MECHANISMS OF TOLERANCE AND IMMUNITY TO CENTRAL NERVOUS SYSTEM ANTIGENS

中枢神经系统抗原的耐受和免疫机制

• 批准号: 7568240
• 负责人: Joan M Goverman
• 金额: $ 38.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568240
• 关键词: Affinity; Alleles; Animal Model; Animals; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Characteristics; Clinical; Complex; Development; Disease; Encephalomyelitis; Epitopes; Etiology; Exhibits; Experimental Autoimmune Encephalomyelitis; Funding; Goals; Home environment; Homing; Immune Tolerance; Immunity; In Vitro; Infection; Infiltration; Inflammatory; Laboratories; MHC Class I Genes; Mediating; Modeling; Molecular; Mouse Strains; Multiple Sclerosis; Mus; Myelin; Myelin Basic Proteins; Nervous System Trauma; Neuraxis; Neurologic; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Shapes; Surface Antigens; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Transgenic Model; Virus Diseases; base; central nervous system demyelinating disorder; clinically relevant; effective therapy; human disease; in vivo; insight; nervous system disorder; response; young adult

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that is believed to have an autoimmune etiology. It is the most common neurological disease in young adults. The pathogenesis of MS is not well understood and this has limited the ability to develop effective therapies. Experimental allergic encephalomyelitis (EAE), a widely used animal model for MS, has provided many insights into the activity of myelin-specific CD4+ T cells that can mediate CNS autoimmune disease. However, the clinical signs and pathology seen in MS patients is very heterogeneous and only a subset of the characteristics of MS patients is reproduced in classical CD4+ T cell-mediated EAE models. This observation suggests that new models are needed to investigate the diverse mechanisms contributing to this disease. Our laboratory developed a new EAE model based on the activity of myelin basic protein (MBP)- specific CDS+ T cells. Transfer of activated MBP-specific T cells induces autoimmune disease that recapitulates some of the clinical signs and pathology seen in MS patients that are not typically seen in classic EAE. We generated T cell receptor transgenic models of these CDS+ T cells and found that an unusual form of tolerance allows CDS+ T cells expressing a high affinity T cell receptor for MBP to escape tolerance and populate the peripheral repertoire. Interestingly, this tolerance can be broken by viral infection. In this application, we will investigate the molecular mechanisms underlying both the CDS+ T cell tolerance and the loss of tolerance due to infection in this model. We will also identify the CNS cells that present the MHC class l-associated MBP epitope to the CDS+ T cells and the consequences of interaction between the CDS+ T cells and CNS cells during disease. Finally, we will determine if the CDS+ and CD4+ T cells subsets utilize different tissue homing molecules to infiltrate the CNS and compare the CNS damage mediated by the CDS+ T cells to the pathology mediated by myelin-specific CD4+ T cells that induce EAE in the same mouse strain. The over-arching hypothesis guiding these studies is that myelin-specific CDS+ T cells differ from CD4+ T cells in the mechanisms used to escape tolerance, in their recognition of targets cells in the CNS and in the pathologic consequences of antigen recognition in the CNS. Testing this hypothesis will determine whether there are unique aspects of CNS autoimmune disease mediated by myelin-specific CDS+ T cells, a subject with significant clinical relevance to human disease.

描述（由申请人提供）：多发性硬化症（MS）是一种炎症性，脱髓鞘性疾病的中枢神经系统（CNS），据信具有自身免疫性病因。它是年轻人中最常见的神经疾病。 MS的发病机理尚不清楚，这限制了开发有效疗法的能力。实验性过敏性脑脊髓炎（EAE）是一种广泛使用的MS动物模型，为髓磷脂特异性CD4+ T细胞的活性提供了许多见解，可以介导CNS自身免疫性疾病。但是，在MS患者中看到的临床体征和病理非常异质，并且在经典的CD4+ T细胞介导的EAE模型中仅重现MS患者特征的一部分。该观察结果表明，需要新的模型来研究导致这种疾病的各种机制。我们的实验室基于髓磷脂碱性蛋白（MBP） - 特定CDS+ T细胞开发了一种新的EAE模型。激活的MBP特异性T细胞的转移会诱导自身免疫性疾病，从而概括了MS患者中通常在Classic EAE中不见的一些临床体征和病理。我们生成了这些CDS+ T细胞的T细胞受体转基因模型，发现一种不寻常的耐受性允许表达高亲和力T细胞受体的MBP的CDS+ T细胞避免耐受性并填充外围库。有趣的是，这种耐受性可能会因病毒感染而破坏。在此应用中，我们将研究CD+ T细胞耐受性和该模型感染引起的耐受性丧失的分子机制。我们还将确定呈现MHC类L相关的MBP表位的CNS细胞与CDS+ T细胞以及疾病期间CDS+ T细胞与CNS细胞之间相互作用的后果。最后，我们将确定CDS+和CD4+ T细胞子集是否利用不同的组织归巢分子浸润CNS，并比较CDS+ T细胞介导的CNS损伤与由髓​​磷脂特异性CD4+ T细胞介导的病理，这些病理诱导EAE诱导EAE，它们以相同的小鼠菌株诱导EAE。指导这些研究的过度假设是，髓磷脂特异性的CDS+ T细胞与CD4+ T细胞的不同，用于避免耐受性的机制，在CNS中识别靶细胞以及CNS中抗原识别的病理后果。检验该假设将确定CNS自身免疫性疾病是否存在由髓磷脂特异性CDS+ T细胞介导的独特方面，这是该受试者与人类疾病具有显着临床相关的受试者。