IMMUNOGENETICS OF RESISTANCE/SUSCEPTIBILITY TO TMEV INDUCED DEMYELINATION

对 TMEV 引起的脱髓鞘的耐药性/敏感性的免疫遗传学

• 批准号: 6112251
• 负责人: BYUNG S KIM
• 金额: $ 20.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112251
• 关键词: animal genetic material tag; autosomal dominant trait; autosomal recessive trait; capsid; cellular immunity; cyclophosphamide; cytotoxic T lymphocyte; disease /disorder model; genetic mapping; host organism interaction; immunity; immunogenetics; laboratory mouse; multiple sclerosis; murine encephalomyelitis virus; mutant; myelinopathy; restriction fragment length polymorphism; suppressor T lymphocyte; viral myelinopathy; whole body irradiation effect

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.

脑内接种Theiler小鼠脑脊髓炎病毒 （TMEV）导致慢性炎性脱髓鞘，导致临床 易感小鼠的症状。TMEV系统被认为是 研究人类多发性硬化症（MS）的最佳动物模型 潜在的病毒病因学和进展中的相似性， 慢性脱髓鞘广泛研究II类限制性，CD4 + TMEV特异性T细胞应答，其似乎在TMEV的免疫应答中起重要作用。 在病毒发病机制中的作用然而，很少有 已知针对TMEV的I类限制性CD8 + T细胞应答， 尽管这种类型的响应已知是最有效的， 保护宿主免受病毒感染。抗性/敏感性 小鼠TMEV诱导的脱髓鞘疾病是由MHC控制的， 特别是通过编码I类分子的H-2D基因座。使用beta2- 微球蛋白（β 2 M）缺乏类分子的小鼠，我们有 进一步证明了MHC的作用可能代表了一种保护性的作用， (or调节）的作用。 在 此外，这样的CD8 + T细胞群体似乎参与了免疫应答。 部分BALB/c亚株的耐药性。根据初步结果，我们 假设MHC II类限制性Th1群体负责 疾病和I类（H-2D）限制性CD8+细胞的发展是 负责预防疾病。我们在此建议审查 MHC I类限制性细胞毒性T细胞在免疫中的潜在作用 泰勒病毒诱导的脱髓鞘的保护和/或发病机制 疾病作为人类多发性硬化症的模型。的具体目标， 提出的研究包括：1）为了产生稳定的靶细胞， 通过病毒DNA与适当的MHC类抗原结合的病毒抗原 2）评估MHC I类限制性T细胞的水平 对耐药和易感小鼠中的病毒抗原具有特异性 3）建立TMEV特异性、I类限制性 T细胞克隆并分析其在TMEV-IDD中的作用 参与细胞毒性T细胞反应性的病毒表位。我们认为 我们提出的研究将产生重要的信息， 针对病毒诱导、免疫介导 脱髓鞘，其是用于研究人类MS的相关动物模型。