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

 描述（由申请人提供）：多发性硬化（MS）是一种中枢神经系统（CNS）慢性疾病，其特征为多灶性炎症和髓鞘破坏。通常，MS的临床病程延长，持续数十年，伴有急性发作，随后是不同的缓解期。现有证据表明，MS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，开发临床和组织病理学与大多数MS患者相似的动物模型势在必行。脱髓鞘病毒模型是研究疾病发病机制的重要工具。小鼠肝炎病毒（MHV）嗜神经性JHM株持续感染小鼠的特征是由炎性T细胞和巨噬细胞介导的持续脱髓鞘，其在临床和组织学上与人类脱髓鞘疾病多发性硬化症（MS）相似。结合环境因子（如病毒）被认为是MS的促成因素这一事实，MHV系统提供了一个极好的模型，用于研究可能驱动MS患者脱髓鞘的潜在免疫病理学机制以及促进髓鞘再生的新治疗方法。 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条令人兴奋的新途径。我们现在已经确定，将人多能源性神经前体细胞（hNPC）椎管内移植到MHV感染的小鼠中，建立脱髓鞘导致持续的临床改善，这与减少神经炎症和髓鞘再生有关。我们的研究结果表明，移植的hNPC被排斥，表明这些细胞能够调节微环境，从而延长临床恢复。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可能有助于髓鞘再生的内源性少突胶质细胞祖细胞的激活/成熟。本申请将询问hNPC有助于修复和恢复运动技能的潜在机制。

 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.