Targeting effector memory T cells with the small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis
Targeting effector memory T cells with the small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis
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DOI：
10.1038/sj.jid.5700717
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发表时间：
2007-06-01
影响因子：
6.5
通讯作者：
Wulff, Heike
中科院分区：
文献类型：
--
作者：
Azam, Philippe;Sankaranarayanan, Ananthakrishnan;Wulff, Heike
电压门控钾通道Kv1.3最近被确定为一个分子靶点，允许选择性药理抑制效应记忆T （T- em）细胞，而不影响初始和中枢记忆T细胞的功能。我们研究了小分子Kv1.3阻滞剂PAP-1 （EC50=2 nm）是否能抑制过敏性接触性皮炎（ACD）。在大鼠ACID模型中，我们首次证实了在诱导期的浸润细胞确实是CD8(+) CD45RC（-）记忆T细胞，具有高Kv1.3表达。根据其对TEM细胞的选择性作用，PAP-1不损害致敏性，但在诱导期通过腹腔或口服给药，通过抑制CD8(+) T细胞的浸润和减少炎症细胞因子ifn - γ、IL-2和IL-17的产生，有效抑制恶唑酮诱导的炎症。当局部应用时，PAP-1同样有效，表明它有效地渗透皮肤。在一项为期28天的毒性研究中，我们进一步证明PAP-1不是致敏剂或刺激物，也没有毒性。基于这些结果，我们建议PAP-1有可能开发成局部治疗炎性皮肤病（如牛皮癣）的药物。
The voltage-gated potassium channel Kv1.3 has been recently identified as a molecular target that allows for selective pharmacological suppression of effector memory T (T-EM) cells without affecting the function of naive and central memory T cells. We here investigated whether PAP-1, a small molecule Kv1.3 blocker (EC50=2 nm), could suppress allergic contact dermatitis (ACD). In a rat model of ACID, we first confirmed that the infiltrating cells in the elicitation phase are indeed CD8(+) CD45RC(-) memory T cells with high Kv1.3 expression. In accordance with its selective effect on TEM cells, PAP-1 did not impair sensitization, but potently suppressed oxazolone-induced inflammation by inhibiting the infiltration of CD8(+) T cells and reducing the production of the inflammatory cytokines IFN-gamma, IL-2, and IL-17 when administered intraperitoneally or orally during the elicitation phase. PAP-1 was equally effective when applied topically, demonstrating that it effectively penetrates skin. We further show that PAP-1 is not a sensitizer or an irritant and exhibits no toxicity in a 28-day toxicity study. Based on these results we propose that PAP-1 could potentially be developed into a drug for the topical treatment of inflammatory skin diseases such as psoriasis.