Human neural precursor cell-mediated therapy in a viral model of demyelination

 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，例如病毒感染。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令人兴奋的新途径。我们现在已经确定，将人多能衍生神经前体细胞(HNP)移植到MHV感染的脱髓鞘小鼠体内可以持续改善临床，这与减少神经炎症和重新髓鞘形成有关。我们的发现表明，移植的hNPC被排斥，这表明这些细胞能够调节微环境，从而允许长期的临床恢复。初步结果表明，hNPC介导的恢复与调节性T细胞的出现有关，调节性T细胞可能抑制神经炎症以及内源性少突胶质细胞前体细胞的激活/成熟，这些细胞可能有助于重新髓鞘形成。这个应用程序将询问hNPC促进运动技能修复和恢复的潜在机制。

 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 now have determined that intraspinal transplantation of human pluripotent-derived neural precursor cells (hNPCs) into MHV-infected mice with established demyelination results in sustained clinical improvement that is associated with reduced neuroinflammation and remyelination. Our findings indicate that transplanted hNPCs are rejected indicating that these cells are capable of modulating the microenvironment that allow for prolonged clinical recovery. Preliminary results indicate that hNPC-mediated recovery is associated with the emergence of regulatory T cells that presumably dampen neuroinflammation as well as activation/maturation of endogenous oligodendrocyte progenitor cells that likely contribute to remyelination. This application will interrogate the underlying mechanisms by which hNPCs contribute to repair and recovery of motor skills.