The voltage-gated Kv1.3 channel in psoriatic disease: A novel therapeutic target

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DESCRIPTION (provided by applicant): The Voltage-Gated Kv1.3 Channel In Psoriatic Disease: A Novel Therapeutic Target. Psoriatic disease is a chronic inflammatory disease that affects 2-3% of the population in the United States. The disease is most commonly restricted to the skin but can also involve the musculoskeletal system and rarely the gastrointestinal tract and the eyes. Autoreactive T cells appear to be crucial for the pathogenesis of psoriatic disease because of their memory phenotype and the ability of activated T lymphocytes to induce psoriasis in transplanted nonlesional skin in the SCID mouse-human skin xenograft model. Selective suppression of autoreactive memory T cells has therefore long been an objective for the development of novel therapies for psoriasis. With the voltage-gated potassium channel Kv1.3 we have recently identified an exciting new molecular target that allows for the pharmacological inhibition of CCR7- effector memory T (TEM) cells. Expression of Kv1.3 is increased in both CD4+ and CD8+ TEM cells and Kv1.3 blockers have been shown to potently inhibit their proliferation and cytokine secretion without impairing the function of naove and central memory T cells. Using both small molecule and peptidic Kv1.3 blockers we have further validated Kv1.3 as a potential therapeutic target for TEM cell mediated autoimmune diseases by demonstrating that autoreactive T cells from patients with multiple sclerosis, type-1 diabetes and rheumatoid arthritis are predominantly Kv1.3high TEM cells and that Kv1.3 blockers can treat experimental autoimmune encephalomyelitis, pristane-induced arthritis, and experimental autoimmune diabetes as well as prevent delayed-type hypersensitivity in rats. Based on the fact that the small molecule Kv1.3 blocker PAP-1 also effectively suppresses allergic contact dermatitis (ACD) in rats when administered orally or topically, we now intend to explore the role of Kv1.3 in psoriasis. Under Aim- 1 of this proposal we will determine the functional significance of Kv1.3high effector memory T cells in the pathogenesis of psoriasis and psoriatic arthritis using a combination of immunohistochemistry, flow cytometry and electrophysiology studies. To further substantiate the pathologic role of Kv1.3high TEM cells in psoriatic disease we will then test the therapeutic efficacy of PAP-1 in the psoriasis SCID mouse model under Aim-2. We will specifically investigate whether treatment with oral and topical PAP-1 reduces rete peg lengths, degree of mononuclear cell infiltrates and the number of lesional CD3+, HLA-DR+ and Kv1.3+ lymphocytes pre and post treatment in the transplanted skin. The overall goal of this proposal is to determine whether Kv1.3 blockade constitutes a potential new therapeutic approach to the treatment of psoriasis.