Immune recognition in a Picornavirus model of MS

项目2标题：多发性硬化症的小核糖核酸病毒模型中的免疫识别拟议的研究检查了针对中枢神经系统(CNS)中持续病毒的有限免疫反应的基础。在小鼠体内感染泰勒氏小鼠脑炎病毒(TMEV)DA株的小鼠，使用H-2D I类抗原提呈分子指导的T细胞介导的免疫来清除病毒，这些分子能够识别病毒并消除注射，但未能做到这一点。通过使用转基因小鼠，通过在K和D基因之间交换序列而产生的嵌合I类基因的表达，将检查I类基因的调节和编码特征的贡献，以评估I类分子在对抗TMEV感染的反应中的差异使用的结构基础。I类基因敲除小鼠将被用来研究单一的天然K或D抗原递呈分子在多发性硬化症TMEV模型神经功能缺陷发展中的功能重要性。嵌合转基因将与I类基因敲除的MHC单倍型杂交，以研究单一I类抗原提呈分子的差异调节如何影响疾病的病理。最近，随着我们对抗TMEV免疫反应的特异性的了解的发展，我们将能够特异性地删除H-2b小鼠中CD8+T细胞识别的免疫优势病毒多肽的免疫反应。这种方法将使我们能够研究多肽显性反应在宿主对持续病毒注射的抵抗和持续感染动物神经功能障碍的发展中的重要性。

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.