Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytes

Article Article scientifique Article Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytes eng 2008 author Calzascia Thomas 97384 author Loh Mei San author Besson-Di Berardino Wilma 111390 author Masson Frédéric 134927 author Guillaume Philippe author Burkhardt Karim 37488 author Herrera Pedro Luis 0000-0003-0771-9504 23981 author Dietrich Pierre-Yves 96532 author Walker Paul Richard 0000-0001-8999-6366 104900 1625-1636 10.1002/glia.20715 18551629 0894-1491 T cell mediated immunotherapies are proposed for many cancers including malignant astrocytoma. As such therapies become more potent, but not necessarily more tumor-specific, the risk of collateral autoimmune damage to normal tissue increases. Tumors of the brain present significant challenges in this respect, as autoimmune destruction of brain tissue could have severe consequences. To investigate local immune reactivity toward a tumor-associated antigen in the brain, transgenic mice were generated that express a defined antigen (CW3 170-179) in astroglial cells. The resulting six transgenic mouse lines expressed the transgenic self-antigen in cells of the gastrointestinal tract and CNS compartments, or in the CNS alone. By challenging transgenic mice with tumor cells that express CW3, self/tumor-specific immune responses were visualized within a normal polyclonal T cell repertoire. A large expansion of the endogenous CW3 170-179-specific CD8 T cell population was observed in nontransgenic mice after both subcutaneous and intracerebral implantation of tumor cells. In contrast, CW3 170-179-specific immune responses were not observed in transgenic mice that exhibited extracerebral transgene expression. Importantly, in certain groups of mice in which transgene expression was restricted to the CNS, antigen-specific immune responses occurred when tumor was implanted subcutaneously, but not intracerebrally. This local immune tolerance in the brain was induced via peripheral (extrathymic) rather than central (thymic) tolerance mechanisms. Thus, this study highlights the role of regional immune regulation in the prevention of autoimmunity in the brain, and the potential impact of these mechanisms for brain tumor immunotherapy. Animals Antigens, Neoplasm/genetics/immunology Astrocytes/immunology/pathology Astrocytoma/immunology/physiopathology Autoantigens/genetics/immunology Autoimmune Diseases of the Nervous System/genetics/immunology/prevention & control Autoimmunity/genetics/immunology Brain/immunology/pathology/physiopathology Brain Neoplasms/immunology/physiopathology Brain Tissue Transplantation CD8-Positive T-Lymphocytes/immunology Immune Tolerance/immunology Immunotherapy/adverse effects/methods Mice Mice, Transgenic Tumor Cells, Cultured Dewey 576.5 Dewey 616 135 Département de médecine génétique et développement 21D 56 Département de médecine 221 false 401 Immunobiologie des tumeurs du cerveau 669 27 Immunothérapie des cancers 42 272 Types cellulaires pancréatiques pendant l'ontogénèse 522 GLIA 56 15 ee447623-698f-4634-b2c9-7ca2d920ccc1 Article (Accepted version) Restricted Article.pdf 582268 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Faculté de médecine / Section de médecine clinique / Département de médecine

Title	Published in	Year	Views	Downloads

Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytes	GLIA	2008	583	11
Understanding the priming and effector phases of brain tumor immunity : roles of brain antigen-presenting cells and tumors in CD8 T-cell programming		2007	963	777

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Masson, Frédéric