passive immunotherapy and the lack of adverse effects of the related products. For the future, we hope that a scale up of production and a lower price will improve the accessibility to these products. The development of new products based on monoclonal antibodies and molecular biology, and which may be cheaper, is promising.

Published
2010

38. Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development

Author

Eric Mosconi, Akira Kanda, Barbara Seitz-Polski, Sébastien Fleury, Akila Rekima, Nicolas Glaichenhaus, Valérie Verhasselt, Renato C. Monteiro, Valérie Julia, David Dombrowicz, Emilie Tissandie, Immunologie des maladies infectieuses allergiques et autoimmunes, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Schistosomiase, paludisme et inflammation, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université Lille Nord de France (COMUE), Réseau International des Instituts Pasteur (RIIP), Immunopathologie rénale, récepteurs et inflammation, and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Asthma, MESH: Interleukin-2 Receptor alpha Subunit, Administration, Oral, Antigen-Antibody Complex, Receptors, Fc, T-Lymphocytes, Regulatory, MESH: Mice, Knockout, MESH: Animals, Newborn, MESH: Histocompatibility Antigens Class I, Mice, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, Immunology and Allergy, MESH: Animals, IL-2 receptor, MESH: Maternal Exposure, Mice, Knockout, MESH: Immunoglobulin G, Mice, Inbred BALB C, 0303 health sciences, MESH: Milk, Human, FOXP3, Forkhead Transcription Factors, MESH: Antigen-Antibody Complex, 3. Good health, Tolerance induction, Breast Feeding, Maternal Exposure, MESH: Breast Feeding, MESH: Administration, Oral, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Receptors, Fc, MESH: Allergens, MESH: Immune Tolerance, Ovalbumin, Immunology, MESH: Mice, Inbred BALB C, Breast milk, 03 medical and health sciences, Immune system, Neonatal Fc receptor, Antigen, MESH: Mice, Inbred C57BL, MESH: Forkhead Transcription Factors, Immune Tolerance, medicine, Animals, MESH: Mice, 030304 developmental biology, Asthma, MESH: Ovalbumin, Milk, Human, business.industry, MESH: T-Lymphocytes, Regulatory, Histocompatibility Antigens Class I, Interleukin-2 Receptor alpha Subunit, Allergens, medicine.disease, MESH: Male, Mice, Inbred C57BL, Animals, Newborn, Immunoglobulin G, MESH: Immunity, Maternally-Acquired, business, Immunity, Maternally-Acquired, MESH: Female, 030215 immunology
Abstract

International audience; Allergic asthma is a chronic lung disease resulting from an inappropriate T helper (Th)-2 response to environmental antigens. Early tolerance induction is an attractive approach for primary prevention of asthma. Here, we found that breastfeeding by antigen-sensitized mothers exposed to antigen aerosols during lactation induced a robust and long-lasting antigen-specific protection from asthma. Protection was more profound and persistent than the one induced by antigen-exposed non-sensitized mothers. Milk from antigen-exposed sensitized mothers contained antigen-immunoglobulin (Ig) G immune complexes that were transferred to the newborn through the neonatal Fc receptor resulting in the induction of antigen-specific FoxP3(+) CD25(+) regulatory T cells. The induction of oral tolerance by milk immune complexes did not require the presence of transforming growth factor-beta in milk in contrast to tolerance induced by milk-borne free antigen. Furthermore, neither the presence of IgA in milk nor the expression of the inhibitory FcgammaRIIb in the newborn was required for tolerance induction. This study provides new insights on the mechanisms of tolerance induction in neonates and highlights that IgG immune complexes found in breast milk are potent inducers of oral tolerance. These observations may pave the way for the identification of key factors for primary prevention of immune-mediated diseases such as asthma.

Published
2010

39. Existence of CD8α-like dendritic cells with a conserved functional specialization and a common molecular signature in distant mammalian species

Author

Rachel Guiton, Karine Crozat, Yannick O. Alexandre, Marc Dalod, Vanessa Contreras, Michel Bonneau, Thibault Andrieu, Thien-Phong Vu Manh, Isabelle Schwartz-Cornil, Mathieu Epardaud, Ariel Savina, Nicolas Bertho, Jayne Hope, Luc Jouneau, Céline Urien, Sebastian Amigorena, Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Immunologie de Marseille Luminy (CIML - INSERM U631 - CNRS UMR 6102), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Energie Atomique, Di- vision of Immuno-Virology, Direction des Sciences du Vivant, Institut des Maladies Emergentes et des The´rapies Innovantes, Fontenay-aux-Rose, Institute for Animal Health, Compton, Institut Curie, PSL Research University, INSERM U932., Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute for Animal Health (IAH), Biotechnology and Biological Sciences Research Council, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Imagerie Interventionnelle (CR2I), Unité de recherche Virologie et Immunologie Moléculaires ( VIM ), Institut National de la Recherche Agronomique ( INRA ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Maladies Emergentes et des Thérapies Innovantes ( IMETI ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institute for Animal Health ( IAH ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Imagerie Interventionnelle ( CR2I ), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biotechnology and Biological Sciences Research Council (BBSRC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5)

Subjects
[SDV]Life Sciences [q-bio], Conserved sequence, Immune tolerance, Interleukin 22, Mice, 0302 clinical medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, MESH: Animals, Domestic, Cells, Cultured, Conserved Sequence, Skin, 0303 health sciences, Cultured, MESH: Conserved Sequence, MESH: Dendritic Cells, MESH : Immune Tolerance, hemic and immune systems, Phenotype, Cell biology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lymph, MESH: Cells, Cultured, MESH: Lymph, XCR1, MESH: Immune Tolerance, Cells, CD8 Antigens, Dipeptidyl Peptidase 4, Immunology, chemical and pharmacologic phenomena, Biology, MESH : Lymph, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Skin, Species Specificity, MESH : Conserved Sequence, MESH : Mice, MESH : Sheep, Domestic, MESH : Cells, Cultured, MESH : Skin, Immune Tolerance, MESH : Species Specificity, MESH: Species Specificity, Animals, Humans, Antigens, Gene, MESH: Mice, Sheep, Domestic, 030304 developmental biology, Sheep, MESH: Humans, MESH : Gene Expression Profiling, Gene Expression Profiling, MESH : Humans, CD8, Dendritic cell, Dendritic Cells, MESH: Dipeptidyl Peptidase 4, MESH : Dendritic Cells, MESH : Dipeptidyl Peptidase 4, MESH : Animals, MESH: Antigens, CD8, MESH: Sheep, Domestic, MESH : Antigens, CD8, MESH: Female, 030215 immunology
Abstract

International audience; The mouse lymphoid organ-resident CD8alpha(+) dendritic cell (DC) subset is specialized in Ag presentation to CD8(+) T cells. Recent evidence shows that mouse nonlymphoid tissue CD103(+) DCs and human blood DC Ag 3(+) DCs share similarities with CD8alpha(+) DCs. We address here whether the organization of DC subsets is conserved across mammals in terms of gene expression signatures, phenotypic characteristics, and functional specialization, independently of the tissue of origin. We study the DC subsets that migrate from the skin in the ovine species that, like all domestic animals, belongs to the Laurasiatheria, a distinct phylogenetic clade from the supraprimates (human/mouse). We demonstrate that the minor sheep CD26(+) skin lymph DC subset shares significant transcriptomic similarities with mouse CD8alpha(+) and human blood DC Ag 3(+) DCs. This allowed the identification of a common set of phenotypic characteristics for CD8alpha-like DCs in the three mammalian species (i.e., SIRP(lo), CADM1(hi), CLEC9A(hi), CD205(hi), XCR1(hi)). Compared to CD26(-) DCs, the sheep CD26(+) DCs show 1) potent stimulation of allogeneic naive CD8(+) T cells with high selective induction of the Ifngamma and Il22 genes; 2) dominant efficacy in activating specific CD8(+) T cells against exogenous soluble Ag; and 3) selective expression of functional pathways associated with high capacity for Ag cross-presentation. Our results unravel a unifying definition of the CD8alpha(+)-like DCs across mammalian species and identify molecular candidates that could be used for the design of vaccines applying to mammals in general.

Published
2010

40. μ-Opioid Receptor Is Induced by IL-13 within Lymph Nodes from Patients with Sézary Syndrome

Author

Jérôme Boué, Pierre Cavaillès, Laurence Lamant, Alan Bénard, Emmanuelle Chapey, Gilles Dietrich, Jagadeesh Bayry, Nicolas Meyer, Srini V. Kaveri, Catherine Blanpied, Pierre Brousset, Centre de Physiopathologie de Toulouse-Purpan (INSERM U563 - CNRS UMR1037), Centre National de la Recherche Scientifique (CNRS)-Centre de lutte contre le cancer (CLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut Claudius Regaud, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], CHU Toulouse [Toulouse]-Institut Claudius Regaud-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de lutte contre le cancer (CLCC)-Centre National de la Recherche Scientifique (CNRS), IFR150, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), Bisanz, Cordelia, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut Claudius Regaud-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de lutte contre le cancer (CLCC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Dermatologie [CHU Toulouse], Pôle Clinique des Voies respiratoires [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche-Santé (Université Pierre et Marie Curie), Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), IFR150 ( Université Paul Sabatier ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] ( LAPM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ), Université Joseph Fourier - Grenoble 1 ( UJF ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité Mixte de Recherche-Santé ( Université Pierre et Marie Curie ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Departement of Dermatology ( CHU Purpan ), CHU Purpan, Service d'anatomie et cytologie pathologiques [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'anatomie pathologique et histologie-cytologie [Rangueil], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil

Subjects
CD4-Positive T-Lymphocytes, MESH: Interleukin-13, Skin Neoplasms, MESH : RNA, Messenger, Enkephalin, Biopsy, Receptors, Opioid, mu, Gene Expression, MESH: Lymph Nodes, CD8-Positive T-Lymphocytes, MESH: Monocytes, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Biochemistry, Monocytes, MESH: Biopsy, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Opioid receptor, polycyclic compounds, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Receptor, Lymph node, Cells, Cultured, MESH : Lymph Nodes, ComputingMilieux_MISCELLANEOUS, Endogenous opioid, MESH: Langerhans Cells, 0303 health sciences, Interleukin-13, MESH : Receptors, Opioid, mu, MESH: Dendritic Cells, MESH : Immune Tolerance, MESH: CD4-Positive T-Lymphocytes, MESH : CD8-Positive T-Lymphocytes, MESH: CD8-Positive T-Lymphocytes, 3. Good health, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH : CD4-Positive T-Lymphocytes, MESH: Sezary Syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Lymph, MESH: Cells, Cultured, MESH: Gene Expression, MESH: Immune Tolerance, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, MESH : Langerhans Cells, MESH: Receptors, Opioid, mu, Dermatology, Biology, 03 medical and health sciences, Immune system, MESH : Cells, Cultured, MESH : Interleukin-13, mental disorders, Immune Tolerance, medicine, Humans, Sezary Syndrome, RNA, Messenger, Opioid peptide, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, 030304 developmental biology, MESH: RNA, Messenger, MESH : Sezary Syndrome, MESH: Humans, MESH: Skin Neoplasms, MESH : Skin Neoplasms, MESH : Humans, Dendritic Cells, Cell Biology, MESH : Gene Expression, MESH : Monocytes, nervous system, Langerhans Cells, MESH : Biopsy, MESH : Dendritic Cells, Immunology, Lymph Nodes, human activities, 030215 immunology
Abstract

International audience; Endogenous opioid peptides mainly produced by neurons are also released by immune cells. They bind to mu- (mu-opioid receptor, MOR), delta-, and kappa-opioid receptors. On the basis of studies on mice showing that MOR is the main mediator of the deleterious effects of opioids on immunity, we wondered whether MOR, absent under normal conditions, is expressed in some pathological situations such as lymphomas. mRNA expression for all three opioid receptors was examined in lymph node biopsy samples from patients with non-Hodgkin's B-cell and T-cell lymphomas. We found that MOR and one of its ligands (enkephalin) are simultaneously expressed almost exclusively in lymph nodes from patients with Sézary cutaneous T cell lymphoma. As MOR was undetectable in circulating malignant T lymphocytes and in normal immune cells, we hypothesized that tumor-released cytokines might induce MOR expression in non-neoplastic lymph node cells. The correlation between mRNA levels of MOR and interleukin-13 (IL-13) within lymph nodes from Sézary patients led us to investigate the ability of IL-13 to upregulate MOR expression in normal immune cell subsets. We found that IL-13 upregulates MOR in activated Langerhans cells. Thus, our data suggest that, under pathological conditions, IL-13 overexpression might allow immune-derived endogenous opioids to down-modulate immune response.

Published
2010

41. [Allergic diseases in children and farming environment]

Author

Hulin, M., Annesi-Maesano, Isabella, Epidémiologie des maladies infectieuses et modélisation (ESIM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Immune Tolerance, Adolescent, MESH: Hypersensitivity, MESH: Air Pollutants, MESH: Environmental Exposure, MESH: Disease Susceptibility, Rural Health, MESH: Models, Immunological, MESH: Prenatal Exposure Delayed Effects, MESH: Pregnancy, Pregnancy, MESH: Child, Hypersensitivity, Immune Tolerance, Prevalence, Respiratory Hypersensitivity, Animals, Humans, MESH: Animals, MESH: Animals, Domestic, Genetic Predisposition to Disease, Child, MESH: Prevalence, MESH: Adolescent, Air Pollutants, MESH: Humans, MESH: Child, Preschool, MESH: Genetic Predisposition to Disease, Models, Immunological, Agriculture, Environmental Exposure, MESH: Rural Health, MESH: Male, MESH: Milk, MESH: Virus Diseases, MESH: Respiratory Hypersensitivity, Milk, Virus Diseases, Air Pollution, Indoor, Animals, Domestic, Child, Preschool, Prenatal Exposure Delayed Effects, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Disease Susceptibility, MESH: Air Pollution, Indoor, MESH: Female, MESH: Agriculture
Abstract

International audience; INTRODUCTION: Children living in rural areas had lower prevalence of allergies than children from cities, in relation to farming exposure. STATE OF ART: Exposure to farm animals and consumption of raw milk appear to play an important role in the protection afforded by the agricultural environment, and this at different stages of child development. The mechanisms involved in these effects are still controversial, and recent publications cast doubt on the role of endotoxins initially suggested. It seems that exposure to indoor air pollution, characterized by excessive biocontaminants (mold, allergens...) is a key element in the development of allergic diseases. PERSPECTIVES: The establishment of cohort studies, a better assessment of exposure to pollution at home but also in farm buildings and the study of gene-environment interactions should improve the knowledge on the protective effect towards allergy of farming environment. CONCLUSIONS: The farming environment, very specific, could be an important model for better understanding the mechanisms involved in allergic and respiratory diseases. In addition, urbanization and thus reduction of the rural environment, may well explain the increased prevalence of allergies observed in the past 50 years.

Published
2010

42. L'immunothérapie antirabique passive d'hier et d'aujourd'hui

Author

Florence Ribadeau-Dumas, Laurent Dacheux, Hervé Bourhy, Centre National de Référence de la Rage-Dynamique des Lyssavirus et adaptation à l'hôte (CNR), Institut Pasteur [Paris], Centre Collaborateur de l'OMS pour la Rage - Dynamique des lyssavirus et adaptation à l'hôte (CC-OMS), and Institut Pasteur [Paris] (IP)

Subjects
History, Passive, medicine.disease_cause, Active immunization, 0302 clinical medicine, MESH: Animals, 030212 general & internal medicine, MESH: Developing Countries, 0303 health sciences, biology, MESH: Rabies Vaccines, 21st Century, 3. Good health, MESH: Rabies virus, 20th Century, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Immunization, Passive, MESH: History, 20th Century, Viral disease, Antibody, MESH: History, 21st Century, MESH: Immune Tolerance, Rabies, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Rabies, medicine, Immune Tolerance, Humans, Animals, Horses, Adverse effect, MESH: Horses, Developing Countries, 030304 developmental biology, 19th Century, MESH: Humans, business.industry, Rabies virus, medicine.disease, Regimen, Immunization, Rabies Vaccines, Immunology, biology.protein, MESH: History, 19th Century, Horse Diseases, business, MESH: Horse Diseases
Abstract

International audience; Rabies is a fatal disease transmitted by infected animals by bite, scratch, licking on broken skin or contamination of mucosis by saliva. The regimen of post-exposure prophylaxis for people not previously vaccinated, that is currently recommended by WHO, consists of a combination of wound cleaning, active immunization and passive immunization when the exposure is of category 3. Most of the products available on the market, in particular human rabies immunoglobulins, highly purified equine rabies immunoglobulins and the derived F(ab')(2) fragments, are now characterized by high potency and safety. Although the interest of passive anti-rabies immunization was first demonstrated in the first half of the 20th century, there is still an inadequate supply of these products to the target populations mostly in developing countries. Therefore, it is urgent to set-up training and information actions for healthcare personnel on the need to use passive immunotherapy and the lack of adverse effects of the related products. For the future, we hope that a scale up of production and a lower price will improve the accessibility to these products. The development of new products based on monoclonal antibodies and molecular biology, and which may be cheaper, is promising.

Published
2010

43. Management of haemophilia A-inhibitor patients: clinical and regulatory perspectives

Author

Zera Tellier, Benoît Polack, Marie-Hélène André, LFB Biomédicaments, TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH: Blood Coagulation Factor Inhibitors, 030204 cardiovascular system & hematology, Epitope, Immune tolerance, MESH: Antibodies, Neutralizing, 0302 clinical medicine, Isoantibodies, hemic and lymphatic diseases, MESH: Child, Haemophilia A, Immunology and Allergy, Medicine, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, Child, Severe complication, MESH: Treatment Outcome, Clinical Trials as Topic, biology, Blood Coagulation Factor Inhibitors, Immunogenicity, General Medicine, MESH: Factor VIII, 3. Good health, Treatment Outcome, Child, Preschool, Antibody, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Immune Tolerance, MESH: Clinical Trials as Topic, Regulatory issues, Haemophilia, Hemophilia A, 03 medical and health sciences, Immune Tolerance, Humans, Factor VIII, MESH: Humans, business.industry, Clinical management, MESH: Child, Preschool, FVIII inhibitors, medicine.disease, MESH: Hemophilia A, Antibodies, Neutralizing, MESH: Isoantibodies, Recombinant factor VIIa, Immunology, biology.protein, business, 030215 immunology
Abstract

International audience; Inhibitors to factor VIII (FVIII) are alloantibodies directed against epitopes able to neutralise FVIII procoagulant activity. They may render FVIII replacement therapy ineffective. They represent the most severe complication of haemophilia A. At least three mechanisms of FVIII neutralisation activity by anti-FVIII antibodies have been described: (1) steric hindrance; (2) recognition of neo-epitopes and (3) catalytic activity. The Nijmegen modification of the Bethesda is the recommended method for inhibitor surveillance. The occurrence of inhibitors is a relatively frequent and early event in previously untreated patients. Conversely, it is rare in previously treated patients. Therapeutic strategies for managing inhibitors include: inhibitor eradication, haemostatic management of bleeding episodes and/or surgery and supportive care. For high responding inhibitors, immune tolerance induction (ITI) is the strategy for achieving antigen-specific tolerance to FVIII. ITI success rate ranges commonly between 60% and 80%. For treatment of patients with high-titre, high-responding inhibitors, 'by-pass' therapy is generally recommended. Activated prothrombin complex concentrates represent the historically primary 'by-pass' treatment. Recombinant factor VIIa has also been widely used as a by-passing agent. Considering the small patient population, it has to be considered that full immunogenicity data cannot be collected premarketing authorisation. Thus, stringent follow-up of patients in the post-authorisation phase is required.

Published
2009

44. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy

Author

Marin, Benoît, Thiébaut, Rodolphe, Bucher, Heiner, Rondeau, Virginie, Costagliola, Dominique, Dorrucci, Maria, Hamouda, Osamah, Prins, Maria, Walker, A. Sarah, Porter, Kholoud, Sabin, Caroline, Chêne, Geneviève, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Basel Institute for Clinical Epidemiology, University Hospital Basel [Basel], Epidémiologie Clinique et Traitement de l'Infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Malattie Infettive, Reparto di Epidemiologia, Istituto Superiore di Sanita [Rome], Department of Infectious Disease Epidemiology, Robert Koch Institute [Berlin] (RKI), Cluster Infectious Diseases, Amsterdam BioMed Cluster, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Research Department of Infection and Population Health [London], and CASCADE has been funded through grants from the European Union BMH4-CT97-2550, QLK2-2000-01431, QLRT-2001-01708 and LSHP-CT-2006-018949.

Subjects
MESH: Immune Tolerance, MESH: Liver Diseases, MESH: CD4 Lymphocyte Count, CD4 cell count, MESH: Epidemiologic Methods, MESH: Antiretroviral Therapy, Highly Active, Hepatitis, MESH: Neoplasms, Causes of death, highly active, MESH: Acquired Immunodeficiency Syndrome, MESH: Adolescent, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: AIDS-Related Opportunistic Infections, MESH: Cardiovascular Diseases, MESH: Adult, Human Immunodeficiency Virus/AIDS, MESH: Male, Antiretroviral therapy, MESH: Young Adult, Neoplasm, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Bacterial infection, MESH: Female
Abstract

International audience; OBJECTIVE: To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death in the era of combination antiretroviral therapy (cART). DESIGN: Observational multicentre cohorts. METHODS: Twenty-three cohorts of adults with estimated dates of human immunodeficiency virus (HIV) seroconversion were considered. Patients were seroconverters followed within the cART era. Measurements were latest CD4, nadir CD4 and time spent with CD4 cell count less than 350 cells/microl. Outcomes were specific causes of death using a standardized classification. RESULTS: Among 9858 patients (71 230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease accounted for 53% of non-AIDS deaths. For each 100 cells/microl increment in the latest CD4 cell count, we found a 64% (95% confidence interval 58-69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18-44%), end-stage liver disease (33, 18-46%) and non-AIDS malignancies (34, 21-45%). Non-AIDS-defining causes of death were also associated with nadir CD4 while being cART-naive or duration of exposure to immunosuppression. No relationship between risk of death from cardiovascular disease and CD4 cell count was found though there was a raised risk associated with elevated HIV RNA. CONCLUSION: In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only cardiovascular disease was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV-infected patients.

Published
2009

45. Lipids of pathogenic Mycobacteria: contributions to virulence and host immune suppression

Author

L Guenin-Macé, Caroline Demangel, Roxane Simeone, Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, Lipopolysaccharides, [SDV]Life Sciences [q-bio], MESH: Virulence, Phagosomes, MESH: Glycolipids, 0303 health sciences, Antigen Presentation, Immunity, Cellular, biology, Virulence, General Medicine, Lipids, 3. Good health, Signal Transduction, Tuberculosis, MESH: Immune Tolerance, Virulence Factors, Antigen presentation, Microbiology, MESH: Immunity, Cellular, Mycobacterium, Mycobacterium tuberculosis, 03 medical and health sciences, Immune system, MESH: Phagosomes, Antigen, Immunity, medicine, MESH: Mycobacterium, Immune Tolerance, Humans, MESH: Mycobacterium Infections, 030304 developmental biology, MESH: Virulence Factors, Antigens, Bacterial, Mycobacterium Infections, MESH: Humans, General Veterinary, General Immunology and Microbiology, 030306 microbiology, biology.organism_classification, medicine.disease, Virology, MESH: Lipids, MESH: Antigen Presentation, MESH: Lipopolysaccharides, Glycolipids, MESH: Antigens, Bacterial
Abstract

International audience; Mycobacteria are characterized by a complex cell wall, the lipid nature of which confers to the bacilli resistance to drying, acid or alkaline conditions, and to chemical disinfectants and therapeutic agents. Pathogenic species, such as Mycobacterium tuberculosis, M. leprae and M. ulcerans, have evolved various strategies to establish residence in their hosts and provoke long-term infections. There is mounting evidence that the unique lipids composing their envelopes, strategically located at the host-pathogen interface, contribute to their escape from immune surveillance. Here, the chemical structure, host cell receptors and biological actions of this emerging class of mycobacterial virulence factors are reviewed.

Published
2009

46. Lack of retinoic acid leads to increased langerin-expressing dendritic cells in gut-associated lymphoid tissues

Author

Sun Young Chang, Mi-Na Kweon, Bernard Malissen, Jae Hoon Chang, Hye Ran Cha, Hyungjun Yang, Hyun-Jeong Ko, Makoto Iwata, Mucosal Immunology Section, International Vaccine Institute (IVI), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Tokushima Bunri University, Laboratory of Biodefense Research, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Aldehyde Oxidoreductases, CD4-Positive T-Lymphocytes, Gut-associated lymphoid tissue, C-C chemokine receptor type 7, Lymphocyte Activation, MESH: Receptors, CCR7, Immune tolerance, Mice, 0302 clinical medicine, MESH: Animals, MESH: Langerhans Cells, 0303 health sciences, Mice, Inbred BALB C, biology, integumentary system, MESH: Dendritic Cells, Vitamin A Deficiency, Gastroenterology, MESH: CD4-Positive T-Lymphocytes, hemic and immune systems, Cell Differentiation, T helper cell, Acquired immune system, Aldehyde Oxidoreductases, Intestines, medicine.anatomical_structure, Antigens, Surface, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Intestines, MESH: Cell Differentiation, Receptors, CCR7, MESH: Immune Tolerance, Langerin, MESH: Antigens, Surface, Lymphoid Tissue, education, MESH: Mice, Inbred BALB C, chemical and pharmacologic phenomena, Tretinoin, 03 medical and health sciences, Immune system, MESH: Mice, Inbred C57BL, MESH: Mannose-Binding Lectins, MESH: Vitamin A Deficiency, medicine, Immune Tolerance, Animals, Lectins, C-Type, Lymphocyte homing receptor, MESH: Lymphocyte Activation, MESH: Mice, 030304 developmental biology, MESH: Tretinoin, Hepatology, Dendritic Cells, Mice, Inbred C57BL, Mannose-Binding Lectins, Langerhans Cells, Immunology, MESH: Lymphoid Tissue, biology.protein, MESH: Lectins, C-Type, 030215 immunology
Abstract

Background & Aims Retinoic acid (RA) is a crucial factor for maintaining homeostasis in the gut, including lymphocyte homing, immunoglobulin (Ig) A production, and T regulatory cells (Treg) and T helper cell 17 (T H 17) generation. Until now, most attention has focused on the function of dendritic cells (DCs) to initiate adaptive immunity including T and B lymphocytes through RA. To investigate the effects of RA on DCs of gut-associated lymphoid tissue (GALT), we analyzed the phenotype and function of DC subsets from GALT of vitamin A-deficient (VAD) mice. Method VAD mice were prepared by feeding them a VAD diet over 12 weeks from gestational days 10–14. Results Here, we report that tremendous increase of langerin + DCs occurred in the mesenteric lymph nodes (MLNs) and gut lamina propria of VAD mice dependent on CCR7 signaling. Langerin + DCs have phenotypes more similar to those of bone marrow-derived dermal langerin + DCs than epidermal Langerhans cells. Moreover, RA receptor antagonists enhance the differentiation of langerin + DCs from mouse and human precursors of bone marrow and peripheral blood. Langerin + DCs were highly differentiated but less inflammatory than langerin − DCs of MLNs of VAD mice. Moreover, tolerance to orally delivered antigen was completely abrogated by depletion of langerin + DCs in the VAD mice. Conclusions These results suggest that generation of langerin + DCs in the GALT is tightly regulated by RA and that the microenvironment of tissues determines the phenotype of DCs.

Published
2009

47. [CD3-specific antibody-induced T-cell apoptosis and apoptotic cell uptake lead to CD3-specific antibody-induced tolerance]

Author

Perruche, Sylvain, Saas, Philippe, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), and Saas, Philippe

Subjects
MESH: Cytokines, MESH: Humans, MESH: Immune Tolerance, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Inbred NOD, MESH: Dendritic Cells, MESH: Antigens, CD3, MESH: Mice, Mutant Strains, MESH: Apoptosis, MESH: Muromonab-CD3, MESH: Macrophages, MESH: Immunosuppression, MESH: T-Lymphocyte Subsets, MESH: Models, Immunological, MESH: Leukocyte Transfusion, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Diabetes Mellitus, Type 1, MESH: Mice, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2009

48. Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue

Author

David Klatzmann, Michelle Rosenzwajg, François M. Lemoine, Frédéric Charlotte, Nathalie Chaput, Armelle Bardier, Julien Taieb, Fabrice Menegaux, Samy Louafi, Jean-Christophe Vaillant, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie environnementale des cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biothérapies [CHU Pitié-Salpétrière], Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), DAM Île-de-France (DAM/DIF), Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
CD4-Positive T-Lymphocytes, Male, MESH: Neoplasm Proteins, MESH: T-Lymphocyte Subsets, Lymphocyte Activation, T-Lymphocytes, Regulatory, Interleukin 21, 0302 clinical medicine, MESH: Aged, 80 and over, T-Lymphocyte Subsets, Cytotoxic T cell, Medicine, IL-2 receptor, MESH: Lymphocytes, Tumor-Infiltrating, Aged, 80 and over, MESH: Aged, MESH: Cytokines, MESH: Middle Aged, Gastroenterology, FOXP3, MESH: CD4-Positive T-Lymphocytes, Forkhead Transcription Factors, MESH: Neoplasm Staging, Middle Aged, Neoplasm Proteins, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cytokines, Female, Colorectal Neoplasms, Adult, MESH: Immune Tolerance, MESH: Lymphocyte Count, MESH: Immunophenotyping, Regulatory T cell, T cell, chemical and pharmacologic phenomena, Adenocarcinoma, Immunophenotyping, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, MESH: Forkhead Transcription Factors, MESH: Cell Proliferation, Immune Tolerance, Humans, Neoplasm Invasiveness, Lymphocyte Count, MESH: Lymphocyte Activation, Aged, Cell Proliferation, Neoplasm Staging, MESH: Humans, business.industry, MESH: T-Lymphocytes, Regulatory, MESH: Adenocarcinoma, MESH: Adult, MESH: Neoplasm Invasiveness, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, MESH: Male, Cancer cell, Immunology, business, MESH: Female, CD8, MESH: Colorectal Neoplasms, 030215 immunology
Abstract

International audience; BACKGROUND: The antitumoral immune response is one determinant of colorectal cancer (CRC) outcome. Recent work suggests that Foxp3(+)CD25(+)CD4(+) regulatory T cells (T4reg) might hamper effective immunosurveillance of emerging cancer cells and impede effective immune responses to established tumours. In this descriptive study, we analysed blood and tissue regulatory T cell populations in patients with CRC. METHODS: Blood and tissue regulatory Foxp3(+) T cells from 40 patients with CRC were compared to regulatory Foxp3(+) T cells from normal colonic tissue and from blood of 26 healthy volunteers. Flow cytometry was used to quantify and phenotype all Foxp3(+) T cell populations. Correlations were sought with the tumour stage and with micro-invasive status. The suppressive capacity of regulatory Foxp3(+) T cells was assessed by their effect on CD4(+)CD25(-) T cell proliferation in vitro and by their capacity to inhibit cytokine production by conventional T cells. RESULTS: We found a significant increase of CD8(+)CD25(+)Foxp3(+) cells (T8reg) in blood and CRC tissue; their phenotype was close to that of T4reg. T8reg cells infiltrating CRC were activated, as suggested by increased cytoxic T lymphocyte-associated antigen-4, glucocorticoid-induced tumour necrosis factor-related protein, and transforming growth factor (TGF)beta1 expression compared to T8reg from normal autologous colonic tissue. Moreover, T8reg were able to suppress CD4(+)CD25(-) T cell proliferation and Th1 cytokine production ex vivo, demonstrating that tumour-infiltrating T8reg have strong suppressive capacities. T8reg numbers correlated with the tumour stage and with micro-invasive status. Finally, interleukin 6 and TGF beta 1 synergistically induced the generation of CD8(+)CD25(+)Foxp3(+) T cells ex vivo. CONCLUSIONS: We have identified a new regulatory T cell population (CD8(+)Foxp3(+)) in colorectal tumours. After isolation from cancer tissue these CD8(+)Foxp3(+) cells demonstrated strong immunosuppressive properties in vitro. These data suggest that these cells may contribute to tumoral immune escape and disease progression.

Published
2009

49. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy

Author

Marin, Benoît, Thiébaut, Rodolphe, Bucher, Heiner, Rondeau, Virginie, Costagliola, Dominique, Dorrucci, Maria, Hamouda, Osamah, Prins, Maria, Walker, A. Sarah, Porter, Kholoud, Sabin, Caroline, Chêne, Geneviève, Mouillet, Evelyne, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Basel Institute for Clinical Epidemiology, University Hospital Basel [Basel], Epidémiologie Clinique et Traitement de l'Infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Malattie Infettive, Reparto di Epidemiologia, Istituto Superiore di Sanita [Rome], Department of Infectious Disease Epidemiology, Robert Koch Institute [Berlin] (RKI), Cluster Infectious Diseases, Amsterdam BioMed Cluster, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Research Department of Infection and Population Health [London], and CASCADE has been funded through grants from the European Union BMH4-CT97-2550, QLK2-2000-01431, QLRT-2001-01708 and LSHP-CT-2006-018949.

Subjects
MESH: Immune Tolerance, MESH: Liver Diseases, MESH: CD4 Lymphocyte Count, CD4 cell count, MESH: Epidemiologic Methods, MESH: Antiretroviral Therapy, Highly Active, Hepatitis, MESH: Neoplasms, Causes of death, highly active, MESH: Acquired Immunodeficiency Syndrome, MESH: Adolescent, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: AIDS-Related Opportunistic Infections, MESH: Cardiovascular Diseases, MESH: Adult, Human Immunodeficiency Virus/AIDS, MESH: Male, Antiretroviral therapy, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Young Adult, Neoplasm, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Bacterial infection, MESH: Female
Abstract

International audience; OBJECTIVE: To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death in the era of combination antiretroviral therapy (cART). DESIGN: Observational multicentre cohorts. METHODS: Twenty-three cohorts of adults with estimated dates of human immunodeficiency virus (HIV) seroconversion were considered. Patients were seroconverters followed within the cART era. Measurements were latest CD4, nadir CD4 and time spent with CD4 cell count less than 350 cells/microl. Outcomes were specific causes of death using a standardized classification. RESULTS: Among 9858 patients (71 230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease accounted for 53% of non-AIDS deaths. For each 100 cells/microl increment in the latest CD4 cell count, we found a 64% (95% confidence interval 58-69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18-44%), end-stage liver disease (33, 18-46%) and non-AIDS malignancies (34, 21-45%). Non-AIDS-defining causes of death were also associated with nadir CD4 while being cART-naive or duration of exposure to immunosuppression. No relationship between risk of death from cardiovascular disease and CD4 cell count was found though there was a raised risk associated with elevated HIV RNA. CONCLUSION: In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only cardiovascular disease was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV-infected patients.

Published
2009

50. [Role of the Regulatory T lymphocytes in hepatitis C fibrosis progression]

Author

Delhem, Nadira, Cottrez, Françoise, Carpentier, Arnaud, Miroux, Céline, Moralès, Olivier, François, Violaine, Groux, Hervé, Auriault, Claude, Pancré, Véronique, Institut de Biologie de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Immunosearch, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), and Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Liver Cirrhosis, MESH : Liver Neoplasms, MESH: Interleukin-10, MESH : Cytokines, Biopsy, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, MESH : Aged, MESH : T-Lymphocytes, Helper-Inducer, Hepacivirus, T-Lymphocytes, Regulatory, MESH : Hepacivirus, MESH : T-Lymphocytes, Regulatory, MESH: Biopsy, Transforming Growth Factor beta, MESH: Liver Neoplasms, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Hepacivirus, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, MESH: Carcinoma, Hepatocellular, MESH: Antigens, CD, MESH: Aged, MESH: Cytokines, MESH: Middle Aged, MESH : Immune Tolerance, Liver Neoplasms, T-Lymphocytes, Helper-Inducer, MESH : Adult, Middle Aged, Hepatitis C, Interleukin-10, MESH: Hepatitis C, Chronic, Liver, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Disease Progression, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA Primers, MESH: Disease Progression, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH: Liver Cirrhosis, MESH : Carcinoma, Hepatocellular, Adult, MESH: DNA Primers, Carcinoma, Hepatocellular, MESH: Immune Tolerance, MESH : Hepatitis C, Chronic, Antigens, CD, MESH : Interleukin-10, MESH : Antigens, CD, Immune Tolerance, MESH : Liver Cirrhosis, Humans, MESH : Middle Aged, MESH: T-Lymphocytes, Helper-Inducer, MESH: Transforming Growth Factor beta, Aged, DNA Primers, MESH: Hepatitis C, MESH: Humans, MESH: T-Lymphocytes, Regulatory, MESH : Humans, MESH : Liver, MESH: Adult, MESH : Disease Progression, MESH : Hepatitis C, Hepatitis C, Chronic, MESH : Transforming Growth Factor beta, MESH : Biopsy, MESH: Liver
Abstract

International audience; Hepatitis C virus (HCV) becomes chronic in about 85 % of infected individuals, whereas only 15 % of infected people clear spontaneously the virus. The progression of hepatitis C to chronic status is associated to a profound down-regulation of CD4 and CD8 multispecific immune response. This immune defect may participate to the immune tolerance of VHC and consequently to its persistence. Recent findings indicate that T regulatory cells as Tr1 play an inhibitory role on T helper responses notably in the context of auto-immune or inflammatory disorders. The existence of immunosuppressive mechanisms supported by Tr1 lymphocytes and their IL-10 production represent an attractive hypothesis. We have previously evaluated the existence of regulatory T cells (Tr1) via high production of IL-10, in liver biopsies of three well-defined cohorts of HCV-1b infected patients. To this purpose, we compared liver biopsies of chronically infected patients including patients without liver lesions, with cirrhosis and with hepatocellular carcinoma (HCC). Using quantitative real time PCR, the results obtained demonstrate, an increased expression of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta)_, in liver biopsies with more severe fibrosis. This observation was correlated with an increased expression during the pathogenesis progression, of the three specific markers of the Tr1 cells sub-population, recently described and confirming the Tr1 phenotype. Evidence of regulatory T cells installation in the liver of chronically infected patient and increased frequency in cirrhosis and HCC suggest a main role of these cells in the aggravation of the liver pathology. This study should bring insight of T regulatory cell implications in VHC persistence and in the pathology progression.

Published
2008

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