Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases
Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases
复制标题
DOI：
10.1096/fj.14-251967
复制
发表时间：
2014-09-01
期刊：
影响因子：
4.8
通讯作者：
Chandy, K. George
中科院分区：
文献类型：
--
作者：
Chhabra, Sandeep;Chang, Shih Chieh;Chandy, K. George
电压门控钾 (Kv) 1.3 通道被广泛认为是自身免疫性疾病免疫调节的治疗靶点。 ShK-186 是 Kv1.3 通道的选择性抑制剂，可改善啮齿动物模型中的自身免疫性疾病，并且该药物在健康志愿者中的人体 1 期试验已经完成。在这项研究中，我们鉴定并鉴定了寄生蠕虫中一大类与向日葵毒素 (ShK) 相关的肽。基于系统发育分析，选择了 2 种蠕虫肽进行研究：AcK1，一种 51 个残基的肽，在感染狗的钩虫犬钩虫和感染人类的钩虫锡兰钩虫的前部分泌腺中表达；以及 BmK1，来自丝虫马来丝虫的金属蛋白酶的 C 末端结构域。溶液中的这些肽采用与 ShK 非常相似的螺旋结构。在纳摩尔-微摩尔范围内的剂量下，它们可阻断人 T 细胞中的天然 Kv1.3，并克隆在 L929 小鼠成纤维细胞中稳定表达的 Kv1.3。它们优先抑制大鼠 CCR7 效应记忆 T 细胞的增殖，而不影响幼稚和中枢记忆亚群，并抑制大鼠皮肤归巢效应记忆 T 细胞引起的迟发型超敏反应 (DTH)。此外，它们还抑制人 T 淋巴细胞产生 IFN γ。寄生虫中的 ShK 相关肽可能有助于益生菌寄生虫疗法对人类自身免疫性疾病的潜在有益作用。
The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7-effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFN gamma production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases.