IMMUNOGENETICS OF RESISTANCE/SUSCEPTIBILITY TO 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，导致临床 易感小鼠的体征。TMEV系统被认为是 研究人类多发性硬化症的最佳动物模型 可能的病毒病原学和进展中的相似之处 慢性脱髓鞘。对第二类限制性的CD4+的广泛研究 对TMEV特异的T细胞反应，似乎发挥了重要作用 在病毒的发病机制上，已有报道。然而，很少有 已知针对TMEV的I类限制性CD8+T细胞反应， 尽管如此，这种类型的反应已知是最有效的 保护宿主免受病毒感染。电阻/敏感度 小鼠对TMEV诱导的脱髓鞘疾病的抵抗力由MHC控制， 尤其是通过编码第I类分子的H-2D基因。使用Beta2- 缺乏类分子的微球蛋白(Beta2M)缺陷小鼠，我们有 进一步证明，MHC的作用可能代表一种保护性 (或调节)这种病毒诱导的脱髓鞘疾病的作用。在……里面 此外，这样的CD8+T细胞群似乎参与了 部分BALB/c亚株的耐药性。根据我们的初步结果，我们 假设MHC II类限制性Th1人群负责 疾病的发展和I类(H-2D)限制性CD8+细胞是 负责防止疾病的发生。我们建议在这里研究一下 MHC-I类限制性细胞毒性T细胞在慢性粒细胞白血病中的作用 泰勒氏病毒所致脱髓鞘的保护和/或发病机制 疾病作为人类多发性硬化症的模型。该计划的具体目标 建议的研究包括：1)产生稳定的靶细胞，表达 病毒DNA结合病毒抗原与MHC类抗原 2)检测MHC-I类限制性T细胞的水平 在耐药和易感小鼠体内特异性检测病毒抗原 脱髓鞘过程；3)建立TMEV特异性、I类限制性 T细胞克隆并分析它们在TMEV-IDD中的作用；4)鉴定 病毒表位参与细胞毒性T细胞反应。我们相信 我们提议的研究将产生关于 对病毒诱导、免疫介导的潜在控制机制(S) 脱髓鞘是研究人类多发性硬化的相关动物模型。

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical signs in susceptible mice. The TMEV system is considered to be one of the best animal models for studying human multiple sclerosis (MS) in light of the potential viral etiology and similarities in the progression of chronic demyelination. Extensive studies on the class II-restricted, CD4+ T cell response specific for TMEV, which appears to play an important role in the viral pathogenesis, have been reported. However, very little is known about the class I-restricted, CD8+ T cell response against TMEV, despite that this type of response is known to be the most efficient in protecting the host from viral infections. The resistance/susceptibility of mice to TMEV-induced demyelinating disease is controlled by the MHC, particularly by the H-2D locus coding for a class I molecule. Using beta2- microglobulin (beta2M) deficient mice lacking class molecules, we have further demonstrated that the effect of the MHC may represent a protective (or regulatory) role for this virus-induced demyelinating disease. In addition, such a CD8+ T cell population appears to be involved in the resistance of some BALB/c substrains. Based on our preliminary results, we hypothesize that MHC class II-restricted Th1 population is responsible for the development of disease and class I (H-2D)-restricted CD8+ cells are responsible for protection from the disease. We propose here to examine the potential role of MHC class I-restricted cytotoxic T cells in the protection and/or pathogenesis of Theiler's virus-induced demyelinating disease as a model for human multiple sclerosis. The specific aims for the proposed studies include: 1) To generate stable target cells expressing viral antigens in conjunction with proper MHC class antigens by viral DNA transfection; 2) To assess the level of MHC class I-restricted T cells specific for viral antigens in resistant and susceptible mice during the course of demyelination; 3) To establish TMEV-specific, class I-restricted T cell clones and analyze their roles in TMEV-IDD; and 4) To identify the viral epitopes involved in the cytotoxic T cell reactivity. We believe that our proposed studies will yield important information on the potential control mechanism(s) against virus-induced, immune-mediated demyelination, which is a relevant animal model for studying human MS.