K-Channels in Lymphocyte Function and Autoimmunity

描述（由申请人提供）：自身反应性效应记忆（TEM）T淋巴细胞与多发性硬化（MS）、1型糖尿病（DM）、银屑病、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通道是一个令人兴奋的新靶点，用于TEM细胞的治疗操作。靶向TEM细胞的基于Kv1.3的自身免疫性疾病疗法将具有优于广泛和不加选择的免疫抑制的优势，因为初始/TCM细胞将通过钙激活的IKCal通道的上调而逃避抑制，从而使大部分免疫应答不受损害。在这个提议中，我们将联合收割机对MS和1型DM患者的研究与MS动物模型中的实验相结合，以建立开发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知识框架。目的-1确定MS患者中髓鞘特异性Kv 1.3high TEM细胞的存在是否是疾病活动的指标，以及这些细胞在治疗后是否减少。我们还将筛选MS患者的死后脑切片中Kv1.3高活化的TEM细胞，以支持这些细胞在发病机制中的作用。目的2评价Kv 1.3和IKCa 1阻断剂在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。目的2.1将研究疾病初始和复发阶段浸润CNS的T细胞的通道和细胞表面表型，并鉴定CNS炎性病变中的Kv 1.3高TEM细胞。目的2.2将确定ShK（最有效的Kv1.3抑制剂）和TRAM-34（特异性IKCa 1抑制剂）单独或联合给药是否能预防和治愈EAE。一个成功的结果将为未来在灵长类动物模型中的MS试验以及最终在人类中的试验铺平道路。目的3检测与1型糖尿病发病机制有关的胰岛素和GAD 65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的增殖和细胞因子产生。如果被证实是真的，它将提高使用基于通道的疗法来改善困扰全球数百万人的自身免疫性疾病的可能性。

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.