EXACERBATION OF EAE BY MURINE GAMMAHERPESVIRUS, MHV-68

描述（改编自申请人摘要）：几十年来， 怀疑一些相对常见的人类病毒可能发挥关键作用，但 在多发性硬化症（多发性硬化症3.一 Epstein巴尔病毒（EBV）与多发性硬化症之间的可能关联 有人提出，但这种联系是脆弱的，并不普遍 接纳的话基本上所有的多发性硬化症患者都表现出先前的 感染EBV，但现有数据表明，这种病毒几乎从来没有 进入中枢神经系统（CNS）。有人认为EBV 感染可能会间接加剧多发性硬化症，但研究， 最终证明这种间接机制不存在。在 初步调查，我们已经开发了一种啮齿动物模型， 探讨EB病毒是否可能增加多发性硬化症。该模型系统采用 最近描述的鼠γ疱疹病毒-68（MHV-68）的优点， 诱发疾病，非常类似于人类的EBV感染。MHV-68感染 随后被动给予髓鞘碱性蛋白特异性T细胞 将被用来解决EB病毒样感染是否会加剧 实验性过敏性脑脊髓炎（EAE）。复制的重要性 与潜伏性MHV-68感染相比，EAE加重将通过 定量CNS炎症的临床评分和标志物。这些初始 研究将首次证明EB病毒样病毒与 病毒感染与多发性硬化模型的恶化。 还将调查造成这种恶化的机制， 包括：1）确定MHV-68是否可以进入CNS以增强 炎症; 2）病毒之间可能的分子模拟的证明 表位和髓鞘碱性蛋白（肽68-88）特异性T细胞受体; 和3）评估MHV-68诱导的TH 1环境及其可能的 髓鞘碱性蛋白增殖或活化的增强 （肽68-88）特异性淋巴细胞。这些研究将 研究MHV-68诱导EAE加重的机制， 第一个实验模型系统适合于理解的作用， 神经免疫事件伴随伴随γ疱疹病毒感染。

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.