Targeting effector memory T cells with the small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis

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.