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

Blockade of Ca2+‐activated K+ channels in T cells: an option for the treatment of multiple sclerosis?

“…Blockers of both channel types have given promising results in various in vitro assays for T cell activation [1][2][3][4]8]. The gold standard for evaluation of the potential of a new molecular target is, however, to obtain effects in validated animal models such as inhibition of host-graft reactions or animal models of autoimmune diseases, such as multiple sclerosis.…”

“…A series of important studies in this respect has been performed previously [2,3]. By repeated in vitro stimulation of the encephalitogenic PAS T cell line with myelin basic protein (MBP), a chronically activated cell phenotype characterized by an overwhelming expression of K V 1.3 relative to IK channels was established [2].…”

“…By repeated in vitro stimulation of the encephalitogenic PAS T cell line with myelin basic protein (MBP), a chronically activated cell phenotype characterized by an overwhelming expression of K V 1.3 relative to IK channels was established [2]. This phenotype was later shown to be comparable to MBP-selective T cells isolated from patients with multiple sclerosis [10].…”

“…Adoptive transfer of these chronically activated T cells into rats caused a severe EAE. In a prevention paradigm where the compound dosing was initiated prior to adoptive transfer, it was shown that a selective blocker of K V 1.3 the engineered peptide blocker Stichodactyla helianthus toxin (ShK)-Dap reduced disease severity, whereas the blocker of the IK channel (the clotrimazole analogue TRAM-34) was without effect [2].…”

“…Novel, low-toxicity immune suppressants are therefore warranted. Many lines of evidence indicate that compounds inhibiting specific K + channels in T cells may represent an entirely new class of immune-suppressants that could fulfill this need [2][3][4].…”