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

基本信息

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
项目类别：
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

项目摘要

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症 (MS) 是一种免疫介导的中枢神经系统 (CNS) 脱髓鞘疾病，影响估计有 100 万美国人1。 MS 的病因不明，无法治愈，目前的治疗方法有限功效。我的实验室专注于识别对致脑炎 T 细胞致病性至关重要的分子。自从中枢神经系统是免疫豁免组织，免疫监视有限，我们假设脑炎 T 细胞表达独特的分子，增强其致脑炎能力，这与 CD4 T 细胞不同保护我们免受感染，并且这些分子可能是多发性硬化症的治疗靶点。这项研究的目标是鉴定致脑炎效应 CD4 T 细胞中的分子靶标，可通过治疗操作将其最小化致脑炎 T 细胞的分化，以及消灭或激活已建立的致脑炎 T 细胞，同时保留病原体特异性 CD4 T 细胞。我们假设致脑炎 T 细胞，无论它们是否是 Th1 或 Th17 共享特定的分子途径，可通过治疗靶向来阻止 CNS 的进展自身免疫。目标 1：确定致脑炎 Th1 和 Th17 细胞中差异表达的基因的作用。目标 2：分析致脑炎分子作为具有最小免疫的 MS 特异性治疗靶点的有效性妥协。这些脑炎相关分子在脑炎的产生和/或功能中发挥的作用将测定小鼠和人类 CD4 T 细胞中的致脑炎 T 细胞，以及是否存在这些分子在致病性 T 细胞和保护性 T 细胞中的不同作用。许多研究都集中在脑炎 T 细胞的分化，但很少有研究分析其独特特征 MS 中的致脑炎效应/记忆 T 细胞。这些数据将有助于确定新分化的治疗靶点脑炎 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 CD4 T 细胞功能至关重要的分子，这些分子可能有助于疾病进展，并且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亚群。这项研究的新颖之处在于，重点是 T 细胞致脑炎性，无论 T 细胞是否具有 Th1 或 Th17 表型。此外，本研究将比较 MS 中的保护性和致病性 CD4 T 细胞反应患者确定不会损害感染保护的治疗靶点。