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（申请人提供）：多发性硬化症（MS）是一种自身免疫性脱髓鞘和中枢神经系统（CNS）退行性疾病，其特点是早期出现复发缓解症状，随后出现继发性进展和永久性残疾。小鼠髓鞘相关糖蛋白诱导的实验性自身免疫性脑脊髓炎 (EAE) 可作为人类多发性硬化症的动物模型。神经干细胞（NSC）是成体中枢神经系统中一群未成熟、未分化的多能细胞，有助于中枢神经系统损伤或疾病时的修复和再生。近年来已提出神经干细胞疗法用于中枢神经系统修复。最近，据报道外源性 NSC 可以通过免疫调节机制抑制 EAE。我们的初步研究表明 NSC 在介导调节性 T 细胞 (Treg) 扩增以及抑制致病性 T 细胞分化中发挥作用。该提案的目的是：1）研究 EAE 中 NSC 介导的免疫抑制机制。我们的假设是 NSC 改变 T 细胞分化，有利于 Treg 分化，并抑制致病性 Th1 和 Th17 细胞。我们将研究 NSC 介导的 Treg 扩增和存活的分子机制。我们还将研究 NSC 介导的抑制致病性 Th1 和 Th17 细胞分化的机制及其体内相关性。 2）研究NSCs和T细胞在体内的相互作用和迁移。外源 NSC 与 T 细胞相互作用的时间和部位可能对于 EAE 抑制的结果至关重要。此外，病理环境中的炎症细胞因子可能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 Treg 在外周淋巴器官中的扩增和迁移，或者 NSC 本身是否迁移到 CNS 并在原位引起这种效应。我们将重点关注EAE不同阶段的NSC和T细胞运输，严格监测受者体内NSC的迁移、存活、增殖或分化。 3) 研究NSCs对抗原呈递细胞功能的调节作用。我们将在 EAE 期间体外和体内检查单核细胞/巨噬细胞、小胶质细胞和树突状细胞在 NSC 影响下的激活和功能。该实验计划将使我们能够更好地了解 EAE 进展过程中 NSC 干预对免疫系统的影响。这些结果将为 NSC 的治疗应用提供宝贵的见解。此外，该提案还将深入了解自身免疫性疾病期间内源性 NSC 与免疫细胞的相互作用，以及增强内源性修复的潜在途径。