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: 10526405
• 负责人: PETER A CALABRESI
• 金额: $ 49.88万
• 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/10526405
• 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; Cell secretion; Cells; Cellular biology; Central Nervous System; Cephalic; Chronic; Clinic; Cross Presentation; Cues; Cuprizone; Cytokine Signaling; Demyelinations; Development; Disease; Drug Targeting; Experimental Autoimmune Encephalomyelitis; Failure; Funding; Genetic; Genetic Transcription; Globulins; Grant; Immune; Immunotherapy; In Vitro; Inflammation; Inflammatory; Interferon Type II; Kinetics; Knowledge; Laboratories; Lentivirus; Lymphocyte; Lymphocyte Activation; Lymphoid; MHC Class I Genes; Maps; Mediating; Meningeal; Microglia; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; NF-kappa B; NFKB Signaling Pathway; Neuroglia; Neurologic; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Oligodendroglia; Paper; Pathogenicity; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; 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 infiltration; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapeutic Intervention; Thinking; Thinness; Trauma; brain tissue; cell motility; chemokine; cytotoxic; cytotoxic CD8 T cells; cytotoxicity; disability; effector T cell; exenatide; immune function; in vivo; inflammatory milieu; intravital microscopy; lymphocyte trafficking; neuroprotection; neurotoxic; new therapeutic target; novel; novel therapeutic intervention; oligodendrocyte precursor; pharmacologic; 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.

项目摘要： 该项目解决了一个重要的问题 - 多发性硬化症（MS），这是最常见的原因 创伤后年轻人的神经残疾。虽然众多免疫疗法的认可 对减少炎症性疾病活性的影响，迄今为止尚无疗法 这可以增强髓磷脂的修复或显着影响疾病的进行性阶段。虽然 非炎症机制可能有助于渐进的MS，最近的几篇论文突出了至关重要的作用 用于在组织损伤部位或旁边的大脑内持续的炎症。 T的直接致病作用 淋巴脑膜卵泡的存在提出了进行性MS的细胞，这是 与皮质脱髓鞘和变薄有关。对免疫细胞如何更详细的了解 抑制再髓样对于开发疗法以增强延期性和停止渐进性MS至关重要。 尽管有观察到的证据表明免疫细胞可能会抑制或促进 再髓，关于这些过程的特定机制鲜为人知 发生。该项目解决了该领域进步的障碍，因为我们的理解 为什么目前在疾病中雷髓式失败是有限的，因为我们尚未阐明 少突胶质细胞前体细胞（OPC）分化涉及的途径。我们计划追求一个令人兴奋的 新颖的观察结果，不仅OPC无法区分髓磷脂的产生细胞，而且在 炎症环境他们采用免疫表型（IOPC）并可以启用CD8 T细胞，因为 并成为细胞毒性淋巴细胞（CTL）的靶标。这代表了思维的范式转变 关于OPC生物学和再髓。 我们将表征IOPC的配置文件，命运和功能。我们试图通过 它们激活CD8 T细胞，而CD8 T细胞又杀死了IOPC作为靶细胞的子集。我们将使用IOPC跟踪 命运映射策略和通过颅骨窗户的两光量插入式显微镜。我们旨在开发毒品 使用几种新型治疗方法靶向NFKB信号途径的疗法 包括2型糖尿病的方法和NLRX-1信号的激动剂 通常调节NFKB表达的分子。