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1. Age-dependent changes in tolerizability with rabbit gamma-globulin in the Biozzi high and low-responder lines of mice

Author

Katsuji Nakano, Short Papers, Brian H. Sabiston, and Bernhard Cinader

Subjects
Lipopolysaccharides, Aging, medicine.medical_specialty, Lipopolysaccharide, Immunology, Age dependent, Biology, T-Lymphocytes, Regulatory, law.invention, Mice, chemistry.chemical_compound, Immune system, law, Internal medicine, Immune Tolerance, medicine, Animals, Immunology and Allergy, B cell, Gamma globulin, Low responder, Endocrinology, medicine.anatomical_structure, Immunization, chemistry, Suppressor, Female, gamma-Globulins
Abstract

The antibody response to rabbit gamma-globulin (RGG) of high-responder, but not of low-responder Biozzi mice decreased with age. Injection with aggregate-freed RGG reduced the response of high-responder but not of low-responder mice to subsequent injections with aggregated RGG. This reduction in the antibody response, formed by high-responder mice, decreased with increasing age; aggregate-freed RGG appeared to sensitize 6-month-old low-responder mice to a subsequent injection with aggregated RGG. When animals, not pretreated with aggregate-freed RGG, were immunized with RGG and lipopolysaccharide (LPS), the immune response was greatly enhanced. The response of both pretreated low and high responders was substantially smaller than that of corresponding animals which were not given aggregate-freed RGG, prior to immunization. LPS revealed an inhibitory effect on low-responder mice of aggregate-freed RGG, which was not detected upon immunization with heat-aggregated RGG alone. The involvement of nonspecific suppressor cells and of B cell tolerance in low-responder mice is discussed.

Published
1979

2. Composition of the lymphoid cell populations from omental milky spots during the immune response in C57BL/Ka mice

Author

Robert V. Rouse, Bruno Kyewski, Short Paper, and Kazimir Dux

Subjects
B-Lymphocytes, Stromal cell, medicine.drug_class, T-Lymphocytes, Immunology, Cell, Mice, Inbred Strains, T lymphocyte, Biology, Monoclonal antibody, Mice, medicine.anatomical_structure, Lymphatic system, Immune system, Antigen, medicine, Animals, Immunology and Allergy, Cytotoxic T cell, Female, Lymphocytes, Omentum
Abstract

The lymphoid cell composition of milky spots was analyzed in unprimed mice before and after i.p. immunization with sheep red blood cells. Milky spots contained surface immunoglobulin-positive B lymphocytes, and T cells of the helper and cytotoxic phenotype. After secondary antigen challenge (a) the number of lymphocytes increased up to 40-fold, (b) B and T cells were found to segregate into distinct areas in situ, and (c) lymphocytes were found to associate with I-A-negative stromal cells in vivo. These findings qualify milky spots as a peripheral lymphoid organ exhibiting a remarkable change in number and composition of lymphocytes in response to a local antigen stimulus.

Published
1986

3. Requirement of H-2 heterozygosity for autoimmunity in (NZB × NZW)F1 hybrid mice

Author

Short Paper, Sachiko Hirose, Genjiro Ueda, Kazuo Noguchi, Takashi Okada, Iwao Sekigawa, Hidetoshi Sato, and Toshikazu Shirai

Subjects
Heterozygote, Receptors, Antigen, T-Cell, alpha-beta, Immunology, Receptors, Antigen, T-Cell, Congenic, chemical and pharmacologic phenomena, urologic and male genital diseases, medicine.disease_cause, Immunoglobulin G, Autoimmune Diseases, Autoimmunity, Pathogenesis, Loss of heterozygosity, Mice, Immune system, immune system diseases, medicine, Animals, Immunology and Allergy, skin and connective tissue diseases, Autoimmune disease, Mice, Inbred NZB, biology, H-2 Antigens, DNA, medicine.disease, Peptide Fragments, biology.protein, Hybridization, Genetic, Antibody
Abstract

In the F1 hybrid of autoimmune New Zealand Black (NZB) and phenotypically normal New Zealand White (NZW) mice, there occurs a severe systemic lupus erythematosus (SLE)-like autoimmune disease more fulminant than that found in the parental NZB mice. To determine the role of the H-2 complex in the pathogenesis of autoimmune disease of the (NZB X NZW)F1 hybrid, we developed H-2-congenic NZB (NZB.H-2z) and NZW (NZW.H-2d) strains, and compared the degree of autoimmune features between congenic H-2d/H-2d and H-2z/H-2z homozygous F1 hybrids and the original H-2d/H-2z heterozygous (NZB X NZW)F1 hybrid. We found that autoimmune features such as productions of IgG class anti-DNA antibodies and retroviral gp70 immune complexes and the development of renal disease were to a great extent reduced in both H-2 homozygous F1 hybrids, as compared with the H-2 heterozygous (NZB X NZW)F1 hybrid. It would thus appear that the heterozygosity of H-2d haplotype derived from NZB and H-2z from NZW is essential for the autoimmune disease characteristic of the (NZB X NZW)F1 hybrid.

Published
1986

4. The interplay between innate lymphoid cells and T cells

Author

Gayetri Ramachandran, Rachel Golub, Marie Cherrier, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), M.C. is supported by INSERM and Association François Aupetit dedicated to patients suffering from IBD. R.G. work is supported by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Université de Paris, and ANR project NASHILCCD8 (#18-CE15-0024-01)., We thank Serge van de Pavert for critical discussions and for review of the paper., ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Vougny, Marie-Christine, APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Context (language use), Cell Communication, Biology, Gut flora, Adaptive Immunity, Lymphocyte Activation, Substrate Specificity, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Immune system, T-Lymphocyte Subsets, Immunology and Allergy, Animals, Humans, skin and connective tissue diseases, Immunity, Cellular, Innate lymphoid cell, Cell Differentiation, Acquired immune system, biology.organism_classification, Immunity, Innate, body regions, 030104 developmental biology, Gene Expression Regulation, Host-Pathogen Interactions, [SDV.IMM]Life Sciences [q-bio]/Immunology, Neuroscience, Immunologic Memory, Function (biology), Homeostasis, Biomarkers, 030215 immunology, Signal Transduction
Abstract

International audience; ILCs and T cells are closely related functionally but they significantly differ in their ability to circulate, expand, and renew. Cooperation and reciprocal functional regulation suggest that these cell types are more complementary than simply redundant during immune responses. How ILCs shape T-cell responses is strongly dependent on the tissue and inflammatory context. Likewise, indirect regulation of ILCs by adaptive immunity is induced by environmental cues such as the gut microbiota. Here, we review shared requirements for the development and function of both cell types and divergences in the orchestration of prototypic immune functions. We discuss the diversity of functional interactions between T cells and ILCs during homeostasis and immune responses. Identifying the location and the nature of the tissue microenvironment in which these interactions are taking place may uncover the remaining mysteries of their close encounters.

Published
2020

5. Aberrant up-regulation of iNOS/NO system is correlated with an increased abundance of Foxp3+ cells and reduced effector/memory cell markers expression during colorectal cancer: immunomodulatory effects of cetuximab combined with chemotherapy

Author

Sonia Ait-Younes, Mourad Belkhelfa, Chafia Touil-Boukoffa, Yvan de Launoit, Hassen Mahfouf, Hayet Rafa, Nadira Delhem, Hayat Ait-Kaci, Olivier Moralès, Sabah Hetit, Oussama Medjeber, Sarra Benkhelifa, Said Belhadef, Mécanismes de tumorigenèse et thérapies ciblées, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), FGMGP/USTHB, Université d'Algérie, Hôpital Rouïba [Algerie], Le centre hospitalier universitaire (CHU) Mustapha Pacha [Alger], Centre Hospitalo-Universitaire de Béni-Messous, CHU Nafissa Hamoud [Hussein Dey], University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-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)-Université de Lille, Droit et Santé, They also thank the national agency of research development in health (ATRSS) which supported their project (code project: 03/06/01/10/011). They have also received support from the SIRIC ONCO Lille., The authors would like to gratefully thank all the participants involved in this study as well as the technical staff of the department of oncology (Rouiba Hospital) and Anatomic Pathology Service (Mustapha Pacha Hospital). They greatly thank Meroua BOUCHEMAL, Arezki CHEKAOUI and Dr. Kahina TOURI (USTHB, Algiers, Algeria) for all help and support of this work. Special thanks are extended to Dr. Mohamed Boudjelal and Science Edit for the Developing World for editing the English Language of the paper., Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Colorectal cancer, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MESH: Up-Regulation/physiology, MESH: Down-Regulation/drug effects, MESH: Aged, 80 and over, 0302 clinical medicine, Host immune responses, MESH: Nitric Oxide/metabolism, MESH: Colorectal Neoplasms/metabolism, Pharmacology (medical), ComputingMilieux_MISCELLANEOUS, MESH: Aged, MESH: Middle Aged, Cetuximab, MESH: Nitric Oxide Synthase Type II/metabolism, FOXP3, 3. Good health, medicine.anatomical_structure, MESH: Cetuximab/therapeutic use, iNOS/NO system, MESH: Up-Regulation/drug effects, medicine.symptom, medicine.drug, Immunology, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Immunologic Factors/metabolism, Peripheral blood mononuclear cell, Immunomodulation, 03 medical and health sciences, Immune system, MESH: Down-Regulation/physiology, medicine, MESH: Biomarkers, Tumor/metabolism, Cetuximab and chemotherapy, Colorectal Cancer, Pharmacology, Chemotherapy, MESH: Humans, business.industry, MESH: Adult, medicine.disease, MESH: Male, 030104 developmental biology, Cancer research, MESH: Colorectal Neoplasms/drug therapy, business, MESH: Female, Memory T cell, MESH: T-Lymphocytes, Regulatory/drug effects, 030217 neurology & neurosurgery, MESH: Forkhead Transcription Factors/metabolism
Abstract

International audience; Colorectal cancer (CRC) remains the most cancer type related to chronic inflammation; however, the mechanisms that link inflammation to CRC development and progression are still poorly understood. Our study aimed to investigate one of the prominent inflammatory response in cancers, iNOS/NO system. In this regard, we evaluated the link between the iNOS/NO system and CRC progression, its relation with the host immune responses and its response to cetuximab combined with chemotherapy. We found that the nitrite levels were nearly twice as high in metastatic CRC plasma and culture supernatants from PBMCs and tumor explants compared with those without metastases and healthy controls. Interestingly, we showed that the highest iNOS expression and NO levels are present in the damaged CRC tissues that have highest leukocyte infiltration. Our findings highlight the implication of iNOS/NO system in tissue alteration and leukocyte invasion. Thus, we observed imbalance between effector/memory T cell markers and Treg transcription factor (Foxp3). Accordingly, we detected higher IFNγ and T-bet expression levels in colorectal tumor tissues at early stage. In contrast, consistent with iNOS and Foxp3 expression, TGFβ, CTLA-4 and IL-10 were significantly related to the tumor stage progression. Furthermore, our study revealed that Cetuximab combined with chemotherapy treatment markedly down-regulates iNOS/NO system as well as IL-10 and TGFβ levels. Altogether, we conclude that cetuximab can potentiate the efficacy of chemotherapy, particularly by iNOS/NO system and immunosuppressive cytokines modulation. Thus, we suggest that iNOS/NO system may represent an attractive candidate biomarker for monitoring CRC progression, malignity and response to therapy.

Published
2019

6. Transcription Profiling of Monocyte-Derived Macrophages Infected In Vitro With Two Strains of Streptococcus agalactiae Reveals Candidate Pathways Affecting Subclinical Mastitis in Cattle

Author

Lewandowska-Sabat, Anna Monika, Solberg, Trygve Roger, Lewandowska-Sabat, Anna, Kirsanova, Elena, Klopp, Christophe, Solberg, Trygve, Heringstad, Bjørg, Østerås, Olav, Boysen, Preben, Olsaker, Ingrid, Norwegian University of Life Sciences (NMBU), Geno Breeding & AI Assoc, Hamar, Norway, Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Norwegian Cattle Hlth Serv, As, Norway, TINE Extens Serv, As, Norway, and This paper is a part of the 'Multimast' project (no. 233778) funded by the Research Council of Norway, Tine and Geno.

Subjects
0301 basic medicine, lcsh:QH426-470, [SDV]Life Sciences [q-bio], Biology, medicine.disease_cause, Microbiology, Streptococcus agalactiae, 03 medical and health sciences, 0302 clinical medicine, Immune system, Transcription (biology), medicine, Genetics, subclinical mastitis, Gene, Genetics (clinical), Subclinical infection, Original Research, Innate immune system, RNA sequencing, In vitro, Complement system, macrophages, pathway analysis, lcsh:Genetics, 030104 developmental biology, cattle, 030220 oncology & carcinogenesis, Molecular Medicine
Abstract

International audience; Macrophages are key cells of innate immune response and serve as the first line of defense against bacteria. Transcription profiling of bacteria-infected macrophages could provide important insights on the pathogenicity and host defense mechanisms during infection. We have examined transcription profiles of bovine monocyte-derived macrophages (bMDMs) isolated from the blood of 12 animals and infected in vitro with two strains of Streptococcus agalactiae. Illumina sequencing of RNA from 36 bMDMs cultures exposed in vitro to either one of two sequence types of S. agalactiae (ST103 or ST12) for 6 h and unchallenged controls was performed. Analyses of over 1,656 million high-quality paired-end sequence reads revealed 5,936 and 6,443 differentially expressed genes (p < 0.05) in bMDMs infected with ST103 and ST12, respectively, versus unchallenged controls. Moreover, 588 genes differentially expressed between bMDMs infected with ST103 versus ST12 were identified. Ingenuity pathway analysis of the differentially up-regulated genes in the bMDMs infected with ST103 revealed significant enrichment for granulocyte adhesion and diapedesis, while significant enrichment for the phagosome formation pathway was found among down-regulated genes. Moreover, Ingenuity pathway analysis of the differentially up-regulated genes in the bMDMs infected with ST12 showed significant enrichment for type 1/type 2 T helper cell activation, while the complement activation pathway was overrepresented in the down-regulated genes. Our study identified pathogen-induced regulation of key genes and pathways involved in the immune response of macrophages against infection but also likely involved in bacterial evasion of the host immune system. These results may contribute to better understanding of the mechanisms underlying subclinical infection such as bovine streptococcal mastitis.

Published
2019
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7. The antibody/microbiota interface in health and disease

Author

Emma Slack, Delphine Sterlin, Guy Gorochov, Jehane Fadlallah, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7), Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie ((EA_3518)), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), D.S. was supported for this work by a Pasteur/APHP interface fellowship, We thank members of the Gorochov and Slack labs for discussions and H. Yssel for critical reading of the paper., CHU Pitié-Salpêtrière [APHP], Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Immunoglobulin A, Immunology, Disease, Biology, Gut flora, digestive system, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Immunology and Allergy, Animals, Homeostasis, Humans, Intestinal Mucosa, Symbiosis, Immunity, Mucosal, Host Microbial Interactions, Compartmentalization (psychology), biology.organism_classification, 3. Good health, Gastrointestinal Microbiome, 030104 developmental biology, Immunoglobulin A, Secretory, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Function (biology), 030215 immunology
Abstract

International audience; The human intestine is densely colonized with commensal microbes that stimulate the immune system. While secretory Immunoglobulin (Ig) A is known to play a crucial role in gut microbiota compartmentalization, secretory IgM, and systemic IgG have recently been highlighted in host-microbiota interactions as well. In this review, we discuss important aspects of secretory IgA biology, but rather than focusing on mechanistic aspects of IgA impact on microbiota, we stress the current knowledge of systemic antibody responses to whole gut microbiota, in particular their generation, specificities, and function. We also provide a comprehensive picture of secretory IgM biology. Finally, therapeutic and diagnostic implications of these novel findings for the treatment of various diseases are outlined.

Published
2019

8. Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii

Author

Laetitia Petit-Jentreau, Ludovic Tailleux, Janine L. Coombes, University of Liverpool, Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris] (IP), Génétique mycobactérienne - Mycobacterial genetics, The present work was supported by the University of Liverpool. JLC is a lecturer at the University of Liverpool, UK, LT is a researcher at Institut Pasteur, France, and LP-J is a postdoctoral researcher on the JLC's Biotechnology and Biological Sciences Research Council (BBSRC) grant (BB/M023540/1) at the University of Liverpool, UK., LP-J wrote the paper with input from LT and JLC. All authors revised the manuscript, and approved it for publication., and Institut Pasteur [Paris]

Subjects
0301 basic medicine, Microbiology (medical), Immunology, lcsh:QR1-502, Toxoplasma gondii, Microbiology, lcsh:Microbiology, 03 medical and health sciences, Immune system, Purinergic Agents, Macrophage, innate immunity, Innate immune system, biology, Intracellular parasite, Purinergic receptor, Mycobacterium tuberculosis, biology.organism_classification, purinergic agents, nucleotides, 3. Good health, macrophages, ATP, 030104 developmental biology, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Intracellular
Abstract

International audience; Immune responses are essential for the protection of the host against external dangers or infections and are normally efficient in the clearance of invading microbes. However, some intracellular pathogens have developed strategies to replicate and survive within host cells resulting in latent infection associated with strong inflammation. This excessive response can cause cell and tissue damage and lead to the release of the intracellular content, in particular the nucleotide pool, into the extracellular space. Over the last decade, new studies have implicated metabolites from the purinergic pathway in shaping the host immune response against intracellular pathogens and proved their importance in the outcome of the infection. This review aims to summarize how the immune system employs the purinergic system either to fight the pathogen, or to control collateral tissue damage. This will be achieved by focusing on the macrophage response against two intracellular pathogens, the human etiologic agent of tuberculosis, Mycobacterium tuberculosis and the protozoan parasite, Toxoplasma gondii.

Published
2017
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9. Standardized whole blood stimulation improves immunomonitoring of induced immune responses in multi-center study

Author

Alain Savenay, Matthew L. Albert, Delphine Louis, Manfred Schmolz, Nina Salabert-Le Guen, Olivier Lantz, Régis Josien, Darragh Duffy, Françoise Mascart, Antoine Toubert, Marie Noelle Ungeheuer, Vincent Rouilly, Raouf Djebali, Lydia Redjah, José J.G. Ruiz de Morales, Catherine Ottone, Véronique Corbière, Eva Martínez-Cáceres, Cécile Braudeau, Samuel S.T. LaBrie, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Laboratoire d’Immunologie, Centre d’Immunomonitorage Nantes Atlantique (CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), laboratoire de vaccinologie et immunité mucosale, Université Libre de Bruxelles [Bruxelles] (ULB), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Myriad RBM, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospital Universitari Germans Trias I Pujol, Immunobiology Clinic, Hôpital Erasme, Complejo Asistencial Universitario de León, Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), HOT Screen GmbH, Genentech, Inc. [San Francisco], TruCulture tubes, stimuli, and protein Luminex XMAP analysis were provided by Myriad RBM, Inc (Austin, USA) and TruCulture tubes were manufactured at HOT Screen (Reutlingen, Germany). Donor recruitment costs were covered by each participating FOCIS center of excellence. Author contributions: DD, VR, VC, SL, OL, EMC, RP, MS, AT & MLA designed the study. CB, RD, MNU, DL, FM, JGRM, CO, LR, AS performed experiments. DD, VR, & MLA performed analysis and wrote the paper. All authors reviewed the manuscript., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Université libre de Bruxelles (ULB), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Translationnelle ( CRT ), Centre Hospitalier Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie ( U1064 Inserm - CRTI - CHU Nantes ), Université de Nantes ( UN ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Alloimmunité-Autoimmunité-Transplantation ( A2T ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
0301 basic medicine, Lipopolysaccharides, Whole blood stimulation, CD3 Complex, medicine.medical_treatment, CD8 Antigens, Point-of-Care Systems, Immunology, Stimulation, Blood Donors, Immunologic Tests, Peripheral blood mononuclear cell, Antibodies, Functional immune responses, 03 medical and health sciences, Immune system, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Humans, Whole blood, biology, business.industry, Immunotherapy, Multi-center clinical studies, 3. Good health, Vaccination, Immunomonitoring, 030104 developmental biology, Gene Expression Regulation, PBMCs, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Antibody, business, Biomarkers
Abstract

Functional immune responses are increasingly important for clinical studies, providing in depth biomarker information to assess immunotherapy or vaccination. Incorporating functional immune assays into routine clinical practice has remained limited due to challenges in standardizing sample preparation. We recently described the use of a whole blood syringe-based system, TruCulture (R), which permits point-of-care standardized immune stimulation. Here, we report on a multi-center clinical study in seven FOCIS Centers of Excellence to directly compare TruCulture to conventional PBMC methods. Whole blood and PBMC5 from healthy donors were exposed to LPS, anti-CD3 anti-CD28 antibodies, or media alone. 55 protein analytes were analyzed centrally by Luminex multi-analyte profiling in a CLIA-certified laboratory. TruCulture responses showed greater reproducibility and improved the statistical power for monitoring differential immune response activation. The use of TruCulture addresses a major unmet need through a robust and flexible method for immunomonitoring that can be reproducibly applied in multi-center clinical studies. One sentence summary: A multi-center study revealed greater reproducibility from whole blood stimulation systems as compared to PBMC stimulation for studying induced immune responses. (C) 2017 Published by Elsevier Inc.

Published
2017

10. Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents

Author

Zahra Sharifzadeh, S. Moein Moghimi, Fatemeh Rahbarizadeh, Davoud Ahmadvand, Mohammad Ali Shokrgozar, Fereidoun Mahboudi, Fatemeh Rahimi Jamnani, Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP), Department of Medical Biotechnology, Tarbiat Modares University [Tehran]-Faculty of Medical Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Biotechnology Research Center, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Nano-Science Center [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU), Nanomedicine Laboratory, Centre of Pharmaceutical Nanotechnology and Nanotoxicology-University of Copenhagen = Københavns Universitet (KU), and This paper was supported by Pasteur Institute of Iran, Tehran, Iran, the Biotechnology Committee of Tarbiat Modares University (TMU-88-8-67), Tehran, Iran and from the Danish Agency for Science, Technology and Innovative (det Strategiske Forskningsråd) reference 09-065746/DSF to SMM.

Subjects
Cancer Research, Leukemia, T-Cell, medicine.medical_treatment, T cell, Recombinant Fusion Proteins, T-Lymphocytes, Biology, Lymphocyte Activation, Transfection, Immunotherapy, Adoptive, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Antibody Specificity, Antigens, Neoplasm, Peptide Library, medicine, Animals, Humans, Chimeric antigen receptor, 030304 developmental biology, Glycoproteins, 0303 health sciences, Immunogenicity, CD28, Immunotherapy, Single-Domain Antibodies, Molecular biology, 3. Good health, Cell biology, Oligoclonal single domain antibodies, Receptors, Antigen, medicine.anatomical_structure, Oncology, TAG-72, 030220 oncology & carcinogenesis, Immunoglobulin G, Colonic Neoplasms, biology.protein, Carcinoma, Squamous Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Genetic Engineering, Camelids, New World, HT29 Cells, Signal Transduction
Abstract

International audience; Despite the preclinical success of adoptive therapy with T cells bearing chimeric nanoconstructed antigen receptors (CARs), certain limitations of this therapeutic approach such as the immunogenicity of the antigen binding domain, the emergence of tumor cell escape variants and the blocking capacity of soluble antigen still remain. Here, we address these issues using a novel CAR binding moiety based on the oligoclonal camelid single domain antibodies. A unique set of 13 single domain antibodies were selected from an immunized camel phage library based on their target specificity and binding affinity. A combination of these single domain antibodies was used to generate four tumor associated glycoprotein (TAG-72)-specific CARs harboring an identical antigen binding site, but with different signaling and spacer domains. Although all four CARs were functionally active against the TAG-72 expressing tumor cells, the combination of CD3ζ, OX40, CD28 as well as the CH3-CH2-hinge-hinge domains most efficiently triggered T cell activation. Importantly, CAR mediated functions were not blocked by the soluble TAG-72 antigen at a supraphysiological concentration. Our approach may have the potential to reverse multiple tumor immune evasion mechanisms, avoid CAR immunogenicity, and overcome problems in cancer gene therapy with engineered nanoconstructs.

Published
2012