EPITOPES INVOLVED IN TMEV-INDUCED DEMYELINATION

脑内接种Theiler小鼠脑脊髓炎病毒 （TMEV）导致慢性炎性脱髓鞘， 与易感小鼠的临床症状相关。 TMEV系统是 被认为是用于研究人类多重免疫缺陷的相关动物模型。 硬化症（MS）的慢性性质的相似性， 脱髓鞘和人类MS的潜在病毒病因学。 关于这个系统与人类MS的相关性，人们对它知之甚少。 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。 我们最近发现 病毒衣壳蛋白的主要线性抗体表位， 各种合成肽和融合蛋白衍生自重组 gammagt 11克隆。 有趣的是，只有一个表位 优先被脑脊液中的抗体识别， 病毒感染后临床受累的SJL小鼠。 另外我们 开发了一个体内实验系统来评估致病作用 病毒抗原决定簇。 此外，我们还建立了几种T细胞， 对TMEV变体特异的株系/克隆，其不导致 脱髓鞘疾病，但诱导保护性免疫， 致病病毒感染。 通过应用我们的这些实用程序， 初步结果，我们建议相关的差异表位 抗体和T细胞的识别与它们在TMEV中的参与- 诱导脱髓鞘。 本文提出了三个具体目标 应用：（1）病毒表位的鉴定- 诱导脱髓鞘，使用融合蛋白，合成肽以及 （2）评估线性变异病毒的作用 病毒诱导的脱髓鞘过程中的抗体表位;和（3） 病毒感染小鼠CNS中浸润T细胞的分析， 包括TCR使用、淋巴因子产生和表位识别。 我们 我相信我们的研究将提供重要的信息， 病毒诱导的免疫介导的脱髓鞘，这似乎是一个 相关的，现实的动物模型系统，用于研究人类MS。

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.