Regulation of Th17 Functions in Autoimmune CNS Inflammation

自身免疫性中枢神经系统炎症中 Th17 功能的调节

• 批准号: 8962148
• 负责人: Mandy J McGeachy
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962148
• 关键词: Adhesions; Adverse effects; Affect; American; Autoimmune Diseases; Autoimmune Process; Automobile Driving; Biological Assay; Blood; Blood Vessels; Bone Marrow; Brain; Candidiasis; Cell physiology; Cells; Chemicals; Chimera organism; Data; Development; Disease; Effector Cell; Endothelial Cells; Experimental Autoimmune Encephalomyelitis; Extracellular Matrix; Goals; Health; Human; ITGB3 gene; In Vitro; Infection; Inflammation; Inflammatory; Integrins; Interleukin-17; Interleukin-6; Investigation; Lead; Lesion; Ligands; Ligation; Mediating; Migration Assay; Modeling; Molecular; Multiple Sclerosis; Mus; Myelogenous; Oral mucous membrane structure; PTK2 gene; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiological; Predisposition; Production; Publishing; Regulation; Reporting; Risk; Role; STAT3 gene; Signal Pathway; Signal Transduction; Slice; Staging; System; T-Lymphocyte; Testing; Tissues; Treatment Efficacy; Work; angiogenesis; base; cell motility; chronic autoimmune disease; cytokine; in vivo; interleukin-23; live cell imaging; migration; mouse model; multiple sclerosis patient; nervous system disorder; new therapeutic target; novel; osteopontin; receptor; reconstitution; response; therapeutic target

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is a debilitating autoimmune neurological disease. Th17 cells have emerged as key drivers of pathogenesis in chronic autoimmune disease and are increased in MS patients. Th17 cells are also critical for driving CNS inflammation in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). Our previous work demonstrated that Th17 cells are dependent on signals from IL-23 for their proliferation and differentiation into effector cells capable of driving inflammation in EAE. Although Th17 cells are mostly considered as IL-17 producers, they have many additional functions and IL-17 is not always sufficient to drive disease. However, IL-23 is critical, and our goal is to understand the specific mechanisms by which IL-23 promotes Th17 functions in inflammatory disease. We have recently discovered a novel integrin that is expressed by effector Th17 cells in an IL-23-dependent manner, and required for EAE. Published reports describe increased expression of this integrin in a number of human inflammatory diseases, including MS. However, almost nothing is known about its functional importance in T cells, and in particular Th17 cells. Collectively, these data form the basis for our central hypothesis that this integrin is a key IL-23-driven molecule involved in determining the inflammatory activity of autoimmune Th17 cells. We now aim to interrogate the role of its expression in Th17-mediated inflammation, and thereby to validate this integrin as a novel Th17-directed therapeutic target.

描述（由申请人提供）：多发性硬化症（MS）是一种使人衰弱的自身免疫性神经系统疾病。Th 17细胞已成为慢性自身免疫性疾病发病机制的关键驱动因素，并在MS患者中增加。Th 17细胞对于在MS（实验性自身免疫性脑脊髓炎（EAE））的鼠模型中驱动CNS炎症也是关键的。我们以前的工作表明，Th 17细胞依赖于IL-23的信号，使其增殖和分化为能够驱动EAE炎症的效应细胞。 虽然Th 17细胞大多被认为是IL-17生产者，但它们具有许多额外的功能，并且IL-17并不总是足以驱动疾病。然而，IL-23是至关重要的，我们的目标是了解IL-23促进炎症性疾病中Th 17功能的具体机制。我们最近发现了一种新的整合素，其由效应Th 17细胞以IL-23依赖性方式表达，并且是EAE所需的。已发表的报道描述了这种整合素在许多人类炎性疾病（包括MS）中的表达增加。然而，关于其在T细胞（特别是Th 17细胞）中的功能重要性几乎一无所知。总的来说，这些数据形成了我们的中心假设的基础，即这种整合素是一种关键的IL-23驱动的分子，参与决定自身免疫性Th 17细胞的炎症活性。我们现在的目标是询问其表达在Th 17介导的炎症中的作用，从而验证这种整合素作为一种新的Th 17导向的治疗靶点。