title: Kv1.3 in psoriatic disease: PAP-1, a small molecule inhibitor of Kv1.3 is effective in the SCID mouse psoriasis--xenograft model.
abstract: Kv1.3 channels regulate the activation/proliferation of effector memory T cells and thus play a critical role in the pathogenesis of autoimmune diseases. Using a combination of immunohistochemistry, confocal microscopy, flow cytometry and electrophysiology methods we observed a significant enrichment of activated Kv1.3(+) memory T cells in psoriasis plaques and synovial fluid from patients with psoriasis/psoriatic arthritis (PsA) compared to non-lesional psoriatic skin, normal skin or peripheral blood lympho-mononuclear cells. In in vitro studies performed with lesional mononuclear cells or T cells derived from skin and joints of psoriatic disease, the small molecule Kv1.3 blocker PAP-1 dose-dependently inhibited proliferation and suppressed IL-2 and IFN-γ production. To further substantiate the pathologic role of Kv1.3 high TEM cells in psoriatic disease we tested whether PAP-1 is able to improve psoriatic disease pathology in the SCID mouse-psoriasis skin xenograft model. Following four weeks of daily treatment with 2% PAP-1 ointment we noticed about 50% reduction in the epidermal thickness (rete peg length) and the number of CD3(+) lymphocytes/mm(2) of dermis decreased by 85%. Vehicle treated and untreated plaques in contrast remained unchanged and showed no reduction in epidermis thickness and infiltrating CD3(+) T cells and HLA-DR(+) T cells. Based on these results we propose the development of Kv1.3 targeted topical immunotherapy for psoriasis and possibly for other inflammatory skin conditions, where effector memory T cells are involved in the pathogenesis.
authors.affiliation: VA Medical Center Sacramento, 10535 Hospital Way, Mather, CA 95655, USA; Department of Pharmacology, University of California Davis, School of Medicine, Davis, CA, USA.
authors.forename: Smriti
authors.initials: S
authors.lastname: Kundu-Raychaudhuri
authors.affiliation: Department of Pharmacology, University of California Davis, School of Medicine, Davis, CA, USA.
authors.forename: Yi-Je
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, University of California Davis, School of Medicine, Davis, CA, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Psoriasis Clinic, Department of Dermatology, VA Medical Center Sacramento, CA, USA; Division of Rheumatology, Allergy & Clinical Immunology, University of California Davis, School of Medicine, Davis, CA, USA. Electronic address: sraychaudhuri@ucdavis.edu.
authors.forename: Siba P
authors.initials: SP
authors.lastname: Raychaudhuri
mesh_terms: D000818:Animals; D015535:Arthritis, Psoriatic / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D064593:Heterografts; D007156:Immunologic Memory / Q000187:drug effects; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D012867:Skin / Q000276:immunology / Q000473:pathology; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers; C000612141:REG3A protein, human
keywords: Effector memory T cells; Kv1.3 channel; PAP-1; Pathogenesis; Psoriasis skin xenograft model; Psoriatic diseases