Immune recognition in a Picornavirus model of MS

项目2标题：在多发性硬化的小核糖核酸病毒模型中的免疫识别所提出的研究检查了对中枢神经系统（CNS）中持续存在的病毒的有限免疫应答的基础。颅内感染泰勒鼠脑炎病毒（TMEV）的DA株的小鼠使用由H-2D I类抗原呈递分子指导的T细胞介导的免疫清除病毒，所述H-2D I类抗原呈递分子能够识别病毒并消除注射，但不能这样做。通过使用转基因小鼠，表达通过交换K和D基因之间的序列而产生的嵌合I类基因，将检查I类基因的调控和编码特征的贡献，以评估I类分子在抗TMEV感染的应答中的差异使用的结构基础。I类基因敲除小鼠将用于研究单一天然K或D抗原呈递分子在多发性硬化症的TMEV模型中神经缺陷发展中的功能重要性。嵌合转基因将与I类敲除MHC单倍型杂交，以研究单个I类抗原呈递分子的差异调节将如何影响疾病的病理学。最近，我们对抗TMEV免疫应答特异性的认识的发展，将允许我们特异性地删除对H-2b小鼠中CD 8 + T细胞识别的免疫显性病毒肽的免疫应答。这种方法将使我们能够调查的重要性，肽的优势反应在宿主的持久性病毒注射和发展的神经功能缺损的持续感染的动物。

PROJECT 2 TITLE: Immune Recognition in a Picornavirus Model of Multiple Sclerosis The proposed studies examine the basis of the limited immune response against a persisting virus in the central nervous system (CNS). Mice infected intracranially with the DA-strain of Theiler's murine encephalitis virus (TMEV) clear the virus using T cell mediated immunity directed by the H-2D class I antigen-presenting molecules that are capable of recognizing the virus and eliminating the injection, yet fail to do so. By using transgenic mice, expressing chimeric class I genes generated by exchanging sequences between the K and D genes, the contribution of regulatory and coding features of the class I genes will be examined to assess the structural basis of the differential use of the class I molecules in the response against TMEV infection. Class I knockout mice will be used to investigate the functional importance of single native K or D antigen- presenting molecules in the development of neurological deficits in the TMEV model of multiple sclerosis. Chimeric transgenes will be intercrossed with the class I knockout MHC haplotype to investigate how differential regulation of single class I antigen presenting molecules will influence the pathology of disease. Recently, developments in our knowledge about the specificity of the anti-TMEV immune response, will permit us to specifically delete the immune response to the immunodominant viral peptide recognized by CD8+ T cells in H-2b mice. This approach will enable us to investigate the importance of the peptide dominant response in host resistance to persistent virus injection and the development of neurological deficits in persistently infected animals.