Neural Stem Cells and Regulatory T Cells

神经干细胞和调节性 T 细胞

• 批准号: 8513575
• 负责人: Samia J. Khoury
• 金额: $ 40.67万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513575
• 关键词: Adult; Affect; Animal Model; Antigen-Presenting Cells; Autoimmune Diseases; Autoimmune Process; Brain; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Central Nervous System Degenerative Diseases; Clinical; Data; Demyelinating Diseases; Demyelinations; Dendritic Cells; Dendritic cell activation; Disease; Effector Cell; Environment; Experimental Autoimmune Encephalomyelitis; Galectin 1; Homing; Human; Immigration; Immune; Immune response; Immune system; Immunosuppression; In Situ; In Vitro; Induction of Apoptosis; Inflammatory; Injection of therapeutic agent; Injury; Intervention; Investigation; Luciferases; Lymphoid; Mediating; Mediator of activation protein; Microglia; Modeling; Molecular; Monitor; Multiple Sclerosis; Mus; Myelin Associated Glycoprotein; Natural regeneration; Neuraxis; Organ; Outcome; Pathway interactions; Peripheral; Phase; Population; Recovery; Regulation; Regulatory T-Lymphocyte; Relapse; Reporting; Role; Site; Speed; Staging; Stem cell transplant; Stem cells; Symptoms; T cell differentiation; T-Lymphocyte; Therapeutic; Time; Transplantation; Undifferentiated; cell motility; cytokine; disability; human disease; improved; in vivo; insight; macrophage; migration; monocyte; multipotent cell; nerve stem cell; novel; protective effect; repaired; stem cell therapy; trafficking

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an autoimmune demyelinating and degenerative disease of the central nervous system (CNS), which is characterized by relapsing-remitting symptoms in the early phase and followed by secondary progression and permanent disability. Myelin associated glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) in mice serves as an animal model for human MS. Neural stem cells (NSCs) are a population of immature, undifferentiated multipotent cells in the adult CNS that contribute to the CNS repair and regeneration upon injury or disease. Neural stem cell therapy has been proposed in recent years for CNS repair. Recently, exogenously administered NSCs were reported to suppress EAE through an immune modulatory mechanism. Our initial studies suggest a role of NSCs in mediating regulatory T cell (Treg) expansion as well as suppression of pathogenic T cells differentiation. The aims for this proposal are: 1) To investigate the mechanisms of NSC-mediated immune suppression in EAE. Our hypothesis is that NSCs alter T cell differentiation in favor of Treg differentiation and suppress pathogenic Th1 and Th17 cells. We will investigate the molecular mechanisms of NSC-mediated Treg expansion and survival. We will also investigate the mechanisms of NSC-mediated suppression of pathogenic Th1 and Th17 cell differentiation and their in vivo correlation. 2) To study NSCs and T cells interaction and migration in vivo. The timing and site of exogenous NSCs interact with T cells may be critical for the outcome of the EAE suppression. Furthermore, the inflammatory cytokines in the pathological environment may stimulate or inhibit NSCs repair. We will investigate the effects of the timing of NSC injection and whether the NSCs suppress pathogenic T cells and promote Treg expansion and migration in the peripheral lymphoid organs or whether the NSCs themselves migrate to the CNS and elicit this effect in situ. We will focus on NSC and T cell trafficking at different stages of EAE and strictly monitor NSC migration, survival, proliferation or differentiation in the recipients. 3) To study the effect of NSCs on modulating the function of antigen-presenting cells. We will examine monocyte/macrophage, microglia and dendritic cell activation and functions under the influence of NSCs in vitro and in vivo during EAE. This experimental plan will allow us to better understand the effects of NSC intervention on the immune system during EAE progression. The results will give valuable insights for using NSC therapeutically. Furthermore, the proposal will provide insight into the interactions of endogenous NSCs with immune cells during autoimmune diseases, and a potential pathway to enhance endogenous repair.

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）的自身免疫性脱髓鞘和退行性疾病，其特征是早期症状复发-缓解，随后继发进展和永久残疾。髓鞘相关糖蛋白诱导的小鼠实验性自身免疫性脑脊髓炎（EAE）是人类MS的动物模型。神经干细胞（Neural stem cells，NSCs）是成体中枢神经系统中一群未成熟、未分化的多能细胞，在损伤或疾病后参与中枢神经系统的修复和再生。近年来，神经干细胞治疗已被提出用于CNS修复。最近，外源性神经干细胞通过免疫调节机制抑制EAE。我们的初步研究表明，神经干细胞在介导调节性T细胞（Treg）扩增以及抑制致病性T细胞分化的作用。本研究的目的是：1）探讨神经干细胞介导的免疫抑制在EAE中的作用机制。我们的假设是，神经干细胞改变T细胞分化，有利于Treg分化，抑制致病性Th 1和Th 17细胞。我们将研究神经干细胞介导的调节性T细胞扩增和存活的分子机制。我们还将研究神经干细胞介导的抑制致病性Th 1和Th 17细胞分化的机制及其在体内的相关性。2)研究神经干细胞与T细胞在体内的相互作用和迁移。外源性神经干细胞与T细胞相互作用的时机和部位可能对EAE抑制的结果至关重要。此外，病理环境中的炎性细胞因子可刺激或抑制神经干细胞的修复。我们将研究NSC注射时机的影响，以及NSC是否抑制致病性T细胞并促进外周淋巴器官中的Treg扩增和迁移，或者NSC本身是否迁移到CNS并原位引发这种效应。我们将重点关注EAE不同阶段的NSC和T细胞运输，并严格监测NSC在受体中的迁移、存活、增殖或分化。3)研究神经干细胞对抗原提呈细胞功能的调节作用。我们将研究单核细胞/巨噬细胞，小胶质细胞和树突状细胞的激活和功能的影响下，神经干细胞在体外和体内EAE期间。该实验计划将使我们能够更好地了解NSC干预对EAE进展期间免疫系统的影响。这些结果将为神经干细胞的治疗提供有价值的见解。此外，该提案将提供深入了解内源性神经干细胞与免疫细胞在自身免疫性疾病中的相互作用，以及增强内源性修复的潜在途径。