Author: "Cédric Ménard" - Searchworks@Jio Institute Digital Library Search Results

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1. Pulmonary fibrosis in patients with autoimmune pulmonary alveolar proteinosis: a retrospective nationwide cohort study

Author: Yoann Guirriec, David Luque-Paz, Gontran Bernard, Axelle Mabo, Mallorie Kerjouan, Cédric Ménard, Delphine Monnier, Hilario Nunes, Yurdagül Uzunhan, Martine Reynaud-Gaubert, Julien Bermudez, Raphaël Borie, Bruno Crestani, Julie Traclet, Lidwine Wémeau-Stervinou, Cécile Chenivesse, Emmanuel Gomez, Grégoire Prévot, Arnaud Bourdin, Benjamin Bondue, Anne Bergeron, Vincent Cottin, Mathieu Lederlin, and Stéphane Jouneau
Subjects: Medicine
Abstract: Background Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease that may progress towards pulmonary fibrosis. Data about fibrosis prevalence and risk factors are lacking. Methods In this retrospective multicentre nationwide cohort, we included patients newly diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected from medical records using a standardised questionnaire. Results 61 patients were included in the final analysis. We identified 5 patients (8%) with fibrosis on initial computed tomography (CT) and 16 patients (26%) with fibrosis on final CT after a median time of 3.6 years. Dust exposure was associated with pulmonary fibrosis occurrence (OR 4.3; p=0.038). aPAP patients treated with whole-lung lavage, rituximab or granulocyte–monocyte colony-stimulating factor therapy did not have more fibrotic evolution than patients who did not receive these treatments (n=25 out of 45, 57% versus n=10 out of 16, 62%; p=0.69). All-cause mortality was significantly higher in fibrotic than in nonfibrotic cases (n=4 out of 16, 25% versus n=2 out of 45, 4.4%; p=0.036, respectively). Conclusion In our population, a quarter of aPAP patients progressed towards pulmonary fibrosis. Dust exposure seems to be an important factor associated with this complication. More studies are needed to analyse precisely the impact of dust exposure impact, especially silica, in patients with aPAP.
Published: 2024
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2. Regulatory B Cells Contribute to the Clinical Response After Bone Marrow-Derived Mesenchymal Stromal Cell Infusion in Patients With Systemic Sclerosis

Author: Séverine Loisel, Pauline Lansiaux, Delphine Rossille, Cédric Ménard, Joëlle Dulong, Céline Monvoisin, Nadège Bescher, Isabelle Bézier, Maëlle Latour, Audrey Cras, Dominique Farge, Karin Tarte, CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie (URP_3518), McGill University = Université McGill [Montréal, Canada], and AOM 11â€'250, National Hospital Clinical Research Program
Subjects: immune monitoring, systemic sclerosis, [SDV]Life Sciences [q-bio], clinical trial, Breg, Cell Biology, General Medicine, mesenchymal stromal cells, Developmental Biology
Abstract: Mesenchymal stromal cells (MSCs) have recently emerged as an interesting therapeutic approach for patients with progressive systemic sclerosis (SSc), a rare and life-threatening orphan autoimmune disease. Whereas MSC immunomodulatory potential is considered as a central mechanism for their clinical benefit, very few data are available on the impact of MSCs on immune cell subsets in vivo. In the current extended study of a phase I/II clinical trial exploring the injection of a single dose of allogeneic bone marrow-MSCs (alloBM-MSCs) in patients with severe SSc (NCT02213705), we performed a longitudinal in-depth characterization of circulating immune cells in 19 MSC-treated patients, including 14 responders and 5 non-responders. By a combination of flow cytometry and transcriptomic analyses, we highlighted an increase in circulating CD24hiCD27posCD38lo/neg memory B cells, the main IL-10-producing regulatory B cell (Breg) subset, and an upregulation of IL10 expression in ex-vivo purified B cells, specifically in responder patients, early after the alloBM-MSC infusion. In addition, a deeper alteration of the B-cell compartment before alloBM-MSC treatment, including a higher expression of profibrotic cytokines IL6 and TGFβ by sorted B cells was associated with a non-responder clinical status. Finally, BM-MSCs were able to directly upregulate IL-10 production in activated B cells in vitro. These data suggest that cytokine-producing B cells, in particular Breg, are pivotal effectors of BM-MSC therapeutic activity in SSc. Their quantification as activity biomarkers in MSC potency assays and patient selection criteria may be considered to reach optimal clinical benefit when designing MSC-based clinical trials.
Published: 2023
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3. Lenalidomide triggers T-cell effector functions in vivo in patients with follicular lymphoma

Author: Nadège Bescher, Maelle Latour, Roch Houot, Isabelle Bezier, Joelle Dulong, Myriam Chouteau, Delphine Rossille, Thierry Fest, Cédric Ménard, Karin Tarte, Ilenia Papa, Franck Morschhauser, Tien-Tuan Nguyen, CHU Pontchaillou [Rennes], 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 ), CHU Lille, Jonchère, Laurent, 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: obinutuzumab, Lymphoma, B-Cell, Immunobiology and Immunotherapy, T cell, lenalidomide, Follicular lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunomodulation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, follicular lymphoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, Obinutuzumab, In vivo, medicine, Humans, Lymphoma, Follicular, t-lymphocytes, B cell, 030304 developmental biology, Lenalidomide, 0303 health sciences, Lymphoid Neoplasia, business.industry, Hematology, medicine.disease, 3. Good health, Lymphoma, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cancer research, business, Ex vivo, medicine.drug
Abstract: The immunomodulatory drug lenalidomide is used in patients with follicular lymphoma (FL) with the aim of stimulating T-cell antitumor immune response. However, little is known about the effects of lenalidomide on T-cell biology in vivo in patients with FL. We thus undertook an extensive longitudinal immunologic study, including phenotypic, transcriptomic, and functional analyses, on 44 first-line and 27 relapsed/refractory patients enrolled in the GALEN trial (Obinutuzumab Combined With Lenalidomide for Relapsed or Refractory Follicular B-Cell Lymphoma) to test the efficacy of lenalidomide and obinutuzumab combination in patients with FL. Lenalidomide rapidly and transiently induced an activated T-cell phenotype, including HLA-DR, Tim-3, CD137, and programmed cell death protein 1 (PD-1) upregulation. Furthermore, sequential RNA-sequencing of sorted PD-1+ and PD-1– T-cell subsets revealed that lenalidomide triggered a strong enrichment for several gene signatures related to effector memory T-cell features, including proliferation, antigen receptor signaling, and immune synapse restoration; all were validated at the phenotypic level and with ex vivo functional assays. Correlative analyses pinpointed a negative clinical impact of high effector T-cell and regulatory T-cell percentages before and during treatment. Our findings bring new insight in lenalidomide mechanisms of action at work in vivo and will fuel a new rationale for the design of combination therapies.
Published: 2021
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4. Immunomonitoring et thérapie cellulaire : l’exemple des patients traités par cellules stromales mésenchymateuses

Author: Cédric Ménard
Subjects: 0301 basic medicine, 03 medical and health sciences, Medical Laboratory Technology, 030104 developmental biology, Biochemistry (medical), Analytical Chemistry
Abstract: Resume Les proprietes immunomodulatrices et anti-inflammatoires des cellules stromales mesenchymateuses sont la base de nombreux essais cliniques dans le monde entier. Un probleme majeur au developpement de cette therapie cellulaire est l’incapacite de predire la reponse ou l’echappement a ce type de traitement couteux. Grâce a l’utilisation combinee de techniques d’analyses transcriptomiques, proteomiques ou fonctionnelles menees sur du sang voire des biopsies tissulaires, il est possible de monitorer aux differentes etapes du traitement les modifications induites par la therapie sur une grande palette de parametres immunologiques. Ce type d’immunomonitoring pousse et standardise permettra, en lien avec l’analyse de la reponse clinique, de degager des biomarqueurs d’efficacite pertinents.
Published: 2018
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5. Integrated Transcriptomic, Phenotypic, and Functional Study Reveals Tissue-Specific Immune Properties of Mesenchymal Stromal Cells

Author: Philippe Collas, Nadège Bescher, Erwan Flecher, Karin Tarte, Joelle Dulong, Benjamin Hébraud, David Roulois, Louis Casteilla, Céline Monvoisin, Léa Verdière, Mélanie Gadelorge, Céline Pangault, Cédric Ménard, Vonick Sibut, Luc Sensebé, Philippe Bourin, Nicolas Espagnolle, Nicolas Bertheuil, Isabelle Bezier, 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), Etablissement français du sang [Rennes] (EFS Bretagne), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), 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 ), Microenvironnement et cancer (MiCa), Recherches Avicoles (SRA), Institut National de la Recherche Agronomique (INRA), Laboratoire de Thérapie Cellulaire, EFS, Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut d'Electronique et de Télécommunications de Rennes (IETR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-SUPELEC-Centre National de la Recherche Scientifique (CNRS), STROMALab, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Akershus University Hospital [Lørenskog], Laboratoire de thérapie cellulaire (EFS), Etablissement Français du Sang, ANR-10-IBHU_0005, Agence Nationale de la Recherche, APR 2016, Etablissement Français du Sang, INCa PLBIO-17-219, Institut National Du Cancer, Appel d'offre local 2008, CHU Toulouse, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], Centre National de la Recherche Scientifique (CNRS)-Ecole Supérieure d'Electricité - SUPELEC (FRANCE)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Supérieure d'Electricité - SUPELEC (FRANCE)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Ménard, Cédric, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Karin, UMR U1236 MICMAC, Cell, Philippe, Adipose tissue, 0302 clinical medicine, Gene expression, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, INSERM, Bone marrow stromal cells (BMSCs), Etablissement Français du Sang, CSA21, Cell Differentiation, Middle Aged, Phenotype, Immunogenicity, Cell interactions Journal Section: Translational and Clinical Research Cell Types: Bone Marrow Stem Cells, Cell biology, medicine.anatomical_structure, CHU Rennes Keywords: adipose stem cells, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, STROMALAB Tarte, Adult, Stromal cell, Nicolas, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adipose Stem Cells/VSF, Biology, Young Adult, 03 medical and health sciences, Immune system, medicine, Humans, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, Direction Espagnolle, Université Rennes 1, 030104 developmental biology, SITI Laboratory, Bone marrow, Transcriptome, 030217 neurology & neurosurgery, Immunosuppression, Developmental Biology
Abstract: Clinical-grade mesenchymal stromal cells (MSCs) can be expanded from bone marrow and adipose tissue to treat inflammatory diseases and degenerative disorders. However, the influence of their tissue of origin on their functional properties, including their immunosuppressive activity, remains unsolved. In this study, we produced paired bone marrow-derived mesenchymal stromal cell (BM-MSC) and adipose-derived stromal cell (ASC) batches from 14 healthy donors. We then compared them using transcriptomic, phenotypic, and functional analyses and validated our results on purified native MSCs to infer which differences were really endowed by tissue of origin. Cultured MSCs segregated together owing to their tissue of origin based on their gene expression profile analyzed using differential expression and weighted gene coexpression network analysis. This translated into distinct immune-related gene signatures, phenotypes, and functional cell interactions. Importantly, sorted native BM-MSCs and ASCs essentially displayed the same distinctive patterns than their in vitro-expanded counterparts. As a whole, ASCs exhibited an immune profile consistent with a stronger inhibition of immune response and a lower immunogenicity, supporting the use of adipose tissue as a valuable source for clinical applications.
Published: 2020
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6. Pulmonary alveolar proteinosis

Author: Mathieu Lederlin, Cédric Ménard, Stéphane Jouneau, Jonchère, Laurent, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Laboratoire Traitement du Signal et de l'Image (LTSI), 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 )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, pulmonary alveolar proteinosis, Cryptococcus, Lung biopsy, Gastroenterology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, rituximab, Internal medicine, Humans, Medicine, 030212 general & internal medicine, Lung, [SDV.IB] Life Sciences [q-bio]/Bioengineering, biology, Inhalation, business.industry, whole lung lavage, Nocardia, biology.organism_classification, medicine.disease, female genital diseases and pregnancy complications, infection, 3. Good health, 030228 respiratory system, granulocyte-macrophage colony-stimulating factor, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Rituximab, Plasmapheresis, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Tomography, X-Ray Computed, business, Pulmonary alveolar proteinosis, Actinomyces, medicine.drug
Abstract: International audience; PAP is an ultra-rare disease in which surfactant components, that impair gas exchange, accumulate in the alveolae. There are three types of PAP. The most frequent form, primary PAP, includes autoimmune PAP which accounts for over 90% of all PAP, defined by the presence of circulating anti-GM-CSF antibodies. Secondary PAP is mainly due to haematological disease, infections or inhaling toxic substances, while genetic PAP affects almost exclusively children. PAP is suspected if investigation for ILD reveals a crazy-paving pattern on chest CT scan, and is confirmed by a milky looking BAL that gives a positive PAS reaction indicating extracellular proteinaceous material. PAP is now rarely confirmed by surgical lung biopsy. WLL is still the first-line treatment, with an inhaled GM-CSF as second-line treatment. Inhalation has been found to be better than subcutaneous injections. Other treatments, such as rituximab or plasmapheresis, seem to be less efficient or ineffective. The main complications of PAP are due to infections by standard pathogens (Streptococcus, Haemophilus and Enterobacteria) or opportunistic pathogens such as mycobacteria, Nocardia, Actinomyces, Aspergillus or Cryptococcus. The clinical course of PAP is unpredictable and spontaneous improvement can occur. The 5-year actuarial survival rate is 95%.
Published: 2020
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7. Adipose mesenchymal stromal cells Definition, immunomodulatory properties, mechanical isolation and interest for plastic surgery

Author: Benoit Chaput, Eric Watier, Cédric Ménard, Audrey Varin, Karin Tarte, Jérôme Laloze, Nicolas Bertheuil, 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 ), STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), 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 ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier
Subjects: medicine.medical_specialty, Adipose stromal cells, Nanofat grafting, Adipose tissue, Tissu adipeux, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030230 surgery, Mesenchymal Stem Cell Transplantation, Regenerative Medicine, Regenerative medicine, Immunomodulation, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Fat grafting, Humans, Medicine, business.industry, Mesenchymal stem cell, Mesenchymal Stem Cells, Immunomodulatory properties, Stromal vascular fraction, Clinical routine, Adipose stem cells, 3. Good health, Plastic surgery, Adipose Tissue, Cellules souches, Cancer research, Surgery, business, Cellules stromales mésenchymateuses du tissu adipeux
Abstract: International audience; Ever since their discovery in 2001, adipose mesenchymal stromal cells (ASC) have profoundly modified clinical indications and our practice of plastic surgery, thereby placing our discipline at the forefront of regenerative medicine. These cells act through paracrine signaling by synthesizing immunosuppressive and pro-angiogenic factors. They are of key importance with regard to the regenerative properties of autologously grafted adipose tissue (AT). Taken together, they make up the stromal vascular fraction (SVF) comprising all AT cells except for adipocytes. As our knowledge evolves, we are moving from fat grafting towards SVF grafting, of which the essential sought-after effect is tissue regeneration. The objective of the present review is to synthesize present-day information on ASCs and their immunomodulatory properties and, from a practical standpoint, to indicate present-day and future steps towards establishment of clinical routine, particularly through application of techniques favoring mechanical digestion of adipose tissue.
Published: 2019
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8. Biomarqueurs prédictifs de réponse aux inhibiteurs de points de contrôle immuns [Predictive biomarkers of response to immune checkpoint inhibitors.]

Author: Alexandra Lespagnol, Cédric Ménard, Romain Corre, Karin Tarte, Samuel Le Sourd, Jean Mosser, Marc Pracht, Julien Edeline, Alexandra Frelau, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), 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 ), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], CRLCC Eugène Marquis (CRLCC), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CRLCC Eugène Marquis ( CRLCC ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), 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 ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Foie, métabolismes et cancer, 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 ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'oncologie médicale, Molecular Engines Laboratories (MEL), Molecular Engines Laboratories, Microenvironnement et cancer (MiCa), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_treatment, Immunothérapie, [SDV.CAN]Life Sciences [q-bio]/Cancer, PD-L1 expression, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Biopsy, Medicine, Radiology, Nuclear Medicine and imaging, Neutrophil to lymphocyte ratio, ComputingMilieux_MISCELLANEOUS, Biomarqueurs, Anti-PD1, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, medicine.diagnostic_test, [ SDV ] Life Sciences [q-bio], business.industry, Hematology, General Medicine, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Expression de PD-L1, Primary tumor, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Biomarker (medicine), Antibody, business, PD-1 blockades, Biomarkers
Abstract: International audience; Les anti-PD-1 s’imposent dernièrement comme un traitement de référence dans de nombreux cancers métastatiques. Ils présentent l’avantage d’une efficacité significative doublée d’un profil de toxicité favorable en monothérapie. Les taux et durées de réponse sont toutefois très variables, ce qui implique, vu leur coût, d’identifier des biomarqueurs prédictifs de réponse. Dans cette revue de la littérature, nous nous intéressons aux biomarqueurs de réponse des immunothérapies anti-PD1 et anti-CTLA-4. L’expression de PD-L1 par les cellules tumorales et du micro-environnement évaluée par immunohistochimie est prédictive de réponse pour certains cancers mais reste une approche mal standardisée avec différents anticorps, différents seuils de positivité et différentes cibles (tumeur ou micro-environnement). Il s’agit aussi d’une expression dynamique au cours du temps et hétérogène donc souvent discordante entre biopsies et pièces opératoires. Les lymphocytes circulants pourraient représenter un biomarqueur prédictif notamment via la mesure du ratio polynucléaires neutrophiles sur lymphocytes (NLR), ratio simple à réaliser en pratique courante. Un taux de néoantigènes élevé serait également associé à une réponse plus importante ce qui expliquerait les taux de réponses particulièrement élevés des tumeurs avec instabilité micro-satellitaire. Des signatures génomiques pourraient également prédire la sensibilité aux anti-PD1. Par ailleurs, la présence de certaines bactéries de la flore intestinale favoriserait la réponse immunitaire antitumorale même si le mécanisme demeure mal compris. Enfin, des signatures d’expression de cytokines, médiatrices de la réponse immune, pourraient constituer des biomarqueurs pertinents. Plusieurs biomarqueurs de réponse potentiels semblent donc intéressants mais aucun n’est encore prospectivement validé à ce jour.
Published: 2018
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9. An open-label phase 1b study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma

Author: Franck Morschhauser, Hervé Tilly, Cédric Ménard, Bettina Fabiani, Roch Houot, Catherine Thieblemont, Krimo Bouabdallah, Karin Tarte, Gilles Salles, Steven Le Gouill, Guillaume Cartron, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pontchaillou [Rennes], 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 ), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie [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), Université de Rennes 1 (UR1), 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 ), and Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Subjects: Adult, Male, medicine.medical_specialty, Lymphoma, B-Cell, Maximum Tolerated Dose, Clinical Trials and Observations, Immunology, Follicular lymphoma, Administration, Oral, Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neutropenia, Antibodies, Monoclonal, Humanized, Biochemistry, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, Refractory, Obinutuzumab, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lenalidomide, Lymphoma, Follicular, Aged, Aged, 80 and over, business.industry, Cell Biology, Hematology, Middle Aged, medicine.disease, 3. Good health, Lymphoma, chemistry, 030220 oncology & carcinogenesis, Rituximab, Female, Neoplasm Recurrence, Local, business, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract: International audience; Obinutuzumab is a type II anti-CD20 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity better than rituximab. Given promising results with lenalidomide and rituximab, this phase 1b study assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN). Patients age ≥18 years with relapsed or refractory (R/R) follicular lymphoma (FL) after rituximab-containing therapy received escalating doses (10 [n = 7], 15 [n = 3], 20 [n = 6], and 25 mg [n = 3]) of daily oral lenalidomide on days 1 to 21 of cycle 1 and on days 2 to 22 of cycles 2 to 6 (28-day cycles). Obinutuzumab 1000 mg IV was administered on days 8, 15, and 22 (cycle 1) and on day 1 (cycles 2-6). Dose was escalated in a 3 + 3 design based on dose-limiting toxicity (DLT) during cycle 1 to establish the maximum tolerated dose (MTD). We observed 164 adverse events (AEs), of which 139 were grade 1/2. The most common AEs were constipation (52.6%), neutropenia (47.4%), and asthenia (36.8%); 64.3% (9 of 14) of the grade 3/4 AEs were neutropenia/neutrophil decrease, but without any febrile neutropenia. Four DLTs occurred in 2 patients, all deemed unrelated to treatment. MTD was not reached. Twelve patients (63.2%) responded: 8 complete, 3 unconfirmed complete, and 1 partial response. Oral lenalidomide plus obinutuzumab is well tolerated and effective in R/R FL. The recommended dose of lenalidomide was established at 20 mg based on the risk of grade 3/4 neutropenia from cycle 2. This trial was registered at www.clinicaltrials.gov as #NCT01582776.
Published: 2018
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10. NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment

Author: Franck Morschhauser, Cédric Ménard, Karin Tarte, Catherine Alexia, Dang-Nghiem Vo, Nerea Allende-Vega, Guillaume Cartron, Martin Villalba, Roch Houot, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Lapeyronie [Montpellier] (CHU), Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), 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 ), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Bio_GALEN, GALEN study, DNV, Ministére de l'Enseignement Superior et de la Recherche France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and 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 )
Subjects: 0301 basic medicine, lcsh:Immunologic diseases. Allergy, obinutuzumab, Immunology, Cell, lenalidomide, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, chemistry.chemical_compound, Obinutuzumab, medicine, Immunology and Allergy, Cytotoxic T cell, NK cell, Original Research, Lenalidomide, Antibody-dependent cell-mediated cytotoxicity, CD20, biology, business.industry, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Lymphoma, 030104 developmental biology, medicine.anatomical_structure, diffuse large B-cell lymphoma (DLBCL), Oncology, chemistry, follicular lymphoma (FL), biology.protein, Cancer research, Rituximab, business, lcsh:RC581-607, medicine.drug
Abstract: International audience; Obinutuzumab (OBZ) shows stronger antibody-dependent cell cytotoxicity (ADCC) compared to rituximab and improved clinical activity for treating certain CD20 neoplasia. However, the efficacy of monoclonal antibody (mAb) as a monotherapy is limited. Natural Killer (NK) cells are mediators of ADCC. Hematological cancer patients possess antitumor NK cells that are unable to control disease, possibly because they are dysfunctional. The immunomodulatory drug lenalidomide (LEN) could be a treatment to restore exhausted NK cell cytotoxic functions. The clinical trial GALEN is a Phase Ib/II study of OBZ combined with LEN for the treatment of relapsed/refractory follicular and aggressive (DLBCL and MCL) B-cell Lymphoma. During treatment, we analyzed specific aspects of NK cell biology. Treatment reversed the immature NK phenotype of patients and increased expression of NK activating receptors. Inhibitory receptors were either unchanged or decreased. There was a strong NK response at the end of the 1st cycle NK number and intracellular granzyme B (GrzB) expression decreased, degranulation increased and NK responded better to allogeneic target challenge. Moreover, the interaction of NK cells with B cell targets, measured by trogocytosis, decreased during treatment. At the end of treatment, when target cells had been wiped out, the proportion of reactive NK cells (CD69, CD45RARO, CD107a, CD19) strongly decreased. Because all patients received LEN and OBZ, it was uncertain which drug was responsible of our observations, or even if a combination of both products was necessary for the described effects on this lymphocyte lineage.
Published: 2018
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11. Liposuction Preserves the Morphological Integrity of the Microvascular Network: Flow Cytometry and Confocal Microscopy Evidence in a Controlled Study

Author: Cédric Ménard, Eric Watier, Benoit Chaput, Jean-Louis Grolleau, Frédéric Mourcin, Karin Tarte, Audrey Varin, Sandra Berger-Müller, Ignacio Garrido, Nicolas Bertheuil, Luc Sensebé, Service de chirurgie plastique, reconstructive et esthétique [Rennes] = Cosmetic Reconstructive and Plastic surgery [Rennes], CHU Pontchaillou [Rennes], EFS, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 Bretagne, Service de Chirurgie Plastique, Chirurgie plastique, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de Chirurgie Oncologique, Institut Claudius Regaud, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IBHU-0005, European Center for Transplantation Sciences and Immunotherapy, Médaille d'or from Rennes University Hospital, ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Service de chirurgie plastique, reconstructive et esthétique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), 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 ), Service Chirurgie plastique - brûlés [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, CD31, medicine.medical_specialty, Pathology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Urology, Adipose tissue, 030230 surgery, Flow cytometry, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Lipectomy, Confocal microscopy, law, Adipocyte, Adipocytes, medicine, Humans, Microscopy, Confocal, medicine.diagnostic_test, business.industry, Abdominoplasty, Endothelial Cells, General Medicine, Middle Aged, Flow Cytometry, Plastic surgery, Microvascular Network, Adipose Tissue, chemistry, 030220 oncology & carcinogenesis, Liposuction, Microvessels, Female, Surgery, business
Abstract: International audience; BACKGROUND: Liposuction is a very popular technique in plastic surgery that allows for the taking adipose tissue (AT) on large surfaces with little risk of morbidity. Although liposuction was previously shown to preserve large perforator vessels, little is known about the effects of liposuction on the microvasculature network. OBJECTIVES: The aim of this study was to analyze the effect of liposuction on the preservation of microvessels at tissue and cellular levels by flow cytometry and confocal microscopy following abdominoplasty procedure. METHODS: Percentage of endothelial cells in AT from liposuction and en bloc AT was determined by multicolor flow cytometry. Moreover, vessel density and adipocyte content were analyzed in situ in 3 different types of AT (en bloc, from liposuction, and residual AT after liposuction) by confocal microscopy. RESULTS: Flow cytometric analysis showed that en bloc AT contained 30.6% ± 12.9% and AT from liposuction 21.6% ± 9.9% of endothelial cells (CD31(pos)/CD45(neg)/CD235a(neg)/CD11b(neg)) (P = .009). Moreover, analysis of paired AT from the same patients (n = 5) confirmed a lower percentage of endothelial cells in AT from liposuction compared to en bloc AT (17.7% ± 4.5% vs 21.9% ± 3.3%, P = .031). Likewise, confocal microscopy showed that en bloc AT contained 8.2% ± 6.3%, AT from liposuction only 1.6% ± 1.0% (P \textless .0001), and AT after liposuction 8.9% ± 4.1% (P = .111) of CD31(pos) vessels. Conversely, adipocyte content was 39.5% ± 14.5% in the en bloc AT, 45% ± 18.4% in AT from liposuction (P = .390), and 18.8 ± 14.8% in AT after liposuction (P = .011). CONCLUSIONS: For the first time, we demonstrate that liposuction preserves the microvascular network. Indeed, a low percentage of endothelial cells was found in AT from liposuction and we confirm the persistence of microvessels in the tissue after liposuction
Published: 2015
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12. WITHDRAWN: Biomarqueurs prédictifs de réponse aux inhibiteurs de points de contrôle immuns

Author: Marc Pracht, Alexandra Lespagnol, Julien Edeline, Cédric Ménard, Samuel Le Sourd, Jean Mosser, Karin Tarte, Romain Corre, and Alexandra Frelau
Subjects: Gynecology, 0303 health sciences, Cancer Research, medicine.medical_specialty, business.industry, Hematology, General Medicine, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Medicine, Radiology, Nuclear Medicine and imaging, business, 030304 developmental biology
Published: 2018
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13. Proteasomal Indoleamine 2,3-Dioxygenase Degradation Reduces the Immunosuppressive Potential of Clinical Grade-Mesenchymal Stromal Cells Undergoing Replicative Senescence

Author: Rémy Pedeux, Nadine Mézière, Maelle Latour, Cédric Ménard, Joelle Dulong, Bezier Isabelle, Luc Sensebe, Séverine Loisel, Nicolas Bertheuil, Erwan Flecher, Karin Tarte, Marie-Laure Renoud, Nadège Bescher, Etablissement français du sang [Rennes] (EFS Bretagne), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), 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 [Pyrénées-Méditerranée] (EFS Pyrénées-Méditerranée), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de chirurgie plastique, reconstructive et esthétique [Rennes] = Cosmetic Reconstructive and Plastic surgery [Rennes], CHU Pontchaillou [Rennes], Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], Funded by Agence Nationale de la Recherche. Grant Number: ANR-11-RPIB-0012, Etablissement Français du Sang. Grant Number: APR 2016, Infrastructure program EcellFRANCE. Grant Number: ANR-11-INSB-005, European Center for Transplantation Sciences and Immunotherapy. Grant Number: IHU CESTI, ANR-10-IBHU_0005, ANR-11-RPIB-0012,SAFE,Production sécurisée de Cellules stromales du tissu adipeux pour la thérapie cellulaire(2011), Etablissement Français du Sang Pyrénées Méditerranée (EFS), CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie plastique, reconstructive et esthétique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], 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 ), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Senescence, Proteasome Endopeptidase Complex, T-Lymphocytes, T cells, Adipose tissue, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell therapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MG132, medicine, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Indoleamine 2,3-dioxygenase, Cellular Senescence, Cell Proliferation, Immunosuppression Therapy, Clinical translation, Mesenchymal stem cell, Bone marrow stromal cells, Cell Biology, Adipose stem cells, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Proteolysis, Immunology, Proteasome inhibitor, Cancer research, Molecular Medicine, Mesenchymal stem cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, Immunosuppression, Developmental Biology, medicine.drug
Abstract: Owing to their immunosuppressive properties, mesenchymal stromal cells (MSCs) obtained from bone marrow (BM-MSCs) or adipose tissue (ASCs) are considered a promising tool for cell therapy. However, important issues should be considered to ensure the reproducible production of efficient and safe clinical-grade MSCs. In particular, high expansion rate, associated with progressive senescence, was recently proposed as one of the parameters that could alter MSC functionality. In this study, we directly address the consequences of replicative senescence on BM-MSC and ASC immunomodulatory properties. We demonstrate that MSCs produced according to GMP procedures inhibit less efficiently T-cell, but not Natural Killer (NK)- and B-cell, proliferation after reaching senescence. Senescence-related loss-of-function is associated with a decreased indoleamine 2,3-dioxygenase (IDO) activity in response to inflammatory stimuli. In particular, although STAT-1-dependent IDO expression is transcriptionally induced at a similar level in senescent and nonsenescent MSCs, IDO protein is specifically degraded by the proteasome in senescent ASCs and BM-MSCs, a process that could be reversed by the MG132 proteasome inhibitor. These data encourage the use of appropriate quality controls focusing on immunosuppressive mechanisms before translating clinical-grade MSCs in the clinic.
Published: 2017
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14. Regulatory myeloid cells: an underexplored continent in B-cell lymphomas

Author: Cédric Ménard, Jonathan M. Irish, Karin Tarte, Thierry Fest, Mikael Roussel, Faustine Lhomme, Jonchère, Laurent, Etablissement français du sang [Rennes] (EFS Bretagne), Service d’immunologie, de thérapie cellulaire et d’hématopoïèse, Hôpital Pontchaillou, 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 ), Vanderbilt University School of Medicine [Nashville], CHU Pontchaillou [Rennes], This work was supported by a research grant from the National Institute of Cancer (INCa Recherche Translationnelle 2010), Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS), LYSA group (Lymphoma Study Association), Comité pour la Recherche Clinique et Translationnelle (CORECT, CHU Rennes), Ligue Nationale Contre le Cancer, R00 CA143231-03, the Vanderbilt-Ingram Cancer Center (VICC, P30 CA68485), VICC Ambassadors, and a VICC Hematology Helping Hands award., 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: 0301 basic medicine, Cancer Research, Lymphoma, B-Cell, Myeloid, [SDV.IMM] Life Sciences [q-bio]/Immunology, Carcinogenesis, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tumor-associated macrophage, Biology, Immunomodulation, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, Regulatory myeloid suppressor cells, medicine, Myeloid-derived suppressor cell, Animals, Humans, Immunology and Allergy, B-cell lymphoma, B cell, Tumor microenvironment, Myeloid-Derived Suppressor Cells, Germinal center, Germinal Center, medicine.disease, 3. Good health, Lymphoma, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Oncology, Myeloid-derived Suppressor Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor Escape, Mass cytometry
Abstract: International audience; In lymphomas arising from the germinal center, prognostic factors are linked to the myeloid compartment. In particular, high circulating monocyte or myeloid-derived suppressor cell counts are associated with poor prognosis for patients with high-grade B-cell lymphomas. Macrophages with an M2 phenotype are enriched within lymphoma tumors. However, the M1/M2 nomenclature is now deprecated and the clinical impact of this phenotype remains controversial. Across cancer types, myeloid cells are primarily thought to function as immune suppressors during tumor initiation and maintenance, but the biological mechanisms behind the myeloid signatures are still poorly understood in germinal center B-cell lymphomas. Herein, we describe the role and clinical relevance of myeloid cells in B-cell lymphoma and propose innovative approaches to decipher this complex cellular compartment. Indeed, characterization of this heterogeneous cell ecosystem has been largely accomplished with "low-resolution" approaches like morphological evaluation and immunohistochemistry, where cells are characterized using a few proteins and qualitative metrics. High-resolution, quantitative approaches, such as mass cytometry, are valuable to better understand myeloid cell diversity, functions, and to identify potential targets for novel therapies.
Published: 2017
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15. Labeling of mesenchymal stromal cells with iron oxide–poly(l-lactide) nanoparticles for magnetic resonance imaging: uptake, persistence, effects on cellular function and magnetic resonance imaging properties

Author: Markus Rojewski, Cédric Ménard, Volker Rasche, Markus Urban, Natalie Fekete, Hubert Schrezenmeier, Gerlinde Schmidtke-Schrezenmeier, Erika Deak, Anna Musyanovych, Karin Tarte, Volker Mailänder, and Katharina Landfester
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Injections, Subcutaneous, Immunology, Endosomes, Biology, Mesenchymal Stem Cell Transplantation, Endocytosis, Ferric Compounds, Regenerative medicine, Dioxanes, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, medicine, Animals, Humans, Immunology and Allergy, Rats, Wistar, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Transplantation, Staining and Labeling, medicine.diagnostic_test, Mesenchymal stem cell, Mesenchymal Stem Cells, Magnetic resonance imaging, Cell Biology, Magnetic Resonance Imaging, Rats, 3. Good health, Radiography, Oncology, chemistry, 030220 oncology & carcinogenesis, Biophysics, Feasibility Studies, Nanoparticles, Agarose, Original Article, Intracellular, Stem Cell Transplantation, Homing (hematopoietic)
Abstract: Background aims. Mesenchymal stromal cells (MSC) are the focus of research in regenerative medicine aiming at the regulatory approval of these cells for specific indications. To cope with the regulatory requirements for somatic cell therapy, novel approaches that do not interfere with the natural behavior of the cells are necessary. In this context in vivo magnetic resonance imaging (MRI) of labeled MSC could be an appropriate tool. Cell labeling for MRI with a variety of different iron oxide preparations is frequently published. However, most publications lack a comprehensive assessment of the noninterference of the contrast agent with the functionality of the labeled MSC, which is a prerequisite for the validity of cell-tracking via MRI. Methods.We studied the effects of iron oxide-poly(L-lactide) nanoparticles in MSC with flow cytom-etry, transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM), Prussian blue staining, CyQuant® proliferation testing, colony-forming unit-fibroblast (CFU-F) assays, flow chamber adhesion testing, immuno-logic tests and differentiation tests. Furthermore iron-labeled MSC were studied by MRI in agarose phantoms and Wistar rats. Results. It could be demonstrated that MSC show rapid uptake of nanoparticles and long-lasting intracellular persistence in the endosomal compartment. Labeling of the MSC with these particles has no influence on viability, differentiation, clonogenicity, proliferation, adhesion, phenotype and immunosuppressive properties. They show excellent MRI properties in agarose phantoms and after subcutaneous implantation in rats over several weeks. Conclusions. These particles qualify for studying MSC homing and trafficking via MRI.
Published: 2011
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16. CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?

Author: Ursula Grohmann, Caroline Robert, Christine Mateus, François Ghiringhelli, Stephan Roux, Sophie Caillat-Zucman, Cédric Ménard, Nathalie Chaput, and Laurence Zitvogel
Subjects: Male, Cancer Research, Skin Neoplasms, MONOCLONAL-ANTIBODY, medicine.medical_treatment, Lymphocyte, Lymphocyte Activation, T-Lymphocytes, Regulatory, LOW-DOSE CYCLOPHOSPHAMIDE, METASTATIC MELANOMA, CANCER REGRESSION, ANTITUMOR LYMPHOCYTES, ANTIGEN-4 BLOCKADE, TUMOR-IMMUNITY, OVARIAN-CANCER, IMMUNOTHERAPY, RESPONSES, Medicine, CTLA-4 Antigen, Melanoma, Aged, 80 and over, Antibodies, Monoclonal, hemic and immune systems, Middle Aged, Flow Cytometry, medicine.anatomical_structure, Oncology, Female, medicine.drug, Adult, Regulatory T cell, T cell, Antineoplastic Agents, chemical and pharmacologic phenomena, Antibodies, Monoclonal, Humanized, Antigens, CD, Humans, Aged, Cell Proliferation, business.industry, Immunotherapy, T lymphocyte, CTLA-4, Immunology, business, Immunologic Memory, Tremelimumab, Biomarkers, CD8
Abstract: Purpose: Anti–CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to encouraging antitumor activity associated with immune-related adverse events in patients with heavily pretreated melanoma. However, mechanisms of action and surrogate immunologic markers of efficacy have not been reported thus far.Experimental Design: We monitored the immune responses of 10 melanoma patients included in a phase II clinical trial, which evaluated the efficacy of a second line of therapy of tremelimumab anti–CTLA-4 mAb in patients with metastatic melanoma. The frequency of blood leukocyte populations in association with T cell and regulatory T cell (Treg) functions were evaluated.Results: Prior to therapy, patients with advanced melanoma presented with a severe CD4+ and CD8+ T cell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned to Treg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to Treg-mediated suppression. Progression-free survival and overall survival was directly correlated with the acquisition of a biological response defined as the resistance of peripheral lymphocytes to Treg-inhibitory effects (obtained in 7 of 10 patients).Conclusion: CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to Treg resulting from anti–CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.
Published: 2008
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17. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity

Author: François Ghiringhelli, François Martin, Florence Bouyer, Lionel Apetoh, and Cédric Ménard
Subjects: Cancer Research, business.industry, medicine.medical_treatment, Immunology, Cancer, Antineoplastic Agents, Immunotherapy, medicine.disease, T-Lymphocytes, Regulatory, Immune tolerance, Immune system, Oncology, Antigen, Neoplasms, Cancer cell, medicine, Animals, Humans, Immunology and Allergy, Cytotoxic T cell, business, Adjuvant, T-Lymphocytes, Cytotoxic
Abstract: Treatment of metastatic cancer mainly relies on chemotherapy. Chemotherapeutic agents kill tumor cells by direct cytotoxicity, thus leading to tumor regression. However, emerging data focus on another side of cancer chemotherapy: its antitumor immunity effect. Although cancer chemotherapy was usually considered as immunosuppressive, some chemotherapeutic agents have recently been shown to activate an anticancer immune response, which is involved in the curative effect of these treatments. Cancer development often leads to the occurrence of an immune tolerance that prevents cancer rejection by the immune system and hinders efficacy of immunotherapy. Cancer cells induce proliferation and local accumulation of immunosuppressive cells such as regulatory T cells and immature myeloid cells, and prevent the maturation of dendritic cells and their capacity to present tumor antigens to T lymphocytes. Many anticancer cytotoxic agents interfere with the molecular and cellular mechanisms leading to tumor-induced tolerance. They can restore an efficient immune response that contributes to the therapeutic effects of chemotherapy. These findings open a novel field of investigations for future clinical trial design, taking into account the immunostimulatory capacity of chemotherapeutic agents, and using them in combined chemo-immunotherapy strategies when tumor-induced tolerance is overcome.
Published: 2008
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18. S233: AXICABTAGENE CILOLEUCEL AS SECOND-LINE THERAPY FOR LARGE B-CELL LYMPHOMA IN TRANSPLANT-INELIGIBLE PATIENTS: FINAL ANALYSIS OF ALYCANTE, A PHASE 2 LYSA STUDY

Author: Roch Houot, Emmanuel Bachy, Guillaume Cartron, Francois-Xavier Gros, Franck Morschhauser, Lucie Oberic, Thomas Gastinne, Pierre Feugier, Rémy Duléry, Catherine Thieblemont, Magalie Joris, Fabrice Jardin, Sylvain Choquet, Rene Olivier Casasnovas, Gabriel Brisou, Morgane Cheminant, Jacques Olivier Bay, Francisco Llamas, Cedric Menard, Karin Tarte, Marie-Helene Delfau-Larue, Emmanuel Itti, Clément Bailly, Yassine Al Tabaa, Camille Laurent, and Francois Lemonnier
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2023
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19. P1123: EARLY CTDNA CLEARANCE AFTER CAR T-CELL INFUSION PREDICTS OUTCOME IN PATIENTS WITH LARGE B-CELL LYMPHOMA: RESULTS FROM ALYCANTE, A PHASE 2 LYSA STUDY

Author: Marie-Helene Delfau-Larue, Lucie Gomes, Guillaume Cartron, Franck Morschhauser, Francois-Xavier Gros, Thomas Gastinne, Lucie Oberic, Emmanuel Bachy, Pierre Feugier, Rémy Duléry, Cedric Menard, Celine Pangault, Alexis Claudel, Cathy Quelen, Cedric Portugues, Pierre-Julien Viailly, Francois Lemonnier, Emmanuel Itti, Clément Bailly, Camille Laurent, and Roch Houot
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2023
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20. Les cellules stromales mésenchymateuses du tissu adipeux : historique, isolement, propriétés immunomodulatrices et perspectives cliniques [Adipose-derived stromal cells: History, isolation, immunomodulatory properties and clinical perspectives]

Author: Benoit Chaput, Ignacio Garrido, J L Grolleau, Karin Tarte, Nicolas Bertheuil, Eric Watier, Luc Sensebé, Audrey Varin, Cédric Ménard, Service de chirurgie plastique, reconstructive et esthétique [Rennes] = Cosmetic Reconstructive and Plastic surgery [Rennes], CHU Pontchaillou [Rennes], STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), 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 ), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), 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 ), Service de chirurgie plastique, reconstructive et esthétique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)
Subjects: Stromal cell, Stromal vascular fraction, [SDV]Life Sciences [q-bio], Mesenchymal stromal cells, Regenerative medicine, Fraction vasculaire stromale, Cell therapy, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, In vivo, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cellules stromales mésenchymateuses, Propriétés anti-inflammatoires, 0303 health sciences, business.industry, Mesenchymal stem cell, Anti-inflammatory effect, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Surgery, Bone marrow, Stem cell, business, Médecine régénérative, Immunosuppression
Abstract: Over the last decade, the clinical use of adipose-derived stromal/stem cells (ASC) in regenerative medicine is rapidly increasing. ASC belong to the mesenchymal stromal cells initially obtained from the bone marrow. Their limited differentiation capacity in vivo into functional mature cells has led to a reassessment of their mechanisms of action. One of the major clinical interests appears related to paracrine effects through a temporary production of trophic and immunomodulatory factors. Our purpose is to provide a review on the latest knowledge in the field of ASC, mechanisms of action, mainly immunomodulatory/immunosuppressive properties, methods of obtention, with a focus on clinical perspectives particularly in the field of cellular therapy and fat grafting technique in plastic surgery.
Published: 2015
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21. The dialogue between natural killer cells and dendritic cells

Author: Cédric Ménard, Laurence Zitvogel, Julien Taieb, Christophe Borg, Magali Terme, Koji Maruyama, and Hiro Wakasugi
Subjects: Interleukin 21, Lymphokine-activated killer cell, Immune system, NK-92, Immunology, Antigen presentation, Interleukin 12, Cytotoxic T cell, General Medicine, Biology, Natural killer T cell, Cell biology
Abstract: Natural killer (NK) cells play an important role in the early innate response against cancer and infections whereas dendritic cells (DC) are critical in the initiation of adaptive immune responses through their unique antigen presentation capacities. It was discovered in 1999 by Fernandez et al. that DC and NK cells make functional interactions. In vitro, IL-12/IL-18, IL-15 and IFN-α/β production by activated DC enhance NK cell IFN-γ production, proliferation and cytotoxic potential, respectively. Activated NK cells induce DC maturation either directly or in synergy with suboptimal levels of microbial signals. NK cell-induced DC activation is dependent on both TNF-α/IFN-γ secretion and a cell–cell contact. Finally, immature DC appear susceptible to autologous NK cell-mediated cytolysis while mature DC are protected. Thus, the outcome of NK/DC cross-talk is likely to influence both innate and adaptive immune responses. In vivo, NK/DC interactions occur at least in lymphoid organs and promote Th1 differentiation. Thus, DC and NK cells are equipped with complementary sets of receptors that allow the recognition of various pathogenic agents, rendering the cross-talk between the two partners mandatory.
Published: 2005
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22. Mechanically Isolated Stromal Vascular Fraction Provides a Valid and Useful Collagenase-Free Alternative Technique

Author: Cédric Ménard
Subjects: 0301 basic medicine, 03 medical and health sciences, Pathology, medicine.medical_specialty, 030104 developmental biology, business.industry, medicine, Collagenase, Surgery, Stromal vascular fraction, business, medicine.drug
Published: 2017
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23. Effects of a ceramic biomaterial on immune modulatory properties and differentiation potential of human mesenchymal stromal cells of different origin

Author: Philippe Bourin, Fabien Guilloton, Frédéric Deschaseaux, Mariano Di Trapani, Karin Tarte, Mauro Krampera, Massimo Dominici, Rosaria Giordano, Luc Sensebé, Hubert Schrezenmeier, Giulio Bassi, Cédric Ménard, Stem Cell Research Laboratory, Università degli studi di Verona = University of Verona (UNIVR), Etablissement Français du Sang, EFS, CHU Pontchaillou [Rennes], STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Institute for transfusion medicine and Immunogenetic Clinics for Aplastic Anaemia, Ulm medical school, Laboratoire de thérapie cellulaire, 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 ), University of Verona (UNIVR), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), 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 ), Università degli Studi di Verona, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)
Subjects: Calcium Phosphates, Ceramics, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biomedical Engineering, Bioengineering, Biochemistry, Biomaterials, Immunomodulation, Immune system, Materials Testing, medicine, Humans, Immunologic Factors, Cells, Cultured, biology, Tissue Scaffolds, Mesenchymal Stromal Cells, Chemistry, Mesenchymal stem cell, Cell Differentiation, Mesenchymal Stem Cells, Immunotherapy, Original Articles, Equipment Design, Cell biology, Equipment Failure Analysis, medicine.anatomical_structure, Durapatite, Bone morphogenetic protein 4, Immunology, Bone Substitutes, Osteocalcin, biology.protein, Tumor necrosis factor alpha, Bone marrow, Stem cell
Abstract: The aim of this study was to assess the immune modulatory properties of human mesenchymal stromal cells obtained from bone marrow (BM-MSCs), fat (ASCs), and cord blood (CB-MSCs) in the presence of a hydroxyapatite and tricalcium-phosphate (HA/TCP) biomaterial as a scaffold for MSC delivery. In resting conditions, a short-term culture with HA/TCP did not modulate the anti-apoptotic and suppressive features of the various MSC types toward T, B, and NK cells; in addition, when primed with inflammatory cytokines, MSCs similarly increased their suppressive capacities in the presence or absence of HA/TCP. The long-term culture of BM-MSCs with HA/TCP induced an osteoblast-like phenotype with upregulation of OSTERIX and OSTEOCALCIN, similar to what was obtained with dexamethasone and, to a higher extent, with bone morphogenetic protein 4 (BMP-4) treatment. MSC-derived osteoblasts did not trigger immune cell activation, but were less efficient than undifferentiated MSCs in inhibiting stimulated T and NK cells. Interestingly, their suppressive machinery included not only the activation of indoleamine-2,3 dioxygenase (IDO), which plays a central role in T-cell inhibition, but also cyclooxygenase-2 (COX-2) that was not significantly involved in the immune modulatory effect of human undifferentiated MSCs. Since COX-2 is significantly involved in bone healing, its induction by HA/TCP could also contribute to the therapeutic activity of MSCs for bone tissue engineering.
Published: 2015
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24. Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab

Author: Pauline Patin, Bertrand Godeau, Claude-Agnès Reynaud, Julie Ripa, Lionel Galicier, Lan Thai, Nicolas Cagnard, Sylvain Audia, Marc Michel, Simon Le Gallou, Jean-Claude Weill, Cédric Ménard, Bernard Bonnotte, Benoît Vingert, Jérôme Mégret, Matthieu Mahévas, David Boutboul, Julien Moroch, Karin Tarte, Service de Médecine Interne [Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Centre de référence maladie rare des cytopénies auto-immunes de l'adulte-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -CHU Saint Louis [APHP], 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 ), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), plateforme de bioinformatique, Université Paris Descartes - Paris 5 ( UPD5 ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), 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 ), Développement du Systeme Immunitaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Service de Médecine Interne, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri-Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), 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 ), CIC - Biotherapie - CHU Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Centre de référence maladie rare des cytopénies auto-immunes de l'adulte-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], 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), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Paris Descartes - Paris 5 (UPD5), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri-Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Ligue Contre le Cancer, Fondation Princesse Grace, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Centre de référence maladie rare des cytopénies auto-immunes de l'adulte-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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 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 )
Subjects: Adult, Male, Hemolytic anemia, Erythrocytes, [SDV]Life Sciences [q-bio], Plasma Cells, Immunology, B-Lymphocyte Subsets, Autoimmunity, Spleen, Plasma cell, Warm autoimmune hemolytic anemia, Anti-CD20, Long-lived plasma cells, Blood cell, Young Adult, B-Cell Activating Factor, medicine, Humans, Immunologic Factors, Immunology and Allergy, Lymphocyte Count, Antibody-secreting cells, Aged, Autoantibodies, Autoimmune disease, B-cell depletion, [ SDV ] Life Sciences [q-bio], business.industry, Gene Expression Profiling, Germinal center, Middle Aged, Germinal Center, medicine.disease, 3. Good health, medicine.anatomical_structure, Splenectomy, Female, Rituximab, Anemia, Hemolytic, Autoimmune, Autoimmune hemolytic anemia, business, medicine.drug
Abstract: International audience; Primary warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease in which red blood cells are eliminated by IgG autoantibodies. We analyzed the antibody-secreting cells in the spleen and the peripheral blood of wAIHA patients in various contexts of treatment. Plasmablasts were observed in peripheral blood of newly diagnosed wAIHA patients and, accordingly, active germinal center reactions were present in the spleen of patients receiving short-term corticosteroid therapy. Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro. In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive. By using a set of diagnostic genes that allowed us to assess the plasma cell maturation stage, we observed that these cells displayed a long-lived program, differing from the one of plasma cells from healthy donors or from wAIHA patients with various immunosuppressant treatments, and more similar to the one of normal long-lived bone-marrow plasma cells. Interestingly, an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients. These results suggest, in line with our previous report on primary immune thrombocytopenia, that the B-cell depletion induced by rituximab promoted a suitable environment for the maturation and survival of auto-immune long-lived plasma cells in the spleen
Published: 2015
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25. Lenalidomide Treatment Restores In Vivo T Cell Activity in Relapsed/Refractory FL and DLBCL

Author: Tien Tuan Nguyen, Isabelle Bezier, Roch Houot, Thierry Lamy, Maelle Latour, Cédric Ménard, Nadège Bescher, Joelle Dulong, Franck Morschhauser, Séverine Loisel, and Karin Tarte
Subjects: Oncology, medicine.medical_specialty, Chronic lymphocytic leukemia, Immunology, Context (language use), Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Obinutuzumab, Internal medicine, medicine, Multiple myeloma, Lenalidomide, CD20, biology, business.industry, Cell Biology, Hematology, medicine.disease, chemistry, 030220 oncology & carcinogenesis, biology.protein, Rituximab, business, Diffuse large B-cell lymphoma, 030215 immunology, medicine.drug
Abstract: The immunostimulatory properties of lenalidomide have been mostly described in vitro while in vivo studies performed in multiple myeloma or chronic lymphocytic leukemia have reported a poorly characterized T-cell activation. A better understanding of lenalidomide kinetics and mechanisms of action is mandatory to optimize its combination with other immunotherapeutic agents in particular for the treatment of non Hodgkin lymphomas. We undertook a thorough immune monitoring of patients enrolled in the French multicenter clinical trial GALEN (ClinicalTrials.gov: NCT01582776) addressing the tolerance and efficacy of the association of lenalidomide and obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody, in relapsed/refractory B-cell lymphomas. A 1-week interval between the start of lenalidomide and the first infusion of obinutuzumab was planned, allowing an assessment of the effect of lenalidomide alone on immune-related parameters separately from the combinatorial therapy. Serial blood samples were collected in 44 patients (16 DLBCL and 28 FL) to investigate T, B, NK, and myeloid subsets. In addition, in vitro functional assays were designed to address T cell functional features (proliferation, immune synapse, activity of regulatory T cells (Treg)). In the context of the association with obinutuzumab, we first checked that CD20 expression was not affected on circulating malignant and normal B cells (p=0.43 and 0.8; respectively). Interestingly, upon 1 week of lenalidomide treatment, normal B cells, unlike malignant B cells, upregulated MHC class II (p We herein report for the first time early in vivo T cell activation by lenalidomide in relapse FL/DLBCL through a detailed phenotypic analysis strengthened by innovative functional assays. The study of T cells heterogeneity at the transcriptomic level is underway and the correlation of these immunomodulatory properties with clinical data is also currently being addressed. Our results will help build new and more relevant lenalidomide-based immunotherapeutic approaches. (This study was supported by research grants from Celgene and Roche companies) Disclosures Menard: Celgene: Consultancy; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Lamy: Roche: Consultancy, Honoraria. Morschhauser: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Servier: Consultancy; Gilead: Consultancy. Tarte: Celgene: Consultancy, Research Funding; Novimmune: Research Funding; Roche: Consultancy.
Published: 2017
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26. EFFECTS OF A NOVEL CERAMIC BIOMATERIAL ON IMMUNE MODULATORY PROPERTIES AND DIFFERENTIATION POTENTIAL OF MESENCHYMAL STROMAL CELLS

Author: M. Di Trapani, Philippe Bourin, Markus Rojewski, Pierre Layrolle, Massimo Dominici, Rosaria Giordano, Giulio Bassi, Martina Midolo, Cédric Ménard, Roberta Carusone, Serge Baroth, Lorenza Lazzari, Fabien Guilloton, Luciano Pacelli, Karin Tarte, Luc Sensebe, Isabelle Bezier, Cristiana Lavazza, Mauro Krampera, Hubert Schrezenmeier, Frederic Deschaseaux, Eliana Amati, Stem Cell Research Laboratory, University of Verona (UNIVR), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 Centre-Atlantique (EA3855), EFS, STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for transfusion medicine and Immunogenetic Clinics for Aplastic Anaemia, Ulm medical school, Institut für Transfusionsmedizin, Universität Ulm - Ulm University [Ulm, Allemagne], Institut für klinische Transfusionsmedizin und Immungenetik, DRK Blutspendedienst Baden-Württemberg—Hessen, Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Thérapie Cellulaire, Groupe d'Etude des Cellules Souches Mésenchymateuses (GECSOM), GECSOM, Università degli Studi di Verona, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Verona = University of Verona (UNIVR), 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 ), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, medicine.medical_specialty, Immunology, Bone healing, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Research & Experimental Medicine, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, medicine, Immunology and Allergy, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Transplantation, Hematology, biology, Chemistry, Mesenchymal stem cell, Cell Biology, Cell biology, medicine.anatomical_structure, Oncology, Biotechnology & Applied Microbiology, 030220 oncology & carcinogenesis, Cord blood, Osteocalcin, biology.protein, Bone marrow
Abstract: International audience; The aim of this study was to assess the immune modulatory properties of human mesenchymal stromal cells obtained from bone marrow (BM-MSCs), fat (ASCs) and cord blood (CB-MSCs) in the presence of a novel hydroxyapatite and tricalcium-phosphate (HA/TCP) biomaterial as scaffold for MSC delivery. In resting conditions, a short-term culture with HA/TCP did not modulate the anti-apoptotic and suppressive features of the various MSC types towards T, B and NK cells; in addition, when primed with inflammatory cytokines, MSC maintained or not on HA/TCP similarlyincreased their suppressive capacities. The long-term culture of BM-MSCs with HA/TCP induced an osteoblast-like phenotype with up-regulation of OSTERIX and OSTEOCALCIN, similarly to what obtained with dexamethasone and, to a higher extent, BMP-4 treatment. MSC-derived osteoblasts did not trigger immune cell activation, but were less efficient than undifferentiated MSCs in inhibiting stimulated T and NK cells. Interestingly, their suppressive machinery included not only the activation of IDO, which plays a central role in T-cell inhibition, but also COX-2 that was not significantly involved in immune modulatory effect of human undifferentiated MSCs. COX-2 is significantly involved in bone healing, suggesting that its induction by HA/TCP could also contribute to the therapeutic activity of MSC for bone tissue engineering.
Published: 2014
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27. Therapy-Induced Tumor Immunosurveillance Involves IFN-Producing Killer Dendritic Cells

Author: Mathieu Bonmort, Laurence Zitvogel, Evelyn Ullrich, Julien Taieb, Cédric Ménard, Guido Kroemer, Thomas Tursz, Grégoire Mignot, Nathalie Chaput, Sophie Viaud, 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), Service d'hépatogastro-entérologie et d'oncologie digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mignot, Grégoire
Subjects: Cancer Research, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Immunotherapy, MESH: Interferon-gamma, medicine.medical_treatment, MESH: Piperazines, Antineoplastic Agents, chemical and pharmacologic phenomena, Biology, Piperazines, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, MESH: Animals, Antigen-presenting cell, MESH: Mice, 030304 developmental biology, 0303 health sciences, Lymphokine-activated killer cell, Innate immune system, MESH: Dendritic Cells, Dendritic Cells, Neoplasms, Experimental, Immunotherapy, Dendritic cell, Natural killer T cell, 3. Good health, Immunosurveillance, Pyrimidines, MESH: Neoplasms, Experimental, Imatinib mesylate, Oncology, MESH: Pyrimidines, Benzamides, Immunology, Imatinib Mesylate, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030215 immunology
Abstract: A unique class of IFN-producing killer dendritic cells (IKDC) resembling natural killer cells has been defined that can recognize and lyse tumor cells through a tumor necrosis factor–related apoptosis-inducing ligand–dependent mechanism. IKDC may mediate the host-dependent antitumor activity of Gleevec/STI571 and other therapeutics that can inhibit the c-kit tyrosine kinase. IKDC represent an important new component of the innate immune system responding to cancer. [Cancer Res 2007;67(3):851–3]
Published: 2007
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28. Human t(14;18)positive germinal center B cells: a new step in follicular lymphoma pathogenesis?

Author: Cédric Ménard, Julie Tellier, Nadine Martin, Sandrine Roulland, Céline Monvoisin, Bertrand Nadel, Lionel Chasson, Philippe Gaulard, Karin Tarte, Claudine Schiff, 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), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 ), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by research grants from the Institut National du Cancer (INCa libre PL06-10 and PAIR Lymphome 2008-019), the Ligue Contre le Cancer (Equipe Labellisée 2013) and institutional grants from INSERM (Institut National de la Santé et de la Recherche Médicale) and CNRS (Centre National de la Recherche Scientifique)., 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), 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 ), Ménard, Cédric, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
Subjects: Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Pathology, [SDV]Life Sciences [q-bio], Follicular lymphoma, Biochemistry, CXCR4, Translocation, Genetic, MESH: Lymphoma, Follicular, MESH: Germinal Center, hemic and lymphatic diseases, Neoplasm, Lymphoma, Follicular, Lymph node, CD20, MESH: Aged, biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, 3. Good health, Cell Transformation, Neoplastic, medicine.anatomical_structure, Real-time polymerase chain reaction, Proto-Oncogene Proteins c-bcl-2, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Neprilysin, Adult, medicine.medical_specialty, Lymphoma, B-Cell, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Aged, MESH: Lymphoma, B-Cell, Chromosomes, Human, Pair 14, MESH: Humans, Germinal center, MESH: Adult, Cell Biology, Antigens, CD20, Germinal Center, medicine.disease, Molecular biology, MESH: Male, Lymphoma, biology.protein, MESH: Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, MESH: Chromosomes, Human, Pair 18, MESH: Female
Abstract: Julie Tellier, Cedric Menard, Claudine Schiff and Karin Tarte contributed equally to this work; International audience; Follicular lymphoma (FL) is a B-cell neoplasm resulting from the transformation of germinal center (GC) B cells. Although t(14;18) and ectopic B-cell lymphoma 2 (BCL2) expression constitute the genetic hallmark of FL, t(14;18)(pos) B cells bearing genotypic and phenotypic features of FL cells can be found in the blood of most healthy individuals. Nevertheless, the localization of these FL-like cells (FLLCs) in nonmalignant GC-rich tissues and the functional consequences of BCL2 overexpression have not been evaluated thus far. Among 85 reactive lymph node (RLN) samples, 14% were found to contain high levels of t(14;18) by quantitative polymerase chain reaction. In t(14;18)(hi) RLNs, CD20(pos)BCL2(pos)CD10(pos) FLLCs consistently accumulated within the GC, essentially as nonproliferative CXCR4(neg) centrocytes. Moreover, they displayed a reduced response to proliferative stimuli in vitro. Altogether, our findings provide new insights into in situ FLLC functional properties and suggest that these cells have not acquired the ultimate genetic events leading to FL transformation.
Published: 2014
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29. Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression

Author: Sandrine Roulland, Lionel Chasson, Nathalie Jouve, Philip Brohawn, Cédric Ménard, Guilhaume Debroas, Céline Monvoisin, Stephanie Sungalee, Fannie Baudimont, Claudine Schiff, Jean Hardwigsen, Jean-Michel Picquenot, Mustapha Faroudi, Julie Tellier, Jean-Marc Navarro, Bruno Chetaille, Charlotte Drevet, Stéphane J. C. Mancini, Christopher Morehouse, Violaine Mechin, Bertrand Nadel, Philippe Ruminy, Emilie Gregoire, Elaine S. Jaffe, David A. Tice, Franziska C. Eberle, Karin Tarte, Paolo Vineis, Rachel S. Kelly, Ester Morgado, Brandon W. Higgs, Emilie Mamessier, 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), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), MedImmune, Inc., Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 ), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Epidemiology and Public Health, Imperial College London, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), This work was funded by grants from the Institut National du Cancer (INCa), the Association pour la Recherche sur le Cancer (ARC), the MedImmune Strategic Collaboration to Fund and Conduct Medical Science Research program, INSERM, and CNRS. S. Sungalee was supported by a fellowship from the French Ministry of Research (MRT) and the Fondation pour la Recherche Medicale (FRM)., 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 ), 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), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille, Microenvironnement cellulaire et moléculaire des tumeurs, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Etablissement français du sang [Rennes] (EFS Bretagne), Physiologie intégrative, cellulaire et moléculaire (PICM), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (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), University of Torino and CPO-Piemonte, Università degli studi di Torino (UNITO), Assistance Publique - Hôpitaux de Marseille (APHM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), 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 Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), MedImmune, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), and mamessier, emilie
Subjects: Male, [SDV]Life Sciences [q-bio], Follicular lymphoma, B-Lymphocyte Subsets, Chromosomal translocation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, Transgenic, Biology, Immunofluorescence, Mice, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, Cell Movement, hemic and lymphatic diseases, Cytidine Deaminase, medicine, Animals, Humans, B-cell lymphoma, Lymphoma, Follicular, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, Germinal center, General Medicine, Cytidine deaminase, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Neoplasms, Experimental, medicine.disease, 3. Good health, Lymphoma, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-bcl-2, Immunology, Cancer research, Commentary, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy
Abstract: International audience; It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients.
Published: 2013
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30. Comparative study of immune regulatory properties of stem cells derived from different tissues

Author: Guido Francesco Fumagalli, Ilaria Decimo, Piero Anversa, P De Coppi, Luciano Pacelli, Emanuela Fontana, Karin Tarte, Francesco Bifari, M. Di Trapani, Luca Giacomello, Mario Ricciardi, Giulio Bassi, Mauro Krampera, Cédric Ménard, Francois Feron, Michela Pozzobon, Stem Cell Research Laboratory, University of Verona (UNIVR), Laboratory of Translation Surgery, Laboratory of Stem Cells and Regenerative Therapy, Universita degli Studi di Padova, CIC - Biotherapie - Marseille, Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Surgery, Hospital for Children, Harvard Medical School [Boston] (HMS), Department of Diagnostics and Public Health [Verona] (UNIVR | DDSP), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 ), Laboratoire SITI, CHU Pontchaillou [Rennes]-Etablissement Français du Sange Bretagne, CARIVERONA, Bando 2008 e 2012, Italian Ministry of University and Scientific Research--PRIN 2009, Ricerca Sanitaria Finalizzata 2008, Gruppo Animazione Lesionati Midollari (GALM)--Verona, Federazione Associazioni Italiane Paratetraplegici (FAIP), 7th Framework Program of the European Commission: CASCADE (FP7-HEALTH-233236), REBORNE (FP7-HEALTH-241879), Università degli studi di Verona = University of Verona (UNIVR), Università degli Studi di Padova = University of Padua (Unipd), 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 ), Università degli Studi di Verona, Department of Medicine and Public Health, and Le Corre, Morgane
Subjects: Cancer Research, Amniotic Fluid, Antigens, CD, Biomarkers, Bone Marrow Cells, Gene Expression, HLA Antigens, Humans, Immunophenotyping, Lymphocyte Subsets, Mesenchymal Stromal Cells, Cell Biology, 0302 clinical medicine, Meninges, Original Research Reports, Immunology and Allergy, Lung, Genetics (clinical), 0303 health sciences, integumentary system, Hematology, Intercellular Adhesion Molecule-1, Olfactory Bulb, 3. Good health, Cell biology, CD, Allogeneic stem cell (SC)-based therapy, Oncology, Organ Specificity, 030220 oncology & carcinogenesis, Stem cell, tissues, Adult stem cell, Immunology, Primary Cell Culture, Vascular Cell Adhesion Molecule-1, Human leukocyte antigen, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, adult stem cells, 03 medical and health sciences, Immune system, Antigen, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Indoleamine-Pyrrole 2,3,-Dioxygenase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Antigens, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Transplantation, Myocardium, Mesenchymal stem cell, Mesenchymal Stem Cells, nervous system, Cell culture, Developmental Biology
Abstract: International audience; : Allogeneic stem cell (SC)-based therapy is a promising tool for the treatment of a range of human degenerative and inflammatory diseases. Many reports highlighted the immune modulatory properties of some SC types, such as mesenchymal stromal cells (MSCs), but a comparative study with SCs of different origin, to assess whether immune regulation is a general SC property, is still lacking. To this aim, we applied highly standardized methods employed for MSC characterization to compare the immunological properties of bone marrow-MSCs, olfactory ectomesenchymal SCs, leptomeningeal SCs, and three different c-Kit-positive SC types, that is, amniotic fluid SCs, cardiac SCs, and lung SCs. We found that all the analyzed human SCs share a common pattern of immunological features, in terms of expression of activation markers ICAM-1, VCAM-1, HLA-ABC, and HLA-DR, modulatory activity toward purified T, B, and NK cells, lower immunogenicity of inflammatory-primed SCs as compared to resting SCs, and indoleamine-2,3-dioxygenase-activation as molecular inhibitory pathways, with some SC type-related peculiarities. Moreover, the SC types analyzed exert an anti-apoptotic effect toward not-activated immune effector cells (IECs). In addition, we found that the inhibitory behavior is not a constitutive property of SCs, but is acquired as a consequence of IEC activation, as previously described for MSCs. Thus, immune regulation is a general property of SCs and the characterization of this phenomenon may be useful for a proper therapeutic use of SCs.
Published: 2013
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31. Medial thighplasty after massive weight loss: are there any risk factors for postoperative complications?

Author: Cédric Ménard, Sophie Thienot, Eric Watier, Nicolas Bertheuil, Vincent Huguier, Service de chirurgie plastique, reconstructive et esthétique [Rennes] = Cosmetic Reconstructive and Plastic surgery [Rennes], CHU Pontchaillou [Rennes], Service de chirurgie plastique et reconstructive, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 ), 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 ), and Martin, Clémence
Subjects: medicine.medical_specialty, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Redundant skin folds, Postoperative Complications, Weight loss, Risk Factors, Weight Loss, medicine, Humans, Medial thighplasty, Retrospective Studies, 2. Zero hunger, Bariatric surgery, business.industry, Wound dehiscence, Postoperative complication, Retrospective cohort study, Middle Aged, Plastic Surgery Procedures, medicine.disease, 3. Good health, Surgery, Plastic surgery, Otorhinolaryngology, Thigh, Seroma, Massive weight loss, Female, medicine.symptom, Complication, business
Abstract: International audience; BACKGROUND: With the increasing incidence of obesity in Western societies, an increasing number of patients undergo bariatric surgery that leads to functional and aesthetic sequelae related to a rapid and massive weight loss, namely, skin and fat excess. The goal of surgical management after massive weight loss is to optimize the functional results obtained from bariatric surgery or diet by removal of the redundant skin folds. The authors report their experience with medial thighplasty after massive weight loss and identify factors predictive of postoperative complications. METHODS: This retrospective study investigated 53 patients who underwent surgery for medial thighplasty after massive weight loss. Data were collected through chart review and submitted to statistical analysis. RESULTS: The average weight loss before thighplasty was 43.5 ± 14.9 kg, and 39.6 % of the patients experienced at least one complication. The complications were seroma (9.4 %), wound dehiscence (20.8 %), scar migration (17 %), wound infection (5.7 %), and partial skin necrosis (1.9 %). The body mass index (BMI) before massive weight loss and the BMI before medial thighplasty were found to be risk factors for the development of a postoperative complication. CONCLUSION: Few guidelines exist for the optimization of care and safety in this complex patient population. The information from this retrospective study complements the current data from the literature and can help surgeons select patients eligible for medial thighplasty. This report shows that the BMI before medial thighplasty should be taken into consideration for patients willing to undergo a body-contouring procedure. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Published: 2013
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32. Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls

Author: Isabelle Bezier, Hubert Schrezenmeier, Mauro Krampera, Maelle Latour, Cédric Ménard, Joelle Dulong, Karin Tarte, Francesco Bifari, Giulio Bassi, Philippe Bourin, Luciano Pacelli, Luc Sensebé, Jasmina Zanoncello, Mario Ricciardi, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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), Stem Cell Research Laboratory, Università degli Studi di Verona, STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Institut für Klinische Transfusionmedizin und Immungenetik, Universität Ulm - Ulm University [Ulm, Allemagne]-German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen, This work was supported by grants from the 7th Framework Program of the European Commission: CASCADE (FP7-HEALTH-233236) and REBORNE (FP7-HEALTH-241879) and by grants from the European Center for Transplantation Sciences and Immunotherapy (IHU CESTI, ANR-10-IBHU-0005)., European Project: 241879,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,REBORNE(2010), University of Verona (UNIVR), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Università degli studi di Verona = University of Verona (UNIVR), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Ménard, Cédric, and Regenerating Bone defects using New biomedical Engineering approaches - REBORNE - - EC:FP7:HEALTH2010-01-01 - 2015-06-30 - 241879 - VALID
Subjects: Blood Platelets, Cell Extracts, Quality Control, Serum, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, T-Lymphocytes, Bone Marrow Cells, Biology, Proinflammatory cytokine, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Immune system, Original Research Reports, medicine, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Interferon gamma, 030304 developmental biology, Cell Proliferation, 0303 health sciences, B-Lymphocytes, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, Hematology, Coculture Techniques, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Adipose Tissue, Organ Specificity, 030220 oncology & carcinogenesis, Immunology, Cancer research, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Platelet lysate, Cattle, Bone marrow, Stem cell, Developmental Biology, medicine.drug
Abstract: International audience; Clinical-grade mesenchymal stromal cells (MSCs) are usually expanded from bone marrow (BMMSCs) or adipose tissue (ADSCs) using processes mainly differing in the use of fetal calf serum (FCS) or human platelet lysate (PL). We aimed to compare immune modulatory properties of clinical-grade MSCs using a combination of fully standardized in vitro assays. BMMSCs expanded with FCS (BMMSC-FCS) or PL (BMMSC-PL), and ADSC-PL were analyzed in quantitative phenotypic and functional experiments, including their capacity to inhibit the proliferation of T, B, and NK cells. The molecular mechanisms supporting T-cell inhibition were investigated. These parameters were also evaluated after pre-stimulation of MSCs with inflammatory cytokines. BMMSC-FCS, BMMSC-PL, and ADSC-PL displayed significant differences in expression of immunosuppressive and adhesion molecules. Standardized functional assays revealed that resting MSCs inhibited proliferation of T and NK cells, but not B cells. ADSC-PL were the most potent in inhibiting T-cell growth, a property ascribed to interferon-γ-dependent indoleamine 2,3-dioxygenase activity. MSCs did not stimulate allogeneic T cell proliferation but were efficiently lysed by activated NK cells. The systematic use of quantitative and reproducible validation techniques highlights differences in immunological properties of MSCs produced using various clinical-grade processes. ADSC-PL emerge as a promising candidate for future clinical trials.
Published: 2013
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33. Immunoregulatory properties of clinical grade mesenchymal stromal cells: evidence, uncertainties, and clinical application

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 ), Etablissement Français du Sang Bretagne, EFS, Framework Program of the European Commission: CASCADE (FP7-HEALTH-233236), REBORNE (FP7-HEALTH-241879), the European Regional Development Fund (ERDF), the European Union, the European Center for Transplantation Sciences and Immunotherapy (IHU CESTI, ANR-10-IBHU-0005), Infrastructure Program ECELLFRANCE (ANR-11-INSB-005), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Corre, Morgane, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, 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: Chemokine, Stromal cell, Medicine (miscellaneous), [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mesenchymal Stem Cell Transplantation, Regenerative Medicine, immunomodulation, Biochemistry, Genetics and Molecular Biology (miscellaneous), Regenerative medicine, Cell therapy, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, mesenchymal stromal cells, immunomodulation, indoleamine 2, 3-dioxygenase, cell therapy, standardization, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, standardization, 0303 health sciences, biology, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, 3. Good health, 3-dioxygenase, Immune System Diseases, 030220 oncology & carcinogenesis, Immunology, biology.protein, Molecular Medicine, indoleamine 2, Stem cell, Chemokines, cell therapy, mesenchymal stromal cells
Abstract: International audience; Mesenchymal stromal cell (MSC)-based therapy holds great promise for treating immune disorders and for regenerative medicine in agreement with their paracrine trophic and immunosuppressive activities. Various processes have been developed worldwide to produce clinical grade MSCs but, so far, it is not known if one given MSC is more efficient than another. In addition, while their broad activity on innate and adaptative immune cell subsets is now widely admitted, the precise mechanisms supporting their immunoregulatory capacities are still a matter of debate. Finally, quantitative immunological potency assays correlated to clinical efficacy and clinically relevant immunomonitoring approaches for MSC-treated patients are sorely needed. Multiple parameters could influence the immunomodulatory potential of therapeutic MSCs. The most important challenge is now to differentiate, within a high number of poorly comparable and even contradictory pre-clinical studies, the parameters that could have some clinical impact from those that are only due to uncontrolled experimental variability. Importantly, besides MSC-related differences, primarily linked to production processes, several important variables associated with immune assays themselves, including selection of effector immune cells, activation signals, and read-out techniques, should be carefully considered to obtain solid results with potential therapeutic application. In this review, we establish a core of common and reproducible immunological properties of MSCs, shed light on technical issues concerning immunomodulatory potential assessment, and put them into perspective when considering clinical application.
Published: 2013
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34. Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes

Author: Olivier Fouquet, Gersende Caron, Fabien Guilloton, Joelle Dulong, Thierry Lamy, Patricia Amé-Thomas, Delphine Rossille, Cédric Ménard, John De Vos, Catherine Henry, Ceéline Pangault, Thierry Fest, Karin Tarte, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 ), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Modélisation Conceptuelle des Connaissances Biomédicales, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], INCa libre PL06-10, INCa PAIR Lymphome 2008-019, and Ligue Régionale Contre le Cancer
Subjects: Male, Cellular differentiation, Follicular lymphoma, MESH: Monocytes, Biochemistry, Monocytes, MESH: Lymphoma, Follicular, 0302 clinical medicine, Cell Movement, Lymphoma, Follicular, MESH: Cell Movement, Cells, Cultured, Chemokine CCL2, Oligonucleotide Array Sequence Analysis, MESH: Aged, B-Lymphocytes, 0303 health sciences, MESH: Middle Aged, MESH: Real-Time Polymerase Chain Reaction, Cell Polarity, Cell Differentiation, Hematology, Middle Aged, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Monocyte differentiation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Cell Polarity, MESH: Cells, Cultured, Adult, MESH: Cell Differentiation, Stromal cell, Blotting, Western, Immunology, Biology, CCL2, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: B-Lymphocytes, MESH: Cell Proliferation, Biomarkers, Tumor, medicine, Humans, MESH: Blotting, Western, RNA, Messenger, MESH: Chemokine CCL2, Aged, Cell Proliferation, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Gene Expression Profiling, Mesenchymal stem cell, Mesenchymal Stem Cells, MESH: Adult, Cell Biology, medicine.disease, MESH: Male, Lymphoma, MESH: Mesenchymal Stem Cells, MESH: Oligonucleotide Array Sequence Analysis, MESH: Tumor Markers, Biological, Cancer research, Bone marrow, Stromal Cells, MESH: Stromal Cells, MESH: Female
Abstract: Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit monocytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated macrophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease.
Published: 2012
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35. [Immunosuppression and mesenchymal stem cells: back to the future]

Author: Cédric, Ménard and Karin, Tarte
Subjects: Immune Tolerance, Animals, Humans, Mesenchymal Stem Cells, Mesenchymal Stem Cell Transplantation, Adaptation, Physiological, Forecasting
Abstract: 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.
Published: 2011

36. 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
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37. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors

Author: Frédéric Commo, Sylvie Rusakiewicz, Jean Franãois Emile, Caroline Flament, Jean-Yves Blay, Nicolas Ibrahim, Véronique Minard-Colin, Saadia Kerdine-Römer, Philippe Terrier, Jacques A. Nunès, Cédric Ménard, Pascale Paul, Benedita Rocha, Laurence Zitvogel, Kariman Chaba, Alessandro Moretta, Dominique Valteau-Couanet, Cristina Bottino, Javier Celis Gutierrez, Luc Lyonnet, A. Lecesne, Nathalie Chaput, Stephan Roux, Hélène Authier, Jean Michel Coindre, Matthieu Sarabi, Pascal Rihet, Véronique Baud, Nicolas F. Delahaye, Laetitia Peaudecerf, Isabelle Martins, Sylvie Bonvalot, Jan Tavernier, Eric Vivier, Nicolas Isambert, Michaela Semeraro, Isabelle Cremer, Marc Pallardy, Paule Opolon, Vichnou Poirier-Colame, Guido Kroemer, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Department of Immunology, Duke University Medical Center, 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 - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), School of Medicine, Université Paris-Sud - Paris 11 (UP11), Recepteurs et Signalisation des Interleukines (U749), 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), Département de Pédiatrie, Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Département de biologie et pathologie médicales [Gustave Roussy], Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Università di Genova, Dipartimento di Medicina Sperimentale, Universita degli studi di Genova, Biochemistry, Ghent University [Belgium] (UGENT), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Département de pathologie, Institut Bergonié - CRLCC Bordeaux, Département de Médecine Nucléaire, Centre Léon Bérard [Lyon], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Laboratory of Human Genetics of Infectious Diseases, Apoptose, cancer et immunité (U848), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), 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 - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Recepteurs et Signalisation des Interleukines ( U749 ), 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 ), Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Vectorologie et transfert de gènes ( VTG / UMR8121 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), University of Genova, Ghent University [Belgium] ( UGENT ), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques ( IP-TPT ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Service de Santé des Armées-Université de Montpellier ( UM ), Université Claude Bernard Lyon 1 ( UCBL ), Apoptose, cancer et immunité ( U848 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Genova = University of Genoa (UniGe), Universiteit Gent = Ghent University (UGENT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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), and Universiteit Gent = Ghent University [Belgium] (UGENT)
Subjects: MESH: Interleukin-12, MESH : Alternative Splicing, MESH: Protein Isoforms, MESH: Lysosomal-Associated Membrane Protein 1, 0302 clinical medicine, Interferon, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Protein Isoforms, Receptor, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, MESH : Prognosis, MESH : Gastrointestinal Stromal Tumors, GiST, MESH : Lysosomal-Associated Membrane Protein 1, MESH: Alternative Splicing, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, General Medicine, Prognosis, Interleukin-12, MESH: Proto-Oncogene Proteins c-kit, Killer Cells, Natural, Proto-Oncogene Proteins c-kit, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, MESH : Killer Cells, Natural, Sarcoma, MESH: Natural Cytotoxicity Triggering Receptor 3, Tyrosine kinase, MESH: Gastrointestinal Stromal Tumors, medicine.drug, MESH: Killer Cells, Natural, Gene isoform, MESH : Natural Cytotoxicity Triggering Receptor 3, MESH: Cell Line, Tumor, Stromal cell, MESH: Interferon-gamma, Gastrointestinal Stromal Tumors, Biology, Polymorphism, Single Nucleotide, MESH : Proto-Oncogene Proteins c-kit, MESH: Prognosis, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, Lysosomal-Associated Membrane Protein 1, Cell Line, Tumor, MESH : Interleukin-12, medicine, Humans, MESH : Interferon-gamma, 030304 developmental biology, MESH: Humans, Natural Cytotoxicity Triggering Receptor 3, MESH : Cell Line, Tumor, Tumor Necrosis Factor-alpha, MESH : Humans, MESH : Protein Isoforms, medicine.disease, Alternative Splicing, MESH: Tumor Necrosis Factor-alpha, Immunology, Cancer research, 030215 immunology
Abstract: International audience; The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.
Published: 2010
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38. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients

Author: Julien Taieb, Jean-François Emile, Jean-Yves Blay, Laurence Zitvogel, Stefan Michiels, Christophe Borg, Nathalie Chaput, Céline Nonn, François Ghiringhelli, Caroline Flament, Cédric Ménard, Axel Le Cesne, Nicolas F. Delahaye, Caroline Robert, 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), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine, Centre Léon Bérard [Lyon], 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 de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Méthodologie et épidémiologie clinique en oncologie moléculaire (U1018 (Équipe 2)), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR), Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Institut Gustave Roussy (IGR), Saas, Philippe, and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Oncology, Cancer Research, MESH: Piperazines, Piperazines, 0302 clinical medicine, Stromal tumor, 10. No inequality, 0303 health sciences, MESH: Middle Aged, GiST, MESH: Dendritic Cells, Hazard ratio, Exons, Middle Aged, 3. Good health, Killer Cells, Natural, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, medicine.anatomical_structure, NK Cell Lectin-Like Receptor Subfamily K, 030220 oncology & carcinogenesis, Benzamides, Imatinib Mesylate, MESH: NK Cell Lectin-Like Receptor Subfamily K, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Natural Cytotoxicity Triggering Receptor 3, MESH: Gastrointestinal Stromal Tumors, medicine.drug, MESH: Killer Cells, Natural, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Gastrointestinal Stromal Tumors, MESH: Interferon-gamma, Antineoplastic Agents, Natural killer cell, Interferon-gamma, 03 medical and health sciences, Internal medicine, medicine, Humans, 030304 developmental biology, Natural Cytotoxicity Triggering Receptor 3, MESH: Humans, Proportional hazards model, business.industry, Cancer, Imatinib, MESH: Interleukin-2, Dendritic Cells, medicine.disease, MESH: Male, Pyrimidines, Imatinib mesylate, MESH: Pyrimidines, Immunology, Interleukin-2, MESH: Antineoplastic Agents, business, MESH: Exons, MESH: Female
Abstract: Clinical outcomes of gastrointestinal stromal tumor (GIST)–bearing patients treated with imatinib mesylate (IM) are variable. Other than the site of mutation within the c-kit gene, prognostic features of GIST remain undefined. IM can exhibit off-target effects such as triggering natural killer (NK) cell activity. We addressed whether NK cell functions could predict long term survival with IM. NK cell functions were followed up in 77 GIST patients enrolled onto two phase III trials. “Immunologic responders” were defined as patients whose NK cell IFN-γ values after 2 months of IM were higher than or equal to the baseline value at entry into the trial. The prognostic effect of IFN-γ on progression-free survival was assessed by a Wald test in a Cox regression analysis using the landmark method and stratified by trial and on the c-kit mutational status. Fifty-six patients were evaluable for the NK cell IFN-γ responses at baseline and 2 months. Their median follow-up for progression-free survival was 3.7 years. Thirty-four of 56 patients were immunologic responders to IM. In the Cox regression analysis, immunologic responders possessed a hazard ratio of progression or death equal to 0.29 (95% confidence interval, 0.12–0.70; P = 0.006) compared with nonresponders. Kaplan-Meier 2-year survival estimates were 85% for immunologic responders and 50% for nonresponders. Moreover, the immunologic response added prognostic value to the c-kit mutation. The NK cell IFN-γ production after 2 months of treatment could be considered an independent predictor of long term survival in advanced GISTs treated with IM. [Cancer Res 2009;69(8):3563–9]
Published: 2009
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39. Imatinib mesylate (Gleevec): targeted therapy against cancer with immune properties

Author: Cédric Ménard, Moustapha Zoubir, Nathalie Chaput, Laurence Zitvogel, and Thomas Tursz
Subjects: Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, T-Lymphocytes, Antineoplastic Agents, Disease, Pharmacology, T-Lymphocytes, Regulatory, Piperazines, Targeted therapy, Immunomodulation, Immune system, Neoplasms, medicine, Immunology and Allergy, Animals, Humans, ABL, business.industry, breakpoint cluster region, Cancer, Dendritic Cells, Protein-Tyrosine Kinases, medicine.disease, Killer Cells, Natural, Imatinib mesylate, Pyrimidines, Benzamides, Mutation, Cancer research, Imatinib Mesylate, Interferons, business, Tyrosine kinase
Abstract: The treatment against cancer is being flooded by targeted therapies. Imatinib mesylate (Gleevec©) was the first molecule to provide the proof of principle that targeting an aberrant tyrosine kinase responsible for the uncontrolled cell cycle progression allows for the eradication of tumors. The ideal targeted therapy should eliminate the molecular event responsible for the disease, an oncogenic product such as c-KIT, ABL/BCR and PDGFRα in the case of Gleevec©. Two issues related to this conceptual advance are raised in clinical practice. First, these therapies might target additional pathways generating side effects. Secondly, non tumoral cells bearing the molecular target might respond and induce additional biological outcomes. This review will summarize the by-stander immune modulations promoted by the paradigmatic compound Gleevec©, leading to unexpected new therapeutic indications.
Published: 2008

40. Dendritic cells and innate defense against tumor cells

Author: Grégoire Mignot, Evelyn Ullrich, Magali Terme, Nathalie Chaput, Laurence Chaperot, Caroline Flament, Cédric Ménard, Mathieu Bonmort, Laurence Zitvogel, Joel Plumas, 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), INSERM U823, équipe 9 (Immunobiologie et Immunothérapie des Cancers), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire recherche et développement, EFS, Laboratoire recherche et développement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), ARC, INCA, Cancéropole, ligue nationale contre le cancer, Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Chaperot, Laurence
Subjects: MESH: Interferon Type I, Endocrinology, Diabetes and Metabolism, MESH: Interleukin-15, MESH: Piperazines, Apoptosis, Piperazines, MESH: Cancer Vaccines, MESH: Uric Acid, 0302 clinical medicine, MESH: HMGB1 Protein, Neoplasms, Immunology and Allergy, MESH: Interferons, MESH: Neoplasms, HMGB1 Protein, MESH: CpG Islands, Interleukin-15, 0303 health sciences, Toll-like receptor, MESH: Cytokines, MESH: Dendritic Cells, T helper cell, T-Lymphocytes, Helper-Inducer, MESH: Granulocyte-Macrophage Colony-Stimulating Factor, 3. Good health, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, Oligodeoxyribonucleotides, 030220 oncology & carcinogenesis, Benzamides, Interferon Type I, Imatinib Mesylate, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Killer Cells, Natural, Fas Ligand Protein, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Interferon Type II, T cell, Immunology, MESH: Receptor Cross-Talk, Biology, Cancer Vaccines, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, Immune system, medicine, Biomarkers, Tumor, Humans, MESH: T-Lymphocytes, Helper-Inducer, Antigen-presenting cell, 030304 developmental biology, MESH: Immunity, Natural, Tumor microenvironment, Innate immune system, MESH: Humans, MESH: Apoptosis, Granulocyte-Macrophage Colony-Stimulating Factor, Dendritic cell, Dendritic Cells, Receptor Cross-Talk, Immunity, Innate, MESH: Fas Ligand Protein, Uric Acid, Pyrimidines, MESH: Pyrimidines, MESH: Tumor Markers, Biological, MESH: Oligodeoxyribonucleotides, CpG Islands, Interferons
Abstract: International audience; Tumor growth results from a delicate balance between intrinsic dysregulation of oncogenes, tumor suppressor and stability genes counteracted by extrinsic defenses composed of immune cells shaping tumor immunogenicity. Although immune subversion might be the ultimate outcome of this process, a complex network of cellular interactions take place eventually leading to tumor specific cognate immune responses. The links between innate and cognate antitumor immunity eliciting protective T cell responses are instigated by cytokines, chemokines and damage associated molecular patterns. The intricate differentiation pathway whereby dendritic cells could undergo an efficient maturation program in the tumor microenvironment appears crucial. We will discuss the role of innate effectors and cancer therapies in the process of defense against tumor cells.
Published: 2008
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41. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner

Author: Jacky Bernard, Antônio C. Freitas, Jean-Yves Blay, Caroline Flament, Orianne Wagner-Ballon, Laurence Zitvogel, Cédric Ménard, A. Lecesne, Magali Terme, T. Tursz, Caroline Robert, Bernard Escudier, William Vainchencker, Eric Vivier, Claude Capron, Julien Taieb, Sophie Caillat-Zucman, François Ghiringhelli, Sophie Novault, Nathalie Chaput, Pierre E. Puig, François Martin, Rôle des cellules dendritiques dans la régulation des effecteurs de l'immunité antitumorale, Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hematopoïèse et Cellules Souches ( U362 ), 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 Jean Godineau, Etablissement Français du Sang, Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Biologie des Populations Lymphocytaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematopoïèse et Cellules Souches (U362), 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), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), 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 Pasteur [Paris], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH : Cytokines, MESH: Flow Cytometry, MESH : Immunity, Natural, MESH: T-Ly, Lymphocyte Activation, T-Lymphocytes, Regulatory, Mice, Interleukin 21, 0302 clinical medicine, T-Lymphocyte Subsets, Transforming Growth Factor beta, Neoplasms, MESH : Receptors, Immunologic, MESH : Cell Proliferation, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Neoplasms, IL-2 receptor, Receptors, Immunologic, 0303 health sciences, MESH: Cytokines, hemic and immune systems, Flow Cytometry, Natural killer T cell, 3. Good health, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, NK Cell Lectin-Like Receptor Subfamily K, Interleukin 12, Cytokines, Receptors, Natural Killer Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, France, MESH : Killer Cells, Natural, MESH : Cytotoxicity Tests, Immunologic, MESH: Killer Cells, Natural, MESH: Cell Line, Tumor, MESH : Flow Cytometry, Immunology, chemical and pharmacologic phenomena, MESH: Cytotoxicity Tests, Immunologic, MESH : Mice, Inbred C57BL, Biology, Article, Natural killer cell, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Cell Line, Tumor, MESH: Cell Proliferation, MESH : Mice, medicine, Animals, Humans, Antigen-presenting cell, MESH: Lymphocyte Activation, MESH : France, MESH: Mice, MESH: Receptors, Immunologic, MESH : Lymphocyte Activation, Cell Proliferation, 030304 developmental biology, MESH: Immunity, Natural, Lymphokine-activated killer cell, MESH: Humans, MESH : Cell Line, Tumor, MESH : Humans, Cytotoxicity Tests, Immunologic, NKG2D, MESH : T-Ly, MESH : Neoplasms, Immunity, Innate, Mice, Inbred C57BL, MESH: France, MESH : Animals, 030215 immunology
Abstract: Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β−/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.
Published: 2007
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42. The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression

Author: François Martin, Laurence Zitvogel, Cédric Ménard, and François Ghiringhelli
Subjects: Lymphokine-activated killer cell, biology, Immunology, hemic and immune systems, chemical and pharmacologic phenomena, Natural killer T cell, NKG2D, T-Lymphocytes, Regulatory, Natural killer cell, Killer Cells, Natural, Interleukin 21, medicine.anatomical_structure, Granzyme, Neoplasms, biology.protein, medicine, Interleukin 12, Cancer research, Disease Progression, Immunology and Allergy, Animals, Humans, IL-2 receptor
Abstract: Tumor immunosurveillance relies on cognate immune effectors [lymphocytes and interferon-gamma (IFN-gamma)] and innate immunity [natural killer (NK) cells, natural killer group 2, member D (NKG2D) ligands, perforin/granzyme, and tumor necrosis factor-related apoptosis-inducing ligand]. In parallel, tumor cells promote the expansion of CD4(+)CD25(+) regulatory T cells (Tregs) that counteract T-cell-based anti-tumor immunity. Moreover, accumulating evidence points to a critical role for Tregs in dampening NK cell immune responses. This review summarizes the findings showing that Tregs suppress NK cell effector functions in vitro and in vivo, i.e. homeostatic proliferation, cytotoxicity, and interleukin-12-mediated IFN-gamma production. The molecular mechanism involve selective expression of membrane-bound transforming growth factor-beta on Tregs, which downregulate NKG2D expression on NK cells in vitro and in vivo. The regulatory events dictating NK cell suppression by Tregs have been studied and are discussed. The pathological relevance of the Treg-NK cell interaction has been brought up in tumor models and in patients with cancer. Consequently, inhibition of Tregs through pharmacological interventions should be considered during NK-cell-based immunotherapy of cancer.
Published: 2006

43. IL-2 production by dendritic cells is not critical for the activation of cognate and innate effectors in draining lymph nodes

Author: Céleste Lebbé, Julien Taieb, Noël E. C. Schartz, Anneliese Schimpl, Cédric Ménard, Patrice Ardouin, Magali Terme, Pierre Bonnaventure, Nathalie Chaput, Laurence Zitvogel, and Helene Trebeden-Negre
Subjects: Lipopolysaccharides, T cell, Immunology, Priming (immunology), Bone Marrow Cells, Biology, Lymphocyte Activation, Interleukin 21, Mice, Bone Marrow, medicine, Immunology and Allergy, Cytotoxic T cell, Animals, Antigen-presenting cell, Lymphokine-activated killer cell, Dendritic Cells, Adoptive Transfer, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, Interleukin 12, Interleukin-2, Female, Lymph Nodes, Ex vivo, T-Lymphocytes, Cytotoxic
Abstract: Dendritic cells (DC) are unique antigen-presenting cells capable of triggering NK cell effector functions and priming naive T cells in vivo. Microbial stimulation induces early IL-2 production by mouse DC. Previous reports demonstrated that IL-2 is enriched at the site of DC/T cell interaction and promotes allogeneic T cell proliferation. However, the direct role of DC-derived IL-2 in the differentiation of cytotoxic T lymphocytes and in NK cell triggering in vivo has not been investigated. Lipopolysaccharide (LPS) stimulation of mouse bone morrow-derived DC results in early IL-2 production unless IL-4 is introduced in DC cultures. Here we show that IL-2 produced by LPS-activated DC is dispensable for cognate T cell responses since IL-2 loss of function DC elicit OVA-specific Tc1 effector and memory lymphocytes in draining lymph nodes in a setting where ex vivo cultured DC do not transfer antigens to host DC. Moreover, adoptively transferred IL-2 loss of function DC maintain their capacity to trigger NK cell proliferation/recruitment in lymph nodes. Therefore, immediate inducible IL-2 production by DC following microbial infection might play a regulatory role at ports of entry rather than in secondary lymphoid organs.
Published: 2005

44. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects

Author: Salah Mecheri, Jonhantan A. Fletcher, Kris Thielemans, Florent Crépineau, Jacky Bernard, Caroline Flament, Julien Taieb, Isabelle Tchou, Jean-Yves Blay, J.F. Emile, Cédric Ménard, Alain Spatz, Vladimir Lazar, Eric Angevin, Véronique Chung-Scott, Magali Terme, François M. Lemoine, Laurence Zitvogel, Christophe Borg, Hiro Wakasugi, Ali G. Turhan, Michael Heinrich, Thomas Tursz, Axel Le Cesne, Koji Maruyama, Caroline Robert, and Physiology
Subjects: tumor, Antineoplastic Agents, Mice, SCID, c-kit tyrosine kinase inhibitors, Article, Neutrophil Activation, Piperazines, Receptor tyrosine kinase, Interferon-gamma, Mice, In vivo, Animals, Humans, Receptors, Platelet-Derived Growth Factor, Longitudinal Studies, Enzyme Inhibitors, Mode of action, Receptor, Gastrointestinal Neoplasms, Mice, Knockout, biology, Receptor Protein-Tyrosine Kinases, Dendritic Cells, General Medicine, Protein-Tyrosine Kinases, Coculture Techniques, Gene Expression Regulation, Neoplastic, Killer Cells, Natural, Mice, Inbred C57BL, Proto-Oncogene Proteins c-kit, Pyrimidines, Imatinib mesylate, Case-Control Studies, Benzamides, Mutation, Imatinib Mesylate, Leukocytes, Mononuclear, Cancer research, biology.protein, Female, Stromal Cells, Tyrosine kinase, Platelet-derived growth factor receptor
Abstract: Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.
Published: 2004

45. Effects Of a Novel Ceramic Biomaterial On Immune Modulatory Properties and Differentiation Potential Of Mesenchymal Stromal Cells

Author: Markus Rojewski, Giulio Bassi, Lazzari Lorenza, Jasmina Zanoncello, Pierre Layrolle, Karin Tarte, Roberta Carusone, Mariano Di Trapani, Hubert Schrezenmeier, Luciano Pacelli, Serge Baroth, Fabien Guilloton, Rosaria Giordano, Luc Sensebe, Francesco Bifari, Fredric Deschaseaux, Cédric Ménard, Cristiana Lavazza, Mauro Krampera, and Philippe Bourin
Subjects: biology, T cell, Immunology, Mesenchymal stem cell, Inflammation, Cell Biology, Hematology, Lymphocyte proliferation, Biochemistry, Proinflammatory cytokine, Immunophenotyping, Immune system, medicine.anatomical_structure, Osteocalcin, biology.protein, medicine, Cancer research, medicine.symptom
Abstract: Bone is one of the most frequently transplanted tissues, with allografts and autografts accounting for more than 80% of total grafts. Synthetic biomaterials in association with autologous or allogeneic mesenchymal stromal cells (MSCs) represent a valid alternative in orthopaedic and maxillofacial surgery. Aim of REBORNE consortium is to perform clinical trials using standardized protocols based on advanced biomaterials and MSCs. Aim of our Unit was to assess MSC immune modulatory properties in presence of a novel biomaterial consisting of hydroxyapatite and tricalcium-phosphate (HA/TCP, Biomatlante, France) as scaffold for MSC delivery. We assessed immune modulatory properties, in terms of immunophenotype, inhibitory and anti-apoptotic effects, of MSCs of different origin when associated with the HA/TCP biomaterial, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), adipose-derived MSCs (ASCs) and cord blood-derived MSCs (CB-MSCs). The culture of all MSCs with HA/TCP, did not modulate the anti-apoptotic and suppressive features of all MSCs toward sorted-T, B and NK lymphocytes as compared to standard culture setting. When exposed to inflammatory cytokines, such as IFN-γ and TNF-α, all MSCs were induced to acquire the suppressive phenotype, characterized by MHC-1 and CAM molecules up-regulation, and de novo expression of HLA-DR molecules. The long-term culture of BM-MSCs with HA/TCP induced an osteoblast-like phenotype, as indicated by the up-regulation of osterix and osteocalcin transcription. The differentiation process is promoted in all MSC types, but especially in BM-MSCs, by dexamethasone and, to a higher extent, BMP-4 treatment. In view of using MSCs for advanced therapies in allogeneic setting, we evaluated the immunogenicity and immune modulatory features of pre-differentiated MSCs in association with HA/TCP towards both innate and adaptive immune cells, as well as the molecular pathways involved in MSC-mediated immune regulation. MSC-derived osteoblasts did not induce immune cell activation, as demonstrated by co-culture of unstimulated immune effector cells with pre-differentiated MSCs. We found a lower suppressive capability of pre-differentiated MSCs towards stimulated T and NK cells. However, some inhibitory effects could be exerted by BMP-4 treated-MSCs, and could be related to the presence of undifferentiated MSCs in culture, which could inhibit lymphocyte proliferation. The balance between the number of bone depositing osteocyte-like MSCs and immunosuppressive undifferentiated MSCs could be useful, in vivo, to promote bone healing and to reduce local inflammation, respectively. We then investigated in pre-differentiated MSCs the molecular mechanisms involved in the inhibition of T cell proliferation, by interfering with IDO and COX-2 activation. We found that pre-differentiated MSCs switched on their suppressive machinery by activating both IDO, which plays a central role in immune regulation, and COX-2, whose role is not significant in undifferentiated MSCs. COX-2 is produced rapidly as inflammation mediator after fracture, and recent data highlighted the role of COX-2 in improving fracture healing. In conclusion, this study increases the knowledge on MSC biology and gives pre-clinical data concerning the use of allogeneic MSC in combination with ceramic scaffolds to treat bone defects. Disclosures: No relevant conflicts of interest to declare.
Published: 2013
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46. Propriétés immunomodulatrices des cellules stromales mésenchymateuses de l’adulte

Author: Cédric Ménard, Karin Tarte, and Luc Sensebé
Subjects: Biochemistry (medical), Clinical Biochemistry, Hematology
Published: 2013
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47. Iterative Germinal Center Re-Entries of Memory B-Cells with t(14;18) Translocation and Early Steps of Follicular Lymphoma Progression

Author: Emilie Gregoire, Céline Monvoisin, Jocelyne Stephanie Sungalee, Karin Tarte, Cédric Ménard, Jean Hardwigsen, Ester Morgado, Emilie Mamessier, Sandrine Roulland, Franziska C. Eberle, Jean-Marc Navarro, Philippe Ruminy, Bertrand Nadel, Elaine S. Jaffe, and Claudine Schiff
Subjects: education.field_of_study, Immunology, Population, Follicular lymphoma, Germinal center, Spleen, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, Centrocyte, medicine.anatomical_structure, Lymphatic system, medicine, Centroblasts, Bone marrow, education
Abstract: Abstract 150 The recent demonstration that memory B-cells can re-enter germinal centers (GCs) and participate to new rounds of GC reactions has opened the possibility that multi-hit B-cell lymphomagenesis could be a much more dynamic process than initially anticipated, gradually progressing throughout the successive passages of memory B-cells in GCs during a lifetime of successive immunological challenges. Here, we provide evidence for this scenario in follicular lymphoma (FL), a GC derived B-cell malignancy initiated in the bone marrow by the hallmark t(14;18) BCL2/IGH translocation. To address this issue, we engineered an original sporadic BCL2tracer mouse model mimicking the rare occurrence of t(14;18) translocation in humans through V(D)J recombination errors (1 in a million B-cells) allowing to track the resultant BCL2-expressing clones; and underwent a molecular/immunofluorescent tracking of t(14;18)+ clones vs. normal memory B-cells in paired lymphoid tissue samples (spleen, lymph nodes, bone marrow) from healthy individuals. We first show that contrary to the current dogma, ectopic BCL2 expression is not sufficient to provoke the FL's characteristic differentiation arrest of activated B-cells as GC B-cells, thereby suggesting that differentiated BCL2+ memory B-cells must return to the GC to acquire additional oncogenic hits and “fix” in situ growth. Strikingly, we further find that in a small fraction of “healthy” humans, such differentiation arrest already operated, and that a clonally expanded population of t(14;18)+ cells with FL-like features have widely disseminated in blood and in multiple lymphoid organs (spleen, lymph nodes, bone marrow), with unprecedentedly reported frequencies (from 1/million to 1/500 cells in some individuals), shaping the systemic disease presentation observed in FL patients. Using molecular/immunofluorescent backtracking of such clones in various paired and remote lymphoid organs, we further demonstrate that t(14;18)+ clones systematically display an extensive history of AID (activation-induced cytidine deaminase)-mediated events compatible with iterative rounds of GC co-opting, in sharp contrast to single memory B-cell clones from the same individuals. We thus show that BCL2-expressing memory B-cells require multiple GC transits to acquire the distinctive FL-like maturation arrest as centrocyte/centroblasts and to progress to advanced FL precursor stages. Altogether, our data argue for a model of lymphomagenesis, in which progression from precursor stages to FL occurs asymptomatically over an extended period of time by subverting the dynamic and plastic attributes of memory B-cells. This understanding of the pre-clinical phases driving FL development in asymptomatic patients should help rationalize prospective approaches designed to identify biomarkers of risk, and innovative therapeutic targets present in early, potentially more curable phases of the disease. Disclosures: No relevant conflicts of interest to declare.
Published: 2012
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48. Mesenchymal Stromal Cells Orchestrate Follicular Lymphoma Cell Niche Through the CCL2-Dependent Recruitment and Polarization of Monocytes

Author: Fabien Guilloton, Gersende Caron, Cédric Ménard, Céline Pangault, Patricia Amé-Thomas, Joelle Dulong, John De Vos, Delphine Rossille, Thierry Lamy, Thierry Fest, and Karin Tarte
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Abstract: Abstract 1566 Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of solid cancers and hematological malignancies. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and bone marrow (BM). In addition, in vitro functional studies have underlined that mesenchymal cells recruit malignant FL B cells and protect them from spontaneous and drug-induced apoptosis. In particular, we have previously demonstrated that mesenchymal stromal cells (MSC) efficiently support in vitro FL B-cell survival, especially after their engagement towards lymphoid differentiation through treatment with TNF-α and Lymphotoxin-α1β2 (TNF/LT) or after coculture with malignant B cells. However, the mechanisms of this supportive activity remain largely unknown. In this study, we used Affymetrix U133 Plus 2.0 microarrays, to compare the gene expression profile (GEP) of bone marrow-derived MSC (BM-MSC) obtained from 10 FL patients at diagnosis versus 6 age-matched healthy donors (HD). In these conditions, neither the CFU-F concentration in the BM nor the cumulative population doubling of BM-MSC significantly differed between HD and FL patients. Unsupervised analysis was able to perfectly segregate FL-MSC from HD-MSC and we identified, using supervised analyzes, a list of 408 probesets defining FL-MSC signature, including 320 nonredundant genes upregulated in FL-MSC compared to HD-MSC. We then defined the GEP of human lymphoid-like stroma using HD-MSC treated in vitro by TNF/LT and demonstrated, by a Gene Set Enrichment Analysis (GSEA) approach, that the FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 was strongly overexpressed by FL-MSC, was upregulated in HD-MSC by coculture with malignant B cells, and was detected at a higher level in FL BM plasma compared to normal BM plasma (504.4 pg/mL [23.8-4413] versus 33.9 pg/mL [5-126.1]; P Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL cell niche. The identification and characterization of this intricate network of cell interactions may provide novel therapeutic targets in this disease. Disclosures: No relevant conflicts of interest to declare.
Published: 2011
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49. Microporous Biphasic Calcium Phosphate Granules (MBCP®) Retain Immunological Properties of Bone Marrow-Derived Mesenchymal Stromal Cells and Promote Osteoblastic Differentiation

Author: Luc Sensebe, Karin Tarte, Pierre Layrolle, Fabien Guilloton, Frederic Deschaseaux, Cédric Ménard, Giulio Bassi, Giovanni Pizzolo, Francesco Bifari, Mauro Krampera, Luciano Pacelli, and Serge Baroth
Subjects: biology, Immunology, Mesenchymal stem cell, Cell Biology, Hematology, Bone healing, Bone morphogenetic protein, Biochemistry, Transplantation, medicine.anatomical_structure, Bone morphogenetic protein 4, medicine, Osteocalcin, biology.protein, Cancer research, Tumor necrosis factor alpha, Bone marrow
Abstract: Abstract 1924 Bone is among the most frequently transplanted tissue with about 1 million procedures annually in Europe. Allografts and autografts account for more than 80% of total graft volume, despite their considerable disadvantages, including the risk of disease transfer and immunologic rejection, limited supply of bone, costs and complications. Significant growth opportunities exist for synthetic bone grafts in association with mesenchymal stromal cells (MSC) from autologous or allogeneic sources as alternatives to biological bone grafts in orthopaedic and maxillofacial surgery. The objective of REBORNE is to perform clinical trials using advanced biomaterials and cells triggering bone healing in patients. To reach this goal, five phase I clinical studies with 20 patients have been planned in 12 clinical Centers spread in 8 European countries. Aim of the Immunological Unit of Reborne is to assess the MSC immunomodulatory properties in presence of the biomaterial used as scaffold for MSC delivery. All the functional experiments were performed in parallel, by comparing the effects of standard culture conditions and three-dimensional culture setting using MBCP (Biomatlante). Material and methods: Bone marrow MSC were provided from REBORNE Consortium Centers. To perform proliferation assays, different immune effector cells (T, B and NK cells) were stained with CFSE according to manufacturer's protocol. Active caspase-3 cell staining was used for survival quantification of immune effector cells after co-culture experiments. Differentiation potential was evaluated by culturing MSC with two different media containing either bone morphogenetic protein 4 (BMP4) or dexamethasone. After three weeks, osteogenic differentiation was quantified by qRT-PCR, alkaline phosphatase activity and alizarin red staining. Results: We found that primed MSC, pre-treated with the inflammatory cytokines IFNg and TNFa, displayed upregulation of HLA-ABC, CD54, CD106 and de novo expression of HLA-DR, both in standard culture conditions and in association with MBCP. Immune effector cells could be cultured and collected even in presence of MBCP and no significant differences were found between standard- (MSC + effector cells) and 3D-coculture conditions (MSC + MBCP + effector cells), in terms of immune effector cell proliferation. In both experimental conditions MSC suppressed T and NK cell proliferation (% suppression: MSC + T = 68.4; MSC + MBCP + T = 62.4; MSC + NK = 17.5; MSC + MBCP + NK = 20.2) and increased B cell proliferation (MSC + B = +13%; MSC + MBCP + B = +12.3%). In addition, immune effector cells viability was not affected by MBCP and MSC co-culture increased their survival even in presence of MBCP; in fact, in each culture condition the percentage of inhibition of T, B and NK cell apoptosis was higher than 20% in comparison to immune effector cells cultured without MSC. Dexamethasone and BMP4 were capable of inducing MSC differentiation into osteoblast-like cells, as confirmed by qRT-PCR analysis. We demonstrated that BMP4-based medium led to fully differentiated osteoblasts (Osterix+, RUNX2+, DLX5+ and alkaline-phosphatase+). Moreover, MBCP was more efficient in increasing osteoblastic differention as compared to standard culture conditions, as shown by the higher expression of Osteocalcin and Osterix. These data show that the association of MBCP and MSC does not affect MSC properties and suggest that it could be a treatment of choice of bone defects instead of allograft and autograft transplantation. Disclosures: No relevant conflicts of interest to declare.
Published: 2011
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50. Quality Controls of Immune Regulatory Properties of Ex-Vivo, GMP-Grade Expanded Mesenchymal Stromal Cells for Clinical Use (European multicenter study CASCADE)

Author: Giulio Bassi, Luciano Pacelli, Hubert Schrezenmeier, Mauro Krampera, Joelle Dulong, Cédric Ménard, Isabelle Bezier, Jasmina Zanoncello, Luc Sensebe, Karin Tarte, and Francesco Bifari
Subjects: MHC class II, CD40, biology, medicine.medical_treatment, T cell, Immunology, Mesenchymal stem cell, Priming (immunology), Cell Biology, Hematology, Biochemistry, Molecular biology, Cytokine, medicine.anatomical_structure, Immune system, Aldesleukin, biology.protein, medicine
Abstract: Abstract 4049 Aim of the European Consortium CASCADE is to standardize GMP-grade production and clinical use of Mesenchymal Stromal Cells (MSC) to treat skin and corneal wounds. MSC possess immunogenicity and immunomodulatory properties that must be carefully addressed before clinical use. CASCADE Immunological Unit is aimed to set up and validate a wide panel of functional assays to fully characterize in a standardized and reproducible manner the immunomodulatory properties of MSC obtained inside CASCADE Units from bone marrow, adipose tissue, cord blood, and amniotic membrane (BM, AT, CB, AM) through different GMP-grade expansion protocols including platelet lysate- and fetal calf serum-based culture conditions. Immune cells were isolated using indirect immunomagnetic depletion; samples with less than 96% of purity were discarded. For the experiments, MSC were expanded in the same medium used for production and harvested at 70% confluence. Primed MSC were obtained by 48h-treatment with 10 ng/ml of rh-INFγ and 15 ng/ml of rh-TNFα. Cocultures were set up by plating primed or unprimed MSC in 96 or 48 flat bottomed – well plates; CFSE-stained T, B, NK cells were seeded at different effector cell:MSC ratios. Cells were harvested after 4 or 6 days of coculture for proliferation evaluation by FACS analysis. T cells were stimulated with mitogenic αCD3 plus αCD28 antibodies at 0.5 μg/ml each; B cells were activated with CD40L at 50 ng/ml, its enhancer at 5 g/ml, IL-2 20 UI/ml, CpG 2006 2.5 μg/mL, and F(ab')2 anti-IgM/IgA/IgG 2 μg/mL; NK cells were activated with 100 U/ml rh-IL2. To identify the molecular mechanisms involved in immunomodulatory properties of MSC, coculture of immune effector cells and MSC were performed in the presence of specific inhibitors, after identifying their non-toxic and effective concentrations: 1 mM for L-1MT (IDO inhibitor), 2 μM for snPP (HO-1 inhibitor), 5 μM for NS-398 (COX2 inhibitor), 1 mM for L-NMMA (iNOS inhibitor) and 10 μg/ml for anti-IFNγ neutralizing antibody. We also studied the capacity of resting and primed MSC to sustain the survival of unstimulated T, B, and NK cells through the evaluation of the percentage of caspase-3negCD45pos viable immune cells after 4 to 6 days in culture with or without MSC. For MSC immunogenicity assay, the proliferation of allogeneic T was evaluated at day 5 of culture by incorporation of 3H-Thymidine; in addition, NK cells were activated for 2 days with 100 U/ml of rh-IL2 whereas resting or primed MSC were loaded with non radioactive fluorophore (BaTDA) or with Cr51 and used as target cells. Inflammatory milieu significantly upregulated MHC class I and II, CD54, CD106, CD40, CD274, CD112, CD155 expression, and downregulated NKG2D ligands (ULBP 1–3, MICA/B) and mesenchymal markers (CD73, CD90, CD105). AT-derived MSC expressed less MHC class II, CD200 and CD106 molecules than BM-MSC. MSC coculture inhibited T and NK cell proliferation without inducing apoptosis, and this effect was greater in presence of primed MSC. On the contrary, only primed MSC were capable of suppressing B cell proliferation. In addition, MSC inhibited apoptosis of resting T, B, and NK cells, while inflammatory priming increased their pro-survival activity. T cell/MSC coculture showed that activation of IDO and HO-1 was the main mechanism involved in MSC immune modulation, as the addition of specific inhibitors (L-1-MT and snPP) significantly reverted the phenomenon. MSC never promoted allogeneic T cell proliferation; by contrast, IL-2-activated NK cells could efficiently recognize and kill allogenic unprimed MSC. However, MSC became insensitive to NK cells once primed with inflammatory cytokines. Some differences were observed depending on the origin and culture conditions of clinical-grade MSC. All the experimental protocols to assess MSC inhibitory effects on immune effector cells have been standardized and will be applied for the release of GMP-grade MSC produced inside the CASCADE Consortium. Disclosures: No relevant conflicts of interest to declare.
Published: 2011
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