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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases
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Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases

机译：Kv1.3通道是T细胞介导的自身免疫性疾病的治疗靶标

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摘要

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4(+)CCR7(-)CD45RA(-) effector memory T cells (T-EM cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naive or central-memory (T-CM) cells. In TEM cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kv beta 2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific T-EM cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.
机译：自身反应性记忆T淋巴细胞与自身免疫性疾病的发病机制有关。在这里，我们证明了患有1型糖尿病或类风湿关节炎（RA）的患者与疾病相关的自身反应性T细胞主要是CD4（+）CCR7（-）CD45RA（-）效应记忆T细胞（T-EM细胞）升高Kv1.3钾通道表达。相反，来自这些患者的具有其他抗原特异性的T细胞，或来自健康个体和疾病控制者的自身反应性T细胞，其Kv1.3的表达水平较低，并且主要是幼稚或中央记忆（T-CM）细胞。在TEM细胞中，Kv1.3在抗原呈递过程中流向免疫突触，并与Kv beta 2，SAP97，ZIP，p56（lck）和CD4共定位。尽管Kv1.3抑制剂[ShK（L5）-酰胺（SL5）和PAP1]不能阻止免疫突触的形成，但它们在药理学相关浓度下可以抑制Ca2 +信号传导，细胞因子生成和自身抗原特异性T-EM细胞的增殖，同时保持一定的免疫力。其他类别的T细胞。 Kv1.3抑制剂可减轻大鼠p烷诱发的关节炎，并降低易患糖尿病（DP-BB / W）大鼠实验性自身免疫性糖尿病的发生率。在大鼠中重复用Kv1.3抑制剂给药并未显示出全身毒性。有必要进一步开发用于自身免疫性疾病治疗的Kv1.3阻滞剂。

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