Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis

Adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), a dis ease resembling multiple sclerosis, is induced in rats by myelin basic prot ein (MBP)-activated CD4(+) T lymphocytes. By patch-clamp analysis, encephal itogenic rat T cells stimulated repeatedly in vitro expressed a unique chan nel phenotype ("chronically activated") with large numbers of Kv1.3 voltage -gated channels (approximate to 1500 per cell) and small numbers of IKCa1 C a2+-activated K+ channels (approximate to 50-120 per cell). In contrast, re sting T cells displayed 0-10 Kv1.3 and 10-20 IKCa1 channels per cell ("quie scent" phenotype), whereas T cells stimulated once or twice expressed appro ximate to 200 Kv1.3 and approximate to 350 IKCa1 channels per cell ("acutel y activated" phenotype). Consistent with their channel phenotype, [H-3]thym idine incorporation by MBP-stimulated chronically activated T cells was sup pressed by the peptide ShK, a blocker of Kv1.3 and IKCa1, and by an analog (ShK-Dap(22)) engineered to be highly specific for Kv1.3, but not by a sele ctive IKCa1 blocker (TRAM-34). The combination of ShK-Dap(22) and TRAM-34 e nhanced the suppression of MBP-stimulated T cell proliferation. Based on th ese in vitro results, we assessed the efficacy of K+ channel blockers in AT -EAE. Specific and simultaneous blockade of the T cell channels by ShK or b y a combination of ShK-Dap(22) plus TRAM-34 prevented lethal AT-EAE. Blocka de of Kv1.3 alone with ShK-Dap(22), but not of IKCa1 with TRAM-34, was also effective. When administered after the onset of symptoms, ShK or the combi nation of ShK-Dap(22) plus TRAM-34 greatly ameliorated the clinical course of both moderate and severe AT-EAE. We conclude that selective targeting of Kv1.3, alone or with IKCa1, may provide an effective new mode of therapy f or multiple sclerosis.