K-Channels in Lymphocyte Function and Autoimmunity

自身反应性效应记忆（TEM）T淋巴细胞与多发性硬化（MS）的发病机制有关， 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。最近的研究 我们的小组认为电压门控Kv1.3通道是一个令人兴奋的新靶点， TEM细胞。针对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的 和不加选择的免疫抑制，因为幼稚/TCM细胞将通过上调免疫抑制而逃避抑制。 钙激活IKCal通道，使大部分免疫反应不受损害。在本提案中，我们将联合收割机 对MS和1型DM患者进行研究，并在MS动物模型中进行实验，以建立智能 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框架 疾病目的-1确定MS患者中髓鞘特异性Kv 1.3high TEM细胞的存在是否是一个指标 以及这些细胞在治疗后是否减少。我们还将筛选死后的大脑切片， MS患者的Kv1.3高活化TEM细胞支持这些细胞在发病机制中的作用。目标2评估 Kv 1.3和IKCal阻滞剂在表现出慢性复发-缓解型MS的大鼠模型中的治疗效果 目的2.1将研究T细胞浸润淋巴结的通道和细胞表面表型。 CNS在疾病的初始和复发阶段，并确定Kv1.3高TEM细胞在炎症病变中， CNS。目标2.2将确定最有效的Kv1.3抑制剂ShK和特异性IKCal抑制剂TRAM-34， 单独或联合给药，预防和治疗EAE。成功的结果将为今后的审判铺平道路 在灵长类动物的多发性硬化症模型中，并最终在人类中。目的3检测胰岛素和GAD 65特异性记忆T细胞是否与胰岛素和GAD 65特异性记忆T细胞有关。 与1型糖尿病发病机制有关的细胞表达Kv1.3高活化TEM 表型。功能研究将确定ShK是否抑制抗原驱动的增殖和细胞因子 这些细胞的生产。如果被证明是真的，它将提高使用基于通道的治疗来改善 自身免疫性疾病困扰着全球数百万人。

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 na'fve/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 IKCal 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 IKCal 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.