K-Channels in Lymphocyte Function and Autoimmunity

描述(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。我们团队最近的研究表明，电压门控Kv1.3通道是一个令人兴奋的治疗操作的新靶点。以Kv1.3为基础的针对Tm细胞的自身免疫性疾病的治疗将比广泛和不分青红皂白的免疫抑制具有优势，因为NAIVE/Medical细胞将通过上调钙激活的IKCal通道来逃避抑制，使大部分免疫反应不受损害。在这项建议中，我们将对多发性硬化症和1型糖尿病患者的研究与多发性硬化症动物模型的实验相结合，以建立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智能框架。AIM-1确定MS患者中髓鞘特异性Kv1.3高透射电子显微镜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。我们还将从MS患者的尸检脑切片中筛选Kv1.3高活性的TEM细胞，以支持这些细胞在发病机制中的作用。目的2评价Kv1.3和IKCa1阻滞剂对慢性复发-缓解型多发性硬化大鼠模型的治疗效果。Aim 2.1将研究疾病初期和复发期T细胞在中枢神经系统的通道和细胞表面表型，并在中枢神经系统炎性病变中鉴定Kv1.3高透射电子显微镜细胞。AIM 2.2将确定最有效的Kv1.3抑制剂ShK和特异性IKCa1抑制剂TRAM-34是否单独或联合使用预防和治疗EAE。一个成功的结果将为未来在多发性硬化症的灵长类动物模型中以及最终在人类身上进行试验铺平道路。目的检测参与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高激活的透射电子显微镜表型。功能研究将确定ShK是否抑制抗原驱动的增殖和这些细胞产生的细胞因子。如果被证明是真的，这将增加使用基于渠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.