IMMUNOPATHOGENESIS OF VIRUS-INDUCED DEMYELINATION

C57 B1/6（B6）小鼠感染嗜神经冠状病毒，小鼠 肝炎病毒JHM株发展为脱髓鞘性脑脊髓炎， 后肢瘫痪的临床症状的临床及病理特点 这种疾病与人类的多发性硬化症有许多相似之处。 MS和MHV感染小鼠之间的一个重要相似之处是， 免疫应答对于脱髓鞘的发展是至关重要的。申请人 最近的研究表明，MHV感染缺乏成熟T和B细胞的小鼠， 由于缺乏重组酶激活基因活性（Rag 1-/-小鼠）， 除非来自免疫活性B6的脾细胞 收养转移。然后脱髓鞘在6-7天内可重复发生。在 此外，他还采用了识别抗原特异性CD 4和CD 8 T的方法 细胞（可溶性MHC/肽四聚体测定和用于测量 细胞内干扰素-γ产生）直接离体分析 从患有MHV诱导的神经系统疾病的小鼠收获的淋巴细胞。 这一建议的中心假设是，过继转移的CD 4或 CD 8 T细胞分泌一种因子或执行一种功能（或两者兼而有之）， 用于诱导和/或增殖Rag -/-中的脱髓鞘过程， 小鼠这一假设将在以下三个具体目标中进行探讨。 1.为了确定抗原特异性CD 4或CD 8 T细胞是否在不存在免疫调节剂的情况下表达。 其它子集足以诱导和传播脱髓鞘过程。 Fas/FasL相互作用和特异性趋化因子的作用， 还将测定细胞因子。2.为了研究一氧化氮在 和轴突变性，两个潜在的关键组成部分， 过程中，在过继转移模型脱髓鞘。3.以确定 MHV抗原非特异性CD 4 T细胞是否被激活并有助于 病毒感染小鼠的脱髓鞘。这些实验将利用 我们检测抗原特异性CD 4 T细胞的能力的最新进展， MHV感染的CNS。 在过继转移到MHV感染的小鼠中后，脱髓鞘是快速和可重复的。 Rag 1-/-小鼠，使其成为研究 病毒引起的脱髓鞘和回答有关病毒引起的脱髓鞘的问题。

C57B1/6 (B6) mice infected with the neurotropic coronavirus, mouse hepatitis virus, strain JHM, develop a demyelinating encephalomyelitis with clinical signs of hindlimb paralysis. The clinical and pathological features of this disease have many similarities to the human disease, multiple sclerosis. One important similarity between MS and the MHV-infected mouse is that the host immune response is critical for the development of demyelination. The applicant has recently shown that MHV infection of mice that lack mature T and B cells due to a deficiency in recombinase-activating gene activity (Rag1 -/- mice) do not develop demyelination unless splenocytes from immunocompetent B6 are adoptively transferred. Demyelination then occurs reproducibly in 6-7 days. In addition, he has adapted methods for identifying antigen-specific CD4 and CD8 T cells (soluble MHC/peptide tetramer assays and assays for measuring intracellular interferon-gamma production) to the direct ex vivo analysis of lymphocyte harvested from mice with MHV-induced neurological disease. The central hypothesis of this proposal is that adoptively transferred CD4 or CD8 T cells secrete a factor or perform a function (or both) that is critical for the induction and/or propagation of the demyelinating process in Rag -/- mice. This hypothesis will be approached in the following three specific aims. 1. To determine if antigen-specific CD4 or CD8 T cells in the absence of the other subset are sufficient to induce and propagate the demyelinating process. The contribution of Fas/FasL interactions and of specific chemokines and cytokines will also be determined. 2. To investigate the role of nitric oxide and axonal degeneration, two potentially key components of the pathogenic process, in the adoptive transfer model of demyelination. 3. To determine whether MHV antigen-nonspecific CD4 T cells become activated and contribute to demyelination in virus-infected mice. These experiments will take advantage of recent advances in our ability to detect antigen-specific CD4 T cells in the MHV-infected CNS. Demyelination is rapid and reproducible after adoptive transfer into the MHV-infected Rag1 -/- mice, making this a unique system for investigating the pathogenesis of virus-induced demyelination and answering questions about virus-induced demyelination.