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

脱髓鞘病毒模型中的人神经前体细胞介导的治疗

基本信息

批准号：
8874463
负责人：
Thomas E Lane
金额：
$ 57.03万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874463
关键词：
Autoimmune Diseases Cell Transplantation Cells Chronic Disease Clinical Data Demyelinating Diseases Demyelinations Disease Disease remission Engraftment Etiology Genetic Growth Factor Histologic Human Immune Individual Infection Infectious Agent Infiltration Inflammation Inflammatory Mediating Methods Modeling Molecular Motor Motor Skills Multiple Sclerosis Murine hepatitis virus Mus Myelin Neuraxis Oligodendroglia Outcome Pathogenesis Pathology Patients Recovery Regulatory T-Lymphocyte Running Stem cells Symptoms System T-Lymphocyte Therapeutic Transplantation Viral Virus Virus Diseases animal model development clinically relevant design environmental agent improved macrophage nerve stem cell neural precursor cell neuroinflammation neurotropic neurotropic virus novel therapeutic intervention novel therapeutics oligodendrocyte precursor precursor cell public health relevance remyelination repaired research study response tool white matter damage

项目摘要

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.

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性疾病，其特征是多灶性区域炎症和髓磷脂破坏，通常，多发性硬化症的临床病程持续数十年，并伴有发作性加重。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、临床动物模型的发展。为了更好地了解多发性硬化症的潜在病理机制，必须采用与大多数多发性硬化症患者观察到的组织学病理学相似的脱髓鞘病毒模型，这是研究多发性硬化症小鼠持续感染发病机制的重要工具。小鼠肝炎病毒 (MHV) 的神经性 JHM 株的特征是由炎症 T 细胞和巨噬细胞介导的持续脱髓鞘，其临床和组织学与人类脱髓鞘疾病相似结合病毒等环境因素被认为是 MS 的诱因这一事实，MHV 系统提供了一个极好的模型，可用于研究可能导致 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为治疗包括多发性硬化症在内的许多自身免疫性疾病提供了令人兴奋的新途径。将 hNPCs 注入已确定脱髓鞘的 MHV 感染小鼠中，可导致持续的临床改善，这与神经炎症和髓鞘再生的减少有关。我们的研究结果表明，移植的 hNPCs 被排斥，表明这些细胞能够调节微环境，从而延长临床恢复时间。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 细胞可能会抑制神经炎症以及内源性少突胶质细胞的激活/成熟该应用将探究 hNPC 促进运动技能修复和恢复的潜在机制。