EPITOPES INVOLVED IN TMEV-INDUCED DEMYELINATION

泰勒氏小鼠脑脊髓炎病毒脑内接种 (TMEV)导致慢性炎性脱髓鞘，很容易 与易感小鼠的临床体征相关。TMEV系统是 被认为是研究人类多发性疾病的相关动物模型 硬化症(MS)与慢性硬化症的相似性 脱髓鞘与人类多发性硬化症的潜在病毒病因学 这个系统与人类多发性硬化症的相关性，人们对此知之甚少 病毒表位可能参与发病机制，主要是由于 病毒抗原的复杂性。我们最近确认了 病毒衣壳蛋白主要线性抗体表位的研究 多种合成肽和融合蛋白来源于重组人 Gammagt11克隆人。有趣的是，只有一个表位是 脑脊液中的抗体优先识别 病毒感染后临床感染的SJL小鼠。此外，我们 开发了一种体内实验系统来评估致病作用 病毒表位。此外，我们还建立了几个T细胞 不会导致TMEV变异的品系/克隆 脱髓鞘疾病，但诱导保护性免疫 感染致病病毒。通过应用我们的这些实用程序 初步结果，我们建议将表位的差异关联起来 抗体和T细胞的识别及其参与TMEV- 诱导脱髓鞘。在这方面提出了三个具体目标 应用：(1)病毒相关表位的鉴定 诱导脱髓鞘，使用融合蛋白，也包括合成肽 作为非致病性变异病毒；(2)线性病毒作用的评估 病毒诱导的脱髓鞘过程中的抗体表位； 病毒感染小鼠中枢神经系统T细胞的渗入分析 包括TCR的使用、淋巴因子的产生和表位识别。我们 相信我们拟议的研究将在以下方面产生重要信息 病毒诱导的、免疫介导的脱髓鞘，这似乎是一种 用于研究人类多发性硬化症的相关、真实的动物模型系统

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination which readily correlates with clinical signs in susceptible mice. The TMEV system is considered to be a relevant animal model for studying human multiple sclerosis (MS) in light of the similarities in the chronic nature of demyelination and the potential viral etiology of human MS. Despite the relevance of this system to human MS, very little is known about the viral epitopes which might be involved in pathogenesis due mainly to the complexity of the viral antigens. We have recently identified predominant linear antibody epitopes of the viral capsid proteins using various synthetic peptides and fusion proteins derived from recombinant gammagt11 clones. Interestingly, only one of the epitopes is preferentially recognized by antibodies in cerebrospinal fluid from clinically affected SJL mice following viral infection. In addition, we have develop an in vivo experimental system to assess the pathogenic role of viral epitopes. Furthermore, we have established several T cell lines/clones specific for TMEV variants which do not result in demyelinating disease but induce a protective immunity to subsequent infection with pathogenic virus. By applying these utilities of our preliminary results, we propose to correlate the differences in epitope recognition by antibodies and T cells with their involvement in the TMEV- induced demyelination. Three specific aims are proposed in this application: (1) Identification of viral epitopes involved in virus- induced demyelination, using fusion proteins, synthetic peptides as well as non-pathogenic variant viruses; (2) Assessment of the role of linear antibody epitopes in the virally induced demyelinating process; and (3) Analysis of infiltrating T cells in the CNS from virus-infected mice, including TCR usage, lymphokine production and epitope recognition. We believe that our proposed studies will yield important information on virally induced, immune-mediated demyelination, which appears to be a relevant, realistic animal model system for studying human MS.