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 Kv1.3highTEM 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/mm2 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.

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

“…However, compared to activated T‐cells and microglia in inflammatory lesions,18, 34 neuronal Kv1.3 staining is typically faint and often only observable with higher antibody concentrations and long incubation times 33. In agreement with these findings, we did not note any significant Kv1.3 staining on neurons, astrocytes, or surveillant microglia in normal mouse brain (data not shown) when using anti‐Kv1.3 antibody concentrations that stain activated lymphocytes in our hands 7, 35…”

“…Interest in Kv1.3 afterward waned but revived following reports from our group that Kv1.3 is overexpressed in activated CCR7 − effector memory T‐cells (T EM ) and that Kv1.3 blockers therefore constitute immunomodulators rather than general immunosuppressants 3, 4, 5. Subsequent proof‐of‐concept animal studies demonstrated that the Kv1.3 blocking sea anemone Stichodactyla helianthus peptide ShK and its derivatives treat rat models of multiple sclerosis and rheumatoid arthritis,4, 5, 6 while our small molecule Kv1.3 blocker PAP‐1 prevents autoimmune diabetes4 in rats and treats psoriasis in a mouse xenograft model 7. As Kv1.3 blockers preferentially target T EM cells, Kv1.3 blockers do not impair the ability to clear acute infections or develop vaccine responses.…”

Ion Channels in Innate and Adaptive Immunity

“…Furthermore, the small molecules Psora-4 and PAP-1 [5-(4-phenoxybutoxy)psoralen]—both of which have low nanomolar potency—prevent antiglomerular basement membrane glomerulonephritis, autoimmune diabetes, and allergic contact dermatitis in rats (220, 221, 369). K V 1.3 blockers are also effective in models of psoriasis and alopecia areata (370–371a), both diseases in which T EM cells are involved in the pathogenesis. In many of these studies, K V 1.3 blockers preferentially inhibited IL-2, IFN-γ, and IL-17 production by human or rat T EM cells but had little effect on TNF-α or on cytokines produced by naive and T CM cells (220, 221).…”

Usefulness of targeting lymphocyte Kv1.3-channels in the treatment of respiratory diseases

“…In previous studies, the overexpression of Kv1.3-channels was demonstrated in cells under such pathologic conditions, including cancer [78,79], ischemic heart disease [80], and autoimmune disorders [81,82]. In autoimmune disorders, such as rheumatoid arthritis [63,81], multiple sclerosis [83][84][85], type-I diabetes mellitus [63], and psoriasis [86,87], the inhibition of the Kv1.3-channel modulated the Ca 2? influx patterns in T lymphocytes, and thus actually exerted therapeutic efficacies for the diseases (Table 1).…”

“…Modified from Ref. [31] autoimmune disorders [63,81,[83][84][85][86][87][88][89][90], renal diseases [61,91,92], and respiratory disease [93,96,123] (Table 1). However, the therapeutic efficacies of these compounds were for the most part observed only in experimental animal models.…”