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: 10461803
• 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/10461803
• 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; Persons; 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，它影响 估计有100万美国人1。多发性硬化症的病因尚不清楚，目前还没有治愈方法，目前的治疗方法也有限 功效。我的实验室专注于识别对脑源性T细胞致病至关重要的分子。自.以来 中枢神经系统是一种免疫特权组织，免疫监测是有限的，我们假设脑源性 T细胞表达独特的分子，增强其脑发育能力，这与CD4T细胞不同 保护我们免受感染，这些分子可能是多发性硬化症的治疗靶点这项研究的目的是 确定生脑效应CD4T细胞的分子靶点，这些分子靶点可以通过治疗来最小化 脑源性T细胞的分化，以及消灭或麻痹已建立的脑源性T细胞， 同时保留病原体特异性的CD4T细胞。我们假设脑源性T细胞，不管它们是否是 Th1或Th17共享特定的分子通路，可以通过治疗靶向阻止中枢神经系统的进展 自身免疫力。目的1：确定脑源性Th1和Th17细胞差异表达基因的作用。 目的2：分析生脑分子作为免疫功能低下的多发性硬化症特异性治疗靶点的有效性 妥协。这些生脑相关分子在脑损伤的发生和/或功能中所起的作用 将在小鼠和人类的CD4T细胞中确定脑源性T细胞，以及是否存在 这些分子在致病T细胞和保护T细胞中的不同作用。许多研究都集中在 脑源性T细胞的分化，但很少有研究分析脑源性T细胞的独特特征 MS中的脑源性效应/记忆T细胞这一数据将有助于确定新分化的治疗靶点 脑源性T细胞限制MS中潜在致病T细胞的生成重要的是，这项研究还将 识别对脑源性效应/记忆CD4T细胞功能至关重要的分子，可能是 有助于疾病的进展，可能不太容易受到针对T细胞分化或特定T细胞的治疗的影响 细胞子集。这项研究是新的，因为重点是T细胞的脑原性，无论T细胞是否有 Th1或Th17的表型。此外，这项研究将比较多发性硬化症患者的保护性和致病性CD4T细胞反应 患者需要确定不会影响对感染的保护的治疗目标。