Does chronic Theiler's demyelination require viral persistence?

描述(申请人提供)：泰勒氏小鼠脑脊髓炎病毒(TMEV)诱导的小鼠脱髓鞘疾病为多发性硬化症提供了一个高度相关的实验动物模型，因为感染发生在其自然宿主中，持续数月，受主要组织相容性复合体遗传等位基因的影响，包括富含巨噬细胞的病变中的CD4+和CD8+T细胞，并且是一种富含巨噬细胞的免疫病理学。TMEV诱导的脱髓鞘主要是通过病毒特异性免疫反应，导致产生促炎性Th1细胞因子干扰素？和肿瘤坏死因子以及髓鞘蛋白表位T细胞反应。关于T和B细胞对髓鞘蛋白表位的反应的报道导致了这样的想法，即自身免疫在观察到这些自身免疫反应的60pi后，会放大这种病毒诱导的免疫病理。此外，最近甚至有人认为，TMEV引起一种慢性T细胞介导的自身免疫性脱髓鞘疾病，通过表位扩散而触发，而对病毒在慢性脱髓鞘中的持久性没有明显的作用。自身免疫在多发性硬化症的病毒模型中进化的可能性很吸引人，因为它支持了人们普遍认为的多发性硬化症是一种由病毒感染引发的自身免疫性疾病。我们假设，这些慢性“自身免疫反应”依赖于持续的病毒感染，在没有病毒的情况下不能自我维持。在缺乏病毒持久性的情况下，检测慢性TMEV诱导的脱髓鞘是否为自身免疫性脱髓鞘，是为了显示抗病毒治疗的持续病毒学应答，同时显示T细胞对免疫优势的髓鞘蛋白表位(表位扩散)的持续应答，T调节细胞减少，脱髓鞘进展和运动功能丧失。然而，如果病毒驱动，T细胞对髓鞘表位的反应应该减少(失去表位扩散)，T调节细胞应该增加，脱髓鞘应该解决或减缓，运动功能应该在没有病毒或较低病毒负荷的情况下恢复。这些方法和本应用中的其他方法试图通过使用最先进的实验方法来更全面地了解宿主和病毒动力学，即Theler‘s小鼠脑脊髓炎病毒感染、病毒持久性和脱髓鞘。

DESCRIPTION (provided by applicant): Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice provides a highly relevant experimental animal model for multiple sclerosis because infection is in its natural host that is chronic for many months, influenced by major histocompatibility complex genetic alleles, includes both CD4+ and CD8+ T-cells in macrophage-rich lesions, and is a macrophage-rich immunopathology. TMEV-induced demyelination is primarily immune-mediated via virus-specific immune responses that lead to production of proinflammatory Th1 cytokines IFN? and TNF¿ as well as myelin protein epitope T cell responses. Reports of both T and B cell responses to myelin protein epitopes have led to the notion that autoimmunity amplifies this virus-induced immunopathology after day 60 pi when these autoimmune responses are observed. Moreover, it has recently even been argued that TMEV causes a chronic T cell-mediated autoimmune demyelinating disease triggered via epitope spreading with no apparent role for viral persistence in chronic demyelination. The possibility that autoimmunity evolves in a viral model of multiple sclerosis is appealing because it supports the widespread belief that multiple sclerosis is an autoimmune disease triggered by a virus infection. We hypothesize that these chronic "autoimmune responses" depend on persistent viral infection and are not self-sustaining in the absence of virus. A test of whether chronic TMEV-induced demyelination is autoimmune in the absence of viral persistence is to show a sustained virological response with antiviral treatment yet demonstrate continuous T cell responses to immunodominant myelin protein epitopes (epitope spreading), decreased T regulatory cells, progression of demyelination and loss of motor function. However, if virus- driven, T cell responses to myelin epitope should decrease (loss of epitope spreading), T regulatory cells should increase, demyelination should resolve or be slowed, and motor function should be restored with the absence of or with a lower viral burden. These and other approaches in this application seeks to gain a more complete understanding of host and viral dynamics of Theiler's murine encephalomyelitis virus infection, viral persistence and demyelination by using state-of-the art experimental approaches.