Viral-induced demyelination and neural stem cell-mediated remyelination

病毒诱导的脱髓鞘和神经干细胞介导的髓鞘再生

• 批准号: 8152289
• 负责人: Thomas E Lane
• 金额: $ 32.91万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8152289
• 关键词: Allogenic; Attention; Autoimmune Diseases; Autoimmune Process; Biological Models; Cell Line; Cell Transplants; Cells; Chemicals; Chronic; Chronic Disease; Clinical; Data; Demyelinating Diseases; Demyelinations; Disease; Disease remission; Engraftment; Etiology; Generations; Genetic; Hematopoietic stem cells; Histologic; Homologous Transplantation; Human; Immune; Immune Tolerance; Immune response; Implant; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Laboratories; Lesion; Life; Longevity; Mediating; Methods; Modeling; Molecular; Motor Skills; Multiple Sclerosis; Murine hepatitis virus; Mus; Myelin; Natural Killer Cells; Neuraxis; Neurodegenerative Disorders; Operative Surgical Procedures; Opportunistic Infections; Organ Transplantation; Pathogenesis; Pathology; Patients; Pluripotent Stem Cells; Predisposition; Recovery; Replacement Therapy; Research Proposals; Running; Signal Transduction; Solid; Source; Spinal Cord; Stem cell transplant; Stem cells; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tissues; Transplantation; Viral; Virus; Virus Diseases; Work; allograft rejection; animal model development; clinically relevant; design; environmental agent; functional outcomes; human embryonic stem cell; human stem cells; immunogenicity; improved; macrophage; nerve stem cell; neuroinflammation; neurotropic; neurotropic virus; novel therapeutics; response; somatic cell nuclear transfer; stem cell therapy; tool; tumor; virus-induced demyelination; white matter; white matter damage

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.

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）慢性疾病，其特征为多灶性区域炎症和髓磷脂破坏。通常，多发性硬化症会经历一个持续数十年的长期临床病程，先有一段时期的恶化，然后出现不同程度的缓解期。现有证据表明，多发性硬化症的病因是多因素的，包括个人的遗传背景以及环境影响，例如环境影响。病毒感染。为了更好地了解导致多发性硬化症的潜在病理机制，必须开发临床和组织病理学与大多数多发性硬化症患者中观察到的相似的动物模型。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) 的嗜神经性 JHM 株持续感染的特点是由炎症 T 细胞和巨噬细胞介导的持续脱髓鞘，这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。结合病毒等环境因素被认为是多发性硬化症的诱因这一事实，MHV 系统提供了一个极好的模型，可用于研究可能导致多发性硬化症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。我们之前已经证明，通过手术将自体神经干细胞（NSC）移植到已发生脱髓鞘的 MHV 感染小鼠中，可改善与广泛髓鞘再生相关的运动技能。此外，我们有数据支持临床和组织学疾病的改善是移植 NSC 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于改善功能结果至关重要。这与临床相关，因为如果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遗传上不相似的供体来源；因此，这些细胞将在移植后早期被排斥，因为它们不是“自体衍生的”。该研究计划将研究临床相关策略，这些策略可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。 公共健康相关性：将同源小鼠神经干细胞 (NSC) 移植到已发生脱髓鞘的小鼠中，会导致髓鞘再生，并与运动技能的恢复相关。然而，同种异体小鼠 NSC 移植会导致快速排斥反应，且不会出现髓鞘再生或临床恢复。该提案将定义与免疫介导的 NSC 排斥相关的机制以及抑制同种异体 NSC 免疫原性的方法。