EXACERBATION OF EAE BY MURINE GAMMAHERPESVIRUS, MHV-68

描述(改编自申请人的摘要)：几十年来一直是 怀疑某种比较常见的人类病毒可能起到关键作用，但 在多发性硬化发病机制中的复杂作用(多发性硬化症3。一个 EB病毒与多发性硬化症的可能联系 已经提出，然而，这种联系是脆弱的，并不是普遍的 109.91接受。基本上所有多发性硬化症患者都表现出 感染EBV，但现有数据表明，这种病毒几乎从未 进入中枢神经系统(CNS)。有人认为，EBV 感染可能间接加剧多发性硬化症，但研究表明 最终证明这种间接机制是不存在的。在……里面 初步调查，我们已经开发了一种啮齿动物模型来直接 解决EBV是否可能加重多发性硬化症。这个模型系统采取了 最近描述的小鼠伽马疱疹病毒68(MHV-68)的优势，它 诱发疾病，与人类的EBV感染非常相似。感染MHV-68 然后被动注射髓鞘碱性蛋白特异性T细胞 将用于解决EBV样感染是否会加剧 实验性过敏性脑脊髓炎(EAE)。复制的重要性 与潜在的MHV-68感染在EAE恶化中的对比将通过 量化中枢神经系统炎症的临床评分和标志物。这些首字母 研究将首次证明EBV样病毒与 病毒感染与多发性硬化症模型的恶化。 还将调查造成这种恶化的机制，并将 包括：1)确定MHV-68是否可以进入中枢神经系统进行增强 炎症；2)证明了病毒之间可能的分子模仿 表位和髓鞘碱性蛋白(68-88肽)特异性T细胞受体； 3)MHV-68诱导的TH1环境及其可能性的评估 促进髓鞘碱性蛋白的增殖或激活 (肽68-88)特异性淋巴细胞。总而言之，这些研究将 应用MHV-68诱导EAE加重机制的研究 第一个实验模型系统适合于理解一个 伴随着伽马疱疹病毒感染的神经免疫事件。

DESCRIPTION (adapted from applicant's abstract): For decades it has been suspected that some relatively common human virus might play a critical, but complex role in the pathogenesis of Multiple Sclerosis (multiple sclerosis3. A possible association between Epstein Barr Virus (EBV) and multiple sclerosis has been proposed, however this association is tenuous and not universally accepted. Essentially all multiple sclerosis patients demonstrate previous infection with EBV, but available data indicate that this virus hardly ever enters the central nervous system (CNS). It has been suggested that EBV infection might indirectly exacerbate multiple sclerosis, but studies which conclusively demonstrate such an indirect mechanism do not exist. In preliminary investigations, we have developed a rodent model to directly address whether EBV might augment multiple sclerosis. This model system takes advantage of the recently described murine gammaherpesvirus-68 (MHV-68), which induces disease, very similar to EBV infection in humans. Infection with MHV-68 followed by passive administration of myelin basic protein-specific T cells will be used to address whether an EBV-like infection can exacerbate Experimental Allergic Encephalomyelitis (EAE). The importance of replicating versus latent MHV-68 infection in the exacerbation of EAE will be addressed by quantifying clinical scores and markers for CNS inflammation. These initial studies will demonstrate for the first time a direct association of an EBV-like viral infection with the exacerbation of a model of multiple sclerosis. Mechanisms responsible for this exacerbation will also be investigated and will include: 1) a determination of whether MHV-68 can enter the CNS to augment inflammation; 2) a demonstration of possible molecular mimicry between viral epitopes and myelin basic protein (peptide 68-88)-specific T cell receptors; and 3) an evaluation of the MHV-68-induced TH1 environment and its possible augmentation of the proliferation or activation of myelin basic protein (peptide 68-88)-specific Lymphocytes. Taken together, these studies will investigate mechanisms responsible for MHV-68 induced exacerbation of EAE using the first experimental model system appropriate for understanding the role of a neuroimmune event accompanied by a concomitant gammaherpesvirus infection.