IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration
| Autor: | Roland S. Liblau, Béatrice Pignolet, Emilie Mauré, Monika C. Brunner-Weinzierl, L. M. Yshii, Jan Bauer, Mandy Pierau, Oliver Hartley |
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| Přispěvatelé: | Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Université de Genève = University of Geneva (UNIGE), Medizinische Universität Wien = Medical University of Vienna, ANR-13-BSV3-0003,T cell Mig,Migration des lymp^hocytes T CD8 T dans le système nerveux central(2013), Pistre, Karine, Blanc 2013 - Migration des lymp^hocytes T CD8 T dans le système nerveux central - - T cell Mig2013 - ANR-13-BSV3-0003 - Blanc 2013 - VALID |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cerebellum Tumor/transplantation Integrin alpha4 T-Lymphocytes Autoimmune diseases MESH: Integrin alpha4 / metabolism [SDV]Life Sciences [q-bio] Autoimmunity ddc:616.07 medicine.disease_cause Autoantigens MESH: Mice Knockout Mice Purkinje Cells 0302 clinical medicine Breast cancer MESH: Mammary Neoplasms Experimental / immunology MESH: Interferon-gamma / metabolism Cancer Mice Knockout biology Neoplasm/immunology Experimental/complications/immunology Purkinje Cells/immunology/metabolism/pathology General Medicine Paraneoplastic cerebellar degeneration Integrin alpha4/antagonists & inhibitors/immunology/metabolism [SDV] Life Sciences [q-bio] medicine.anatomical_structure MESH: Paraneoplastic Cerebellar Degeneration / drug therapy 030220 oncology & carcinogenesis MESH: Autoantigens / immunology [SDV.IMM]Life Sciences [q-bio]/Immunology Female Antibody Autoantibodies/immunology Research Article MESH: T-Lymphocytes / metabolism MESH: Interferon-gamma / immunology MESH: Interferon-gamma / antagonists & inhibitors MESH: Paraneoplastic Cerebellar Degeneration / pathology MESH: T-Lymphocytes / immunology [SDV.IMM] Life Sciences [q-bio]/Immunology Knockout Integrin Immunology MESH: Purkinje Cells / metabolism [SDV.CAN]Life Sciences [q-bio]/Cancer Interferon-gamma/antagonists & inhibitors/immunology/metabolism Paraneoplastic Cerebellar Degeneration Cell Line MESH: Integrin alpha4 / immunology 03 medical and health sciences Interferon-gamma T-Lymphocytes/drug effects/immunology/metabolism [SDV.CAN] Life Sciences [q-bio]/Cancer Autoantigens/immunology Immunity Antigens Neoplasm Cell Line Tumor medicine Animals MESH: Cell Line Tumor / transplantation Antigens MESH: Mice Autoantibodies business.industry Mammary Neoplasms Autoantibody MESH: Purkinje Cells / pathology Mammary Neoplasms Experimental MESH: Integrin alpha4 / antagonists & inhibitors medicine.disease Immune checkpoint 030104 developmental biology MESH: Paraneoplastic Cerebellar Degeneration / immunology Cancer research biology.protein MESH: Mammary Neoplasms Experimental / complications MESH: Purkinje Cells / immunology MESH: T-Lymphocytes / drug effects business Paraneoplastic Cerebellar Degeneration/drug therapy/immunology/pathology MESH: Female |
| Zdroj: | JCI Insight JCI Insight, 2019, 4 (7), pp.1-12. ⟨10.1172/jci.insight.127001⟩ JCI Insight, Vol. 4, No 7 (2019) P. e127001 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.127001⟩ |
| Popis: | International audience; Paraneoplastic neurological disorders result from an autoimmune response against neural self-antigens that are ectopically expressed in neoplastic cells. In paraneoplastic disorders associated to autoantibodies against intracellular proteins, such as paraneoplastic cerebellar degeneration (PCD), current data point to a major role of cell-mediated immunity. In an animal model, in which a neo-self-antigen was expressed in both Purkinje neurons and implanted breast tumor cells, immune checkpoint blockade led to complete tumor control at the expense of cerebellum infiltration by T cells and Purkinje neuron loss, thereby mimicking PCD. Here, we identify 2 potential therapeutic targets expressed by cerebellum-infiltrating T cells in this model, namely α4 integrin and IFN-γ. Mice with PCD were treated with anti-α4 integrin antibodies or neutralizing anti-IFN-γ antibodies at the onset of neurological signs. Although blocking α4 integrin had little or no impact on disease development, treatment using the anti-IFN-γ antibody led to almost complete protection from PCD. These findings strongly suggest that the production of IFN-γ by cerebellum-invading T cells plays a major role in Purkinje neuron death. Our successful preclinical use of neutralizing anti-IFN-γ antibody for the treatment of PCD offers a potentially new therapeutic opportunity for cancer patients at the onset of paraneoplastic neurological disorders. |
| Databáze: | OpenAIRE |
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