K-Channels in Lymphocyte Function and Autoimmunity

淋巴细胞功能和自身免疫中的 K 通道

• 批准号: 7219987
• 负责人: GEORGE KANIANTHARA CHANDY
• 金额: $ 25.66万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219987
• 关键词: Acute; Adhesions; Animal Model; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Autopsy; Blood; Brain; Calcium; Cell Proliferation; Cell surface; Cells; Chronic; Clinical; Development; Diabetes Mellitus; Diagnostic; Diagnostic tests; Disease; Exhibits; Experimental Autoimmune Encephalomyelitis; Future; Glutamate Decarboxylase; Human; Immune response; Immunosuppression; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Lead; Left; Lesion; Life; Lymphocyte Function; MRI Scans; Magnetic Resonance Imaging; Mediating; Memory; Modeling; Monoclonal Antibody HuM291; Multiple Sclerosis; Myelin; Numbers; Outcome; Pathogenesis; Patients; Phase; Phenotype; Potassium Channel; Prevention; Primates; Production; Psoriasis; Rattus; Relapse; Rheumatoid Arthritis; Role; Severity of illness; System; T memory cell; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Transcriptional Activation; Up-Regulation; base; chronic graft versus host disease; cytokine; early onset; inhibitor/antagonist; prevent; research study; terminally differentiated effector memory (TEM) T cells; therapeutic effectiveness; therapeutic target; treatment trial; voltage

DESCRIPTION (provided by applicant): Autoreactive effector memory (TEM) T lymphocytes are implicated in the pathogenesis of multiple sclerosis (MS), type-1 diabetes mellitus (DM), psoriasis, rheumatoid arthritis and chronic graft-versus-host disease. Recent studies by our group suggest that the voltage-gated Kv1.3 channel is an exciting new target for the therapeutic manipulation of TEM cells. Kv1.3-based therapy for autoimmune disease that target TEM cells would have an advantage over broad and indiscriminate immunosuppression because naive/TCM cells would escape inhibition through up-regulation of the calcium-activated IKCal channel, leaving the bulk of the immune response unimpaired. In this proposal, we combine studies on patients with MS and type-1 DM with experiments in an animal model of MS, to establish the intellectual framework for the development of Kv1.3 as a therapeutic and diagnostic target for T cell-mediated autoimmune diseases. Aim-1 determines if the presence of myelin-specific Kv 1.3high TEM cells in patients with MS is an indicator of disease activity and whether these cells decrease after therapy. We will also screen postmortem brain sections from MS patients for Kv1.3high activated TEM cells to support a role for these cells in pathogenesis. Aim 2 evaluates the therapeutic effectiveness of Kv 1.3 and IKCa1 blockers in a rat model of MS that exhibits a chronic relapsing-remitting clinical course similar to MS. Aim 2.1 will investigate the channel and cell surface phenotype of T cells infiltrating the CNS during the initial and relapsing phases of disease and identify Kv1.3high TEM cells in inflammatory lesions in the CNS. Aim 2.2 will determine if ShK, the most potent Kv1.3 inhibitor, and TRAM-34, a specific IKCa1 inhibitor, administered alone or in combination, prevent and cure EAE. A successful outcome would pave the way to future trials in primate models of MS and eventually in humans. Aim 3 examines whether insulin- and GAD65-specific memory T cells that are implicated in disease pathogenesis of type-1 diabetes mellitus, express the Kv1.3high activated TEM phenotype. Functional studies will ascertain whether ShK suppresses antigen-driven proliferation and cytokine production by these cells. If proven true, it would raise the possibility of using a channel-based therapy to ameliorate autoimmune disorders that afflict several million people globally.

描述（由申请人提供）：自体反应效应记忆（TEM） T淋巴细胞与多发性硬化症（MS）、1型糖尿病（DM）、牛皮癣、类风湿性关节炎和慢性移植物抗宿主病的发病机制有关。我们小组最近的研究表明，电压门控Kv1.3通道是TEM细胞治疗操作的一个令人兴奋的新靶点。针对TEM细胞的基于kv1.3的自身免疫性疾病治疗将比广泛和不加区分的免疫抑制具有优势，因为幼稚/TCM细胞可以通过上调钙激活的IKCal通道来逃避抑制，从而使大部分免疫反应不受损。在本提案中，我们将MS和1型DM患者的研究与MS动物模型的实验相结合，为Kv1.3作为T细胞介导的自身免疫性疾病的治疗和诊断靶点的发展建立知识框架。Aim-1确定MS患者中髓磷脂特异性Kv 1.3高TEM细胞的存在是否是疾病活动性的指标，以及这些细胞在治疗后是否减少。我们还将筛选MS患者的死后脑切片，寻找kv1.3高活化TEM细胞，以支持这些细胞在发病机制中的作用。Aim 2评估Kv1.3和IKCa1阻滞剂在MS大鼠模型中的治疗效果，该模型表现出与MS相似的慢性复发-缓解临床过程。Aim 2.1将研究疾病初始期和复发期浸润中枢神经系统的T细胞的通道和细胞表面表型，并鉴定中枢神经系统炎症病变中的kv1.3高TEM细胞。Aim 2.2将确定ShK（最有效的Kv1.3抑制剂）和TRAM-34（一种特定的IKCa1抑制剂）单独或联合使用是否可以预防和治愈EAE。一个成功的结果将为未来在灵长类动物模型上的多发性硬化症试验铺平道路，并最终在人类身上进行试验。目的3研究参与1型糖尿病发病机制的胰岛素和gad65特异性记忆T细胞是否表达kv1.3高活化TEM表型。功能研究将确定ShK是否抑制这些细胞的抗原驱动增殖和细胞因子的产生。如果被证明是正确的，它将提高使用基于通道的疗法来改善自身免疫性疾病的可能性，这种疾病折磨着全球数百万人。