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）是一种中枢神经系统（CNS）炎症性脱髓鞘疾病，据信其病因学为自身免疫性疾病。它是年轻人中最常见的神经系统疾病。 MS 的发病机制尚不清楚，这限制了开发有效疗法的能力。实验性过敏性脑脊髓炎 (EAE) 是一种广泛使用的多发性硬化症动物模型，它为了解可介导中枢神经系统自身免疫性疾病的髓磷脂特异性 CD4+ T 细胞的活性提供了许多见解。然而，多发性硬化症患者的临床症状和病理学非常异质，并且在经典的 CD4+ T 细胞介导的 EAE 模型中仅重现了多发性硬化症患者的一部分特征。这一观察结果表明，需要新的模型来研究导致这种疾病的多种机制。我们的实验室基于髓鞘碱性蛋白 (MBP) 特异性 CDS+ T 细胞的活性开发了一种新的 EAE 模型。活化的 MBP 特异性 T 细胞的转移会诱发自身免疫性疾病，这种疾病概括了 MS 患者中常见的一些临床症状和病理，而这些症状和病理在经典 EAE 中通常不常见。我们生成了这些 CDS+ T 细胞的 T 细胞受体转基因模型，并发现一种不寻常的耐受形式允许表达 MBP 高亲和力 T 细胞受体的 CDS+ T 细胞逃避耐受并填充外周库。有趣的是，这种耐受性可以被病毒感染打破。在此应用中，我们将研究该模型中 CDS+ T 细胞耐受性和因感染而丧失耐受性的分子机制。我们还将鉴定向 CDS+ T 细胞呈递 MHC I 类相关 MBP 表位的 CNS 细胞，以及疾病期间 CDS+ T 细胞和 CNS 细胞之间相互作用的后果。最后，我们将确定 CDS+ 和 CD4+ T 细胞亚群是否利用不同的组织归巢分子浸润 CNS，并将 CDS+ T 细胞介导的 CNS 损伤与髓磷脂特异性 CD4+ T 细胞介导的病理学进行比较，后者在相同的条件下诱导 EAE小鼠品系。指导这些研究的首要假设是，髓磷脂特异性 CDS+ T 细胞与 CD4+ T 细胞在逃避耐受的机制、对 CNS 中靶细胞的识别以及 CNS 中抗原识别的病理后果方面有所不同。检验这一假设将确定是否存在由髓磷脂特异性 CDS+ T 细胞介导的中枢神经系统自身免疫性疾病的独特方面，这一主题与人类疾病具有显着的临床相关性。