Role of CNS CD4+ T cells in TMEV-induced Demyelination

CNS CD4 T 细胞在 TMEV 诱导的脱髓鞘中的作用

• 批准号: 6869030
• 负责人: BYUNG S KIM
• 金额: $ 32.1万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869030
• 关键词: T cell receptor; active immunization; autoantibody; autoantigens; autoimmune disorder; chronic disease /disorder; cytokine; disease /disorder etiology; disease /disorder model; enzyme linked immunosorbent assay; genetically modified animals; helper T lymphocyte; inflammation; injection /infusion; laboratory mouse; major histocompatibility complex; murine encephalomyelitis virus; myelin proteolipid; neuropathology; neuroprotectants; tissue /cell culture; viral myelinopathy

DESCRIPTION (provided by applicant): Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical symptoms in susceptible mice. In light of the potential viral etiology and similarities in the immune-mediated pathology and progression of chronic demyelination, this TMEV system is considered to be one of the best animal models for studying human multiple sclerosis (MS). The previous studies in the field are heavily based on CD4+ T cell responses to TMEV capsid epitopes in the periphery. We have recently focused our efforts on analysis of T cells infiltrating the CNS during the course of TMEV-infection in resistant and susceptible mice. Surprisingly, <5% of the CNS infiltrating CD4+ T cells are reactive to the capsid epitopes in susceptible SJL mice, compared to >45% in resistant C57BL/6 mice. The type, nature and reactivity of the remainder of CD4+ T cells in the CNS are unclear at this time. Our preliminary studies suggest that major CNS-infiltrating CD4+ T cells in virus infected susceptible SJL mice recognize non-capsid epitopes residing on viral RNA polymerase (3D). In addition, we have successfully generated I-AS-tetramers, transgenic mice carrying viral capsid protein genes and TCR transgenic mice expressing TMEV capsid-specific TCRs. Thus, further assessment of the reactivity of the Th cells in susceptible SJL mice will be very important in understanding the potential pathogenic mechanisms of demyelination and these studies are now feasible. We hypothesize that T cells in the CNS specific for non-capsid viral antigens following viral infection may play a critical role in protection or pathogenesis. The specific aims for the proposed studies include: 1) Determination of the level, expansion and nature of capsid-specific CD4+ T cells in the CNS and periphery, including activation states and effector functions; 2) Identification of the specificity and nature of non-capsid viral epitope-reactive T cells infiltrating the CNS during TMEV-infection; 3) Assessment of the role of TMEV capsid- and noncapsid-specific T cells in the pathogenesis of demyelination. We believe that our proposed studies will yield important information on the potential control and pathogenic mechanism(s) against virus-induced immune-mediated demyelination, which is a relevant virus model for studying human MS.

描述（由申请方提供）：脑内接种Theiler小鼠脑脊髓炎病毒（TMEV）导致慢性炎性脱髓鞘，导致易感小鼠出现临床症状。鉴于潜在的病毒病因学以及免疫介导的病理学和慢性脱髓鞘进展的相似性，该TMEV系统被认为是研究人类多发性硬化症（MS）的最佳动物模型之一。该领域的先前研究主要基于CD 4 + T细胞对外周中TMEV衣壳表位的应答。我们最近集中我们的努力，在耐药和易感小鼠中TMEV感染过程中渗透CNS的T细胞的分析。令人惊讶的是，与抗性C57 BL/6小鼠中>45%相比，在易感SJL小鼠中<5%的CNS浸润性CD 4 + T细胞对衣壳表位具有反应性。目前尚不清楚CNS中其余CD 4 + T细胞的类型、性质和反应性。我们的初步研究表明，在病毒感染的易感SJL小鼠中，主要CNS浸润的CD 4 + T细胞识别位于病毒RNA聚合酶上的非衣壳表位（3D）。此外，我们已经成功地产生了I-AS-四聚体、携带病毒衣壳蛋白基因的转基因小鼠和表达TMEV衣壳蛋白特异性TCR的TCR转基因小鼠。因此，进一步评估敏感SJL小鼠Th细胞的反应性将是非常重要的，在了解脱髓鞘的潜在致病机制，这些研究现在是可行的。我们推测，在病毒感染后，CNS中对非衣壳病毒抗原具有特异性的T细胞可能在保护或发病机制中起关键作用。拟定研究的具体目的包括：1）确定CNS和外周中衣壳特异性CD 4 + T细胞的水平、扩增和性质，包括活化状态和效应功能; 2）鉴定TMEV感染期间浸润CNS的非衣壳病毒表位反应性T细胞的特异性和性质; 3）评估TMEV衣壳和非衣壳特异性T细胞在脱髓鞘发病机制中的作用。我们相信，我们提出的研究将产生关于病毒诱导的免疫介导的脱髓鞘的潜在控制和致病机制的重要信息，这是研究人类MS的相关病毒模型。