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1. GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism

Author

Laura Mondragón, Philippe Gaulard, Jaap G Neels, Camila Rubio-Patiño, Frédéric Coutant, Laurent Boyer, François Lemonnier, Florian Muller, Elodie Villa, Rana Mhaidly, Vahid Asnafi, Thierry Passeron, Gian Marco De Donatis, Jean-François Peyron, Nicole Fabien, Els Verhoeyen, Sandrine Marchetti, Pascal Dao, Laura Sormani, Marie Jacquin, Marie Tosolini, Jean-Ehrland Ricci, Emma Proïcs, Anne Doye, Laurent Genestier, Jozef P. Bossowski, Anthony Martin, Véronique Imbert, Frederic Luciano, Jean-Jacques Fournié, Rachid Benhida, Caroline Pons, Johanna Chiche, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), Institut de Chimie de Nice (ICN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Hospices Civils de Lyon (HCL), Centre méditérannéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Physiopathologie de la survie et de la mort cellulaire et infection virale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Immunogenomique et Inflammation, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre de Recherche en Cancérologie de Toulouse (CRCT), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, Male, Cancer Research, [SDV]Life Sciences [q-bio], T-Lymphocytes, Datasets as Topic, chemistry.chemical_compound, 0302 clinical medicine, Glyceraldehyde 3-phosphate dehydrogenase, ComputingMilieux_MISCELLANEOUS, biology, NF-kappa B, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Female, Signal Transduction, Genetically modified mouse, Angioimmunoblastic T-cell lymphoma, Lineage (genetic), T cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Serine-Threonine Kinases, Lymphoma, T-Cell, 03 medical and health sciences, stomatognathic system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Animals, Humans, Cell Lineage, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Protein Kinase Inhibitors, Aged, NF-κB, medicine.disease, Lymphoma, Disease Models, Animal, 030104 developmental biology, HEK293 Cells, chemistry, Immunoblastic Lymphadenopathy, biology.protein, Cancer research, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Function (biology)
Abstract

GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.

Published
2018

2. Inhibition of Noninfectious Uveitis Using Intravenous Administration of Collagen II-Specific Type 1 Regulatory T Cells

Author

Frédérique Ménard, Nicole Bobak, Grégory Lara, Marie-Francoise Hubert, Marie Jacquin, Arnaud Foussat, Julie Gertner-Dardenne, Clémence Ginet, André Sales, Irène Marchetti, Hélène Asnagli, Nathalie Belmonte, and Papa Babacar Fall

Subjects
medicine.medical_treatment, chemical and pharmacologic phenomena, Enzyme-Linked Immunosorbent Assay, Mice, Transgenic, Biology, T-Lymphocytes, Regulatory, Flow cytometry, Uveitis, Mice, Antigen, medicine, Animals, IL-2 receptor, Interleukin-7 receptor, Collagen Type II, Immunity, Cellular, medicine.diagnostic_test, FOXP3, hemic and immune systems, Immunotherapy, Flow Cytometry, Molecular biology, Granzyme B, Disease Models, Animal, Mice, Inbred DBA, Injections, Intravenous, Cytokine secretion
Abstract

Purpose To evaluate the therapeutic potential of Col-Treg, a collagen II-specific type 1 regulatory T-cell immunotherapy for the treatment of noninfectious uveitis (NIU). Methods Col-Treg cells were produced from collagen II-specific T cell receptor (TCR) transgenic mice or peripheral blood of healthy donors. Phenotypic characterization was performed by flow cytometry, and cytokine secretion was evaluated with Flowcytomix or ELISA. In vitro functional characterization included ATP hydrolysis, cytotoxicity, and contact-independent T-cell suppression and plasticity assays. Col-Treg migration was assessed by quantitative PCR specific to Col-Treg TCR. Col-Treg cells were administered intravenously in mice displaying experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein (IRBP) immunizations. Efficacy of Col-Treg was assessed by ophthalmology, histology, and immunohistochemistry. Results Mice Col-Treg cells displayed identity features of type 1 Treg cells with expression of CD25, FoxP3, low surface expression of CD127, and cytokine secretion profile (IL-10(high), IL-4(low), IFN-γ(int)). In vitro functional assays demonstrated Col-Treg suppressive capacity via soluble factor-dependent immunosuppression, cytotoxicity, and ATP hydrolysis. Col-Treg cells expressed granzyme B, CD39, and glucocorticoid-induced TNF-related protein (GITR). Administration of Col-Treg in EAU mice inhibited clinical and morphologic signs of uveitis and decreased ocular leukocyte infiltration. Col-Treg cells homed in the ocular tissues 24 hours after intravenous injection. Human Col-Treg cells were comparable to mice Col-Treg cells in identity and function and did not show the capacity to differentiate into Th17 cells in vitro. Conclusions These results demonstrate the therapeutic potential of Col-Treg cells as a targeted approach for the treatment of NIU and the feasibility of translating this approach to the human clinical setting.

Published
2015

3. Immunotherapy of non-infectious uveitis using antigen-specific regulatory T (Treg) cells

Author

Arnaud Foussat, André Sales, Hélène Asnagli, Marie-Francoise Hubert, Marie Jacquin, and Nathalie Belmonte

Subjects
Cancer Research, Transplantation, business.industry, medicine.medical_treatment, Immunology, Cell Biology, Immunotherapy, Treg cell, Infectious uveitis, Oncology, Antigen specific, medicine, Immunology and Allergy, business, Genetics (clinical)
Published
2015

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