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

Philippe Azam, Ananthakrishnan Sankaranarayanan, Daniel Homerick, Stephen M Griffey, Heike Wulff

Research output: Contribution to journalArticle

76 Citations (Scopus)

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 (TEM) 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 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-γ, 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.

Original languageEnglish (US)
Pages (from-to)1419-1429
Number of pages11
JournalJournal of Investigative Dermatology
Volume127
Issue number6
DOIs
StatePublished - Jun 2007

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Dermatitis
Allergic Contact Dermatitis
T-cells
T-Lymphocytes
Data storage equipment
Molecules
Toxicity
Skin
Oxazolone
Transmission electron microscopy
Voltage-Gated Potassium Channels
Interleukin-17
Irritants
Psoriasis
Infiltration
Skin Diseases
Interleukin-2
Rats
Pharmacology
Cytokines

ASJC Scopus subject areas

  • Dermatology

Cite this

Targeting effector memory T cells with the small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis. / Azam, Philippe; Sankaranarayanan, Ananthakrishnan; Homerick, Daniel; Griffey, Stephen M; Wulff, Heike.

In: Journal of Investigative Dermatology, Vol. 127, No. 6, 06.2007, p. 1419-1429.

Research output: Contribution to journalArticle

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