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 naïve 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 ACD, 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 T(EM) 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.
Azam
Philippe
P
Department of Medical Pharmacology and Toxicology, University of California, Davis, California 95616, USA.
Sankaranarayanan
Ananthakrishnan
A
Homerick
Daniel
D
Griffey
Stephen
S
Wulff
Heike
H
D000276:Adjuvants, Immunologic; D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000276:immunology; D004423:Ear; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D011564:Furocoumarins / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D007156:Immunologic Memory / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010081:Oxazolone; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000276:Adjuvants, Immunologic; D011564:Furocoumarins; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers; C000612141:REG3A protein, human; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens