Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases
Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases
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DOI：
10.1073/pnas.0605136103
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发表时间：
2006-11-14
影响因子：
11.1
通讯作者：
Chandy, K. George
中科院分区：
文献类型：
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作者：
Beeton, Christine;Wulff, Heike;Chandy, K. George
自身反应性记忆T淋巴细胞参与自身免疫性疾病的发病机制。在这里，我们证明了1型糖尿病或类风湿性关节炎（RA）患者的疾病相关自身反应性T细胞主要是具有升高的Kv1.3钾通道表达的CD 4（+）CCR 7（-）CD 45 RA（-）效应记忆T细胞（T-EM细胞）。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对照的自身反应性T细胞，表达低水平的Kv1.3，并且主要是幼稚或中央记忆（T-CM）细胞。在TEM细胞中，Kv1.3在抗原呈递期间运输到免疫突触，在那里它与Kv β 2、SAP 97、ZIP、p56（lck）和CD 4共定位。尽管Kv1.3抑制剂[ShK（L5）-酰胺（SL 5）和PAP 1]不能阻止免疫突触的形成，但它们抑制Ca 2+信号传导、细胞因子产生和自身抗原特异性T-EM细胞的增殖，同时保留其他类型的T细胞。Kv1.3抑制剂改善降植烷诱导的大鼠关节炎，并降低糖尿病易感（DP-BB/W）大鼠实验性自身免疫性糖尿病的发生率。在大鼠中重复给予Kv1.3抑制剂未显示全身毒性。进一步开发Kv1.3阻断剂用于自身免疫性疾病治疗是必要的。
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.