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: 6302773
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302773
• 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.

泰勒氏鼠脑脊髓炎病毒脑内接种 （TMEV）导致慢性炎症脱髓鞘，导致临床 易感小鼠的迹象。 TMEV系统被认为是其中之一 研究人类多发性硬化症 (MS) 的最佳动物模型 潜在的病毒病因和进展的相似性 慢性脱髓鞘。对 II 类限制性 CD4+ 的广泛研究 T 细胞对 TMEV 的特异性反应，似乎发挥着重要作用 在病毒发病机制方面，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， 尽管这种类型的响应被认为是最有效的 保护宿主免受病毒感染。电阻/敏感性 小鼠对 TMEV 诱导的脱髓鞘疾病的影响是由 MHC 控制的， 特别是 I 类分子的 H-2D 基因座编码。使用 beta2- 微球蛋白（β2M）缺陷小鼠缺乏类分子，我们有 进一步证明 MHC 的作用可能具有保护作用 （或调节）这种病毒引起的脱髓鞘疾病的作用。 在 此外，这样的 CD8+ T 细胞群似乎参与了 一些 BALB/c 亚株的抗性。根据我们的初步结果，我们 假设 MHC II 类限制性 Th1 群体负责 疾病的发展和 I 类 (H-2D) 限制性 CD8+ 细胞 负责预防疾病。我们建议在这里检查 MHC I 类限制性细胞毒性 T 细胞在 泰勒病毒引起的脱髓鞘的保护和/或发病机制 疾病作为人类多发性硬化症的模型。具体目标为 拟议的研究包括：1）生成稳定的靶细胞表达 病毒抗原通过病毒 DNA 与适当的 MHC 类抗原结合 转染； 2) 评估MHC I类限制性T细胞的水平 对耐药和易感小鼠的病毒抗原具有特异性 脱髓鞘过程； 3) 建立 TMEV 特定的 I 类限制 T 细胞克隆并分析其在 TMEV-IDD 中的作用； 4) 识别 参与细胞毒性 T 细胞反应的病毒表位。我们相信 我们提出的研究将提供有关 针对病毒诱导、免疫介导的潜在控制机制 脱髓鞘，这是研究人类多发性硬化症的相关动物模型。