Mechanisms by which effector T cells modulate endogenous remyelination

效应T细胞调节内源性髓鞘再生的机制

• 批准号: 10308713
• 负责人: PETER A CALABRESI
• 金额: $ 50.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308713
• 关键词: Adaptive Immune System; Address; Adopted; Adoptive Transfer; Affect; Agonist; Antigen Presentation; Antigens; Area; Astrocytes; Autopsy; Axon; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Cellular biology; Cephalic; Chronic; Clinic; Cross Presentation; Cues; Cuprizone; Cytokine Signaling; Demyelinations; Development; Disease; Drug Targeting; Experimental Autoimmune Encephalomyelitis; Failure; Funding; Genetic; Genetic Transcription; Grant; Immune; Immunotherapy; In Vitro; Inflammation; Inflammatory; Interferon Type II; Kinetics; Knowledge; Laboratories; Lentivirus; Lymphocyte; Lymphocyte Activation; Lymphoid; MHC Class I Genes; Mediating; Meningeal; Microglia; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; NFKB Signaling Pathway; Neuraxis; Neuroglia; Neurologic; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Oligodendroglia; Paper; Pathogenicity; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Process; Property; Receptor Signaling; Refractory; Regulatory Pathway; Relapsing-Remitting Multiple Sclerosis; Reporter; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; System; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapeutic Intervention; Thinking; Thinness; Trauma; Tumor-infiltrating immune cells; brain tissue; chemokine; cytotoxic; cytotoxic CD8 T cells; cytotoxicity; disability; effector T cell; exenatide; in vivo; inflammatory milieu; intravital microscopy; lymphocyte trafficking; neuroprotection; neurotoxic; new therapeutic target; novel; novel therapeutic intervention; oligodendrocyte precursor; precursor cell; remyelination; repaired; response; single-cell RNA sequencing; success; targeted treatment; therapy development; tissue injury; trafficking; two-photon; young adult

Project Summary: The project addresses an important problem - multiple sclerosis (MS), which is the most common cause of neurological disability in young adults after trauma. While the approval of numerous immunotherapies has had an impact on reducing inflammatory disease activity in relapsing remitting MS, there are no therapies to date that enhance repair of the myelin or markedly influence the progressive stage of the disease. Although non-inflammatory mechanisms may contribute to progressive MS, several recent papers highlight a critical role for ongoing inflammation within the brain at or next to sites of tissue injury. A direct pathogenic role for T cells in progressive MS has been suggested by the presence of lymphoid meningeal follicles, which are associated with cortical demyelination and thinning. A more detailed understanding of how immune cells inhibit remyelination is critical for developing therapies to enhance remyelination and halt progressive MS. Despite observational evidence that immune cells may suppress or promote remyelination, there is remarkably little known regarding the specific mechanisms by which these processes occur. This project addresses a barrier to progress in the field because our understanding of why remyelination fails in disease is presently limited because we have not elucidated the pathways involved in failed oligodendrocyte precursor cell (OPC) differentiation. We plan to pursue an exciting novel observation that not only do OPCs fail to differentiate into myelin producing cells, but in an inflammatory environment they adopt an immune phenotype (iOPCs) and can prime CD8 T cells, as well as become targets of the cytotoxic lymphocytes (CTL). This represents a paradigm shift in thinking about OPC biology and remyelination. We will characterize the profile, fate and function of iOPC. We seek to understand the mechanisms by which they activate CD8 T cells that in turn kill a subset of the iOPC as target cells. We will track iOPC using fate mapping strategies and two-photon intravital microscopy through cranial windows. We aim to develop drug therapies that target the NFkB signaling pathway involved in MHC expression using several novel therapeutic approaches including the type 2 diabetes mellitus drug exenatide and an agonist of the NLRX-1 signaling molecule that normally regulates NFkB expression.

项目总结： 该项目解决了一个重要的问题-多发性硬化症(MS)，这是导致 青壮年创伤后的神经功能障碍。虽然大量免疫疗法的批准已经 复发缓解期MS对减少炎症性疾病活动性的影响，到目前为止还没有治疗方法 增强髓鞘修复或显著影响疾病进展阶段的物质。虽然 非炎症机制可能有助于进展性多发性硬化症，最近的几篇论文强调了关键作用 用于大脑内组织损伤部位或邻近部位的持续炎症。T细胞的直接致病作用 进展性多发性硬化症的细胞是由淋巴样脑膜滤泡的存在所提示的，淋巴样脑膜滤泡是 与皮质脱髓鞘和变薄有关。更详细地了解免疫细胞如何 抑制再髓鞘形成对于开发促进再髓鞘形成和阻止进行性多发性硬化的治疗方法至关重要。 尽管有观察证据表明免疫细胞可能抑制或促进 髓鞘再分化，人们对这些过程的具体机制知之甚少 发生。这个项目解决了在该领域取得进展的障碍，因为我们的理解 为什么在疾病中重新髓鞘形成失败目前是有限的，因为我们还没有阐明 少突胶质前体细胞(OPC)分化失败的途径。我们计划追求一种激动人心的 新的观察结果表明，OPC不仅不能分化为髓鞘生成细胞，而且在 炎症环境它们采用免疫表型(IOPC)，并能激活CD8T细胞，如 并成为细胞毒性淋巴细胞(CTL)的靶点。这代表着思维方式的转变。 关于OPC生物学和重新髓鞘形成。 我们将描述iOPC的概况、命运和功能。我们试图通过以下方式来理解这些机制 它们激活CD8T细胞，进而杀死作为靶细胞的iOPC的一个子集。我们将使用以下工具跟踪iOPC 通过颅窗的命运标测策略和双光子活体显微镜。我们的目标是开发药物 以NFkB信号通路为靶点的治疗涉及MHC表达 治疗2型糖尿病的药物埃塞那肽和NLRX-1信号激动剂 正常调节NFkB表达的分子。