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

J Invest Dermatol. 2007 Jun;127(6):1419-29. doi: 10.1038/sj.jid.5700717. Epub 2007 Feb 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic
  • Administration, Oral
  • Administration, Topical
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Dermatitis, Allergic Contact / drug therapy*
  • Dermatitis, Allergic Contact / immunology
  • Ear
  • Edema / chemically induced
  • Edema / drug therapy
  • Female
  • Furocoumarins / blood
  • Furocoumarins / pharmacokinetics*
  • Furocoumarins / toxicity
  • Immunologic Memory / drug effects*
  • Immunosuppressive Agents / pharmacology
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Kv1.3 Potassium Channel / metabolism*
  • Leukocyte Common Antigens / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Oxazolone
  • Pancreatitis-Associated Proteins
  • Potassium Channel Blockers / blood
  • Potassium Channel Blockers / pharmacokinetics*
  • Potassium Channel Blockers / toxicity
  • Rats
  • Rats, Inbred Lew
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adjuvants, Immunologic
  • Furocoumarins
  • Immunosuppressive Agents
  • Interleukin-17
  • Kv1.3 Potassium Channel
  • Pancreatitis-Associated Proteins
  • Potassium Channel Blockers
  • REG3A protein, human
  • Tumor Necrosis Factor-alpha
  • Oxazolone
  • Interferon-gamma
  • Leukocyte Common Antigens