MECHANISMS OF TOLERANCE AND IMMUNITY TO CENTRAL NERVOUS SYSTEM ANTIGENS

描述(申请人提供)：多发性硬化症(MS)是一种炎症性、脱髓鞘的中枢神经系统(CNS)疾病，据信有自身免疫性病因。这是年轻人最常见的神经系统疾病。多发性硬化的发病机制尚不清楚，这限制了开发有效治疗方法的能力。实验性变态反应性脑脊髓炎(EAE)是一种广泛使用的MS动物模型，它为研究髓鞘特异性的CD4+T细胞的活性提供了许多线索，这些细胞可以介导中枢神经系统自身免疫性疾病。然而，MS患者的临床症状和病理表现非常不同，在经典的CD4+T细胞介导的EAE模型中，只复制了MS患者特征的一部分。这一观察结果表明，需要新的模型来研究导致这种疾病的不同机制。本实验室建立了一种新的基于髓鞘碱性蛋白(MBP)特异性CDS+T细胞活性的EAE模型。活化的MBP特异性T细胞的转移会导致自身免疫性疾病，这些疾病概括了MS患者的一些临床症状和病理，这些症状和病理在经典的EAE中是不常见的。我们建立了这些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细胞逃避耐受并聚集在外周血库中。有趣的是，这种耐受性可以被病毒感染打破。在这个应用中，我们将在这个模型中研究CDS+T细胞耐受和感染导致耐受丧失的分子机制。我们还将确定向CDS+T细胞呈递MHC类L相关MBP表位的中枢神经系统细胞，以及CDS+T细胞和中枢神经系统细胞在疾病过程中相互作用的后果。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渗透到中枢神经系统，并将CDS+T细胞介导的中枢神经系统损伤与同一小鼠品系中诱发EAE的髓鞘特异性CD4+T细胞介导的病理进行比较。指导这些研究的最重要的假设是，髓鞘特异性CDS+T细胞与CD4+T细胞在逃避耐受的机制、在CNS中识别靶细胞以及在CNS中识别抗原的病理后果方面不同。验证这一假说将确定髓鞘特异性CDS+T细胞介导的中枢神经系统自身免疫性疾病是否存在独特的方面，这是一个与人类疾病具有重大临床相关性的课题。

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.