Defining the Role of Molecules Unique to Encephalitogenic T Cells in MS

定义致脑炎 T 细胞特有分子在多发性硬化症中的作用

• 批准号: 10227187
• 负责人: Amy E Lovett-Racke
• 金额: $ 39万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-04 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227187
• 关键词: Advanced Development; Affect; Antigen-Presenting Cells; CD4 Positive T Lymphocytes; CNS autoimmunity; Cells; Characteristics; Data; Development; Disease Progression; Experimental Autoimmune Encephalomyelitis; Generations; Genes; Goals; Homeostasis; Human; Immune; Immunologic Surveillance; Incidence; Infection; Inflammatory; Interleukin-12; Interleukin-6; Laboratories; Mediating; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neurologic Deficit; Pathogenicity; Pathway interactions; Phenotype; Play; Prevalence; Role; STAT3 gene; STAT4 gene; Signal Transduction; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Tissues; central nervous system demyelinating disorder; cost; cytokine; differential expression; interleukin-23; memory CD4 T lymphocyte; mouse model; multiple sclerosis patient; novel; pathogen; prevent; targeted treatment; therapeutic target

Specific Aims Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that affects an estimated 1 million Americans1. The cause of MS is unknown, there is no cure, and the current therapies have limited efficacy. My laboratory focuses on identifying molecules critical to the pathogenicity of encephalitogenic T cells. Since the CNS is an immune-privileged tissue and immunological surveillance is limited, we hypothesize that encephalitogenic T cells express unique molecules that enhance their encephalitogenic capacity, which are distinct from the CD4 T cells that protect us from infection, and that these molecules may be therapeutic targets for MS. The goal of this study is to identify molecular targets in encephalitogenic effector CD4 T cells that could be therapeutically manipulated to minimize the differentiation of encephalitogenic T cells, as well as extinguish or anergize established encephalitogenic T cells, while sparing pathogen-specific CD4 T cells. We hypothesize that encephalitogenic T cells, regardless of whether they are Th1 or Th17, share specific molecular pathways that can be therapeutically targeted to halt progression of CNS autoimmunity. Aim 1: Determine the role of genes differentially expressed in both encephalitogenic Th1 and Th17 cells. Aim 2: Analyze the validity of encephalitogenic molecules as MS-specific therapeutic targets with minimal immune compromise. The role that these encephalitogenic-associated molecules play in the generation and/or function of encephalitogenic T cells will be determined in both mouse and human CD4 T cells, as well as whether there is a differential role of these molecules in pathogenic versus protective T cells. Many studies have focused on the differentiation of encephalitogenic T cells, but far fewer studies have analyzed the unique characteristics of encephalitogenic effector/memory T cells in MS. This data will help identify therapeutic targets in newly differentiating encephalitogenic T cells to limit the generation of potentially pathogenic T cells in MS. Importantly, this study will also identify molecules that are critical to the function of encephalitogenic effector/memory CD4 T cells that may be contributing to disease progression and may be less vulnerable to therapies that target T cell differentiation or specific T cell subsets. This study is novel in that the focus is on T cell encephalitogenicity, irrespective of whether the T cells have a Th1 or Th17 phenotype. Furthermore, this study will compare protective versus pathogenic CD4 T cell responses in MS patients to identify therapeutic targets that would not compromise protection to infections.

具体目标 多发性硬化（MS）是一种免疫介导的中枢神经系统（CNS）脱髓鞘疾病， 估计有100万美国人。MS的原因是未知的，没有治愈方法，并且目前的治疗方法有限。 功效我的实验室致力于鉴定致脑炎T细胞致病性的关键分子。以来 中枢神经系统是一种免疫豁免组织，免疫监视是有限的，我们假设致脑炎性 T细胞表达增强其致脑炎能力的独特分子，其不同于CD 4 T细胞。 保护我们免受感染，这些分子可能是MS的治疗靶点。 鉴定致脑炎效应CD 4 T细胞中的分子靶点，其可以在治疗上操作以最小化 致脑炎性T细胞的分化，以及使已建立的致脑炎性T细胞消失或无能量化， 同时保留病原体特异性CD 4 T细胞。我们假设致脑炎性T细胞，不管它们是否是 Th 1或Th 17共享特定的分子途径，可以在治疗上靶向阻止CNS进展 自身免疫目的1：确定致脑炎Th 1和Th 17细胞中差异表达基因的作用。 目的2：分析致脑炎分子作为MS特异性治疗靶点的有效性， 妥协这些致脑炎相关分子在致脑炎相关基因的产生和/或功能中所起的作用， 将在小鼠和人CD 4 T细胞中确定致脑炎性T细胞，以及是否存在致脑炎性T细胞。 这些分子在致病性与保护性T细胞中的不同作用。许多研究都集中在 致脑炎性T细胞的分化，但很少有研究分析了致脑炎性T细胞的独特特征， 致脑炎效应/记忆T细胞在MS中的作用。这些数据将有助于确定新分化的治疗靶点。 致脑炎性T细胞，以限制MS中潜在致病性T细胞的产生。重要的是，这项研究还将 鉴定对致脑炎效应/记忆CD 4 T细胞功能至关重要的分子， 有助于疾病进展，并且可能不太容易受到靶向T细胞分化或特异性T细胞的治疗。 细胞亚群这项研究是新颖的，因为重点是T细胞致脑炎性，无论T细胞是否具有 Th 1或Th 17表型。此外，本研究将比较MS中的保护性与致病性CD 4 T细胞应答， 患者确定不会损害感染保护的治疗靶点。