Viral-induced demyelination and neural stem cell-mediated remyelination

描述(申请人提供)：多发性硬化症(MS)是一种慢性中枢神经系统(CNS)疾病，以多灶性炎症和髓鞘破坏为特征。通常情况下，多发性硬化症的临床病程漫长，持续数十年，伴随着不同的病情加重和不同的缓解期。现有证据表明，多发性硬化症的病因是多因素的，包括个体的遗传背景以及环境影响，如病毒感染。为了更好地了解MS的潜在病理机制，临床和组织病理学与大多数MS患者相似的动物模型的建立势在必行。脱髓鞘的病毒模型是研究疾病发病机制的重要工具。小鼠持续感染嗜神经性小鼠肝炎病毒(MHV)JHM株的特征是由炎性T细胞和巨噬细胞介导的持续脱髓鞘，在临床和组织学上与人类多发性硬化症(MS)相似。结合诸如病毒等环境因素被认为是MS的诱因这一事实，MHV系统提供了一个很好的模型，在其中既可以研究可能导致MS患者脱髓鞘的潜在免疫病理机制，也可以研究促进重新髓鞘形成的新的治疗方法。干细胞为治疗包括MS在内的许多自身免疫性疾病提供了一种令人兴奋的新途径。我们之前已经证明，将自体神经干细胞(NSCs)移植到MHV感染的脱髓鞘小鼠体内，可以改善与广泛髓鞘再分化相关的运动技能。此外，我们有数据支持临床和组织学疾病的改善是移植神经干细胞的结果。我们现在将注意力集中在如何延长移植干细胞的寿命上，因为我们相信这些细胞对改善功能结果至关重要。这在临床上是有意义的，因为如果将人类干细胞用于治疗多发性硬化症或其他人类脱髓鞘疾病，它们很可能来自与多发性硬化症患者在基因上不相似的捐赠者来源；因此，这些细胞在移植后早期将被排斥，因为它们不是“自生”的。这项研究提案将检验临床相关的策略，这些策略可能用于通过抑制受体宿主的免疫反应来提高移植干细胞的存活率。 公共卫生相关性：将同基因小鼠神经干细胞(NSCs)植入已确定脱髓鞘的小鼠体内，可导致与运动技能恢复相关的重新髓鞘形成。然而，同种异体小鼠神经干细胞移植会导致快速排斥反应，且无髓鞘再生或临床恢复。该提案将定义与免疫介导的神经干细胞排斥反应相关的机制，以及抑制同种异体神经干细胞免疫原性的方法。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by multifocal regions of inflammation and myelin destruction. Typically, MS runs a protracted clinical course lasting over several decades with episodes of exacerbation followed by variable periods of remission. Available evidence indicates that the cause of MS is multifactorial and includes the genetic background of the individual as well as environmental influences e.g. viral infection. The development of animal models in which the clinical and histologic pathology is similar to that observed in the majority of MS patients is imperative in order to attempt to better understand the underlying pathological mechanisms contributing to MS. Viral models of demyelination are important tools for studying the pathogenesis of disease. Persistent infection of mice with the neurotropic JHM strain of mouse hepatitis virus (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Combined with the fact that an environmental agent such as a virus is considered to be a contributing cause of MS, the MHV system offers an excellent model in which to study both the underlying immunopathological mechanisms that may drive demyelination in MS patients as well as novel therapeutic methods for promoting remyelination. Stem cells offer an exciting new avenue for treatment of many autoimmune diseases including MS. We have previously demonstrated that surgical engraftment of self-derived neural stem cells (NSCs) into MHV- infected mice with established demyelination results in improved motor skills associated with extensive remyelination. In addition, we have data supporting that the improvement in both clinical and histologic disease is the result of the engrafted NSCs. We have now focused our attention on how to prolong the life- span of transplanted stem cells as we believe these cells are critical in improving functional outcome. This is clinically relevant in that if human stem cells are used for treatment of MS or other human demyelinating diseases, it is likely they will be derived from a donor source that is not genetically similar to an MS patient; therefore, these cells will be rejected early following transplantation as they are not "self-derived". This research proposal will examine clinically-relevant strategies that may be used for improving the survival of transplanted stem cells by dampening immune responses in the recipient host. PUBLIC HEALTH RELEVANCE: Engraftment of syngeneic mouse neural stem cells (NSCs) into mice with established demyelination results in remyelination associated with recovery of motor skills. However, transplantation of allogeneic mouse NSCs results in rapid rejection associated with no remyelination nor clinical recovery. This proposal will define mechanisms associated with immune-mediated rejection of NSCs as well as methods to dampen the immunogenicity of allogeneic NSCs.