Selective Blocking of Voltage-Gated K+ Channels Improves Experimental Autoimmune Encephalomyelitis and Inhibits T Cell Activation

Abstract

Kaliotoxin (KTX), a blocker of voltage-gated potassium channels (Kv), is highly selective for Kv1.1 and Kv1.3. First, Kv1.3 is expressed by T lymphocytes. Blockers of Kv1.3 inhibit T lymphocyte activation. Second, Kv1.1 is found in paranodal regions of axons in the central nervous system. Kv blockers improve the impaired neuronal conduction of demyelinated axons in vitro and potentiate the synaptic transmission. Therefore, we investigated the therapeutic properties of KTX via its immunosuppressive and symptomatic neurological effects, using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The T line cells used to induce adoptive EAE were myelin basic protein (MBP)-specific, constitutively contained mRNA for Kv1.3. and expressed Kv1.3. These channels were shown to be blocked by KTX. Activation is a crucial step for MBP T cells to become encephalitogenic. The addition of KTX during Ag-T cell activation led to a great reduction in the MBP T cell proliferative response, in the production of IL-2 and TNF, and in Ca2+ influx. Furthermore, the addition of KTX during T cell activation in vitro led a decreased encephalitogenicity of MBP T cells. Moreover, KTX injected into Lewis rats impaired T cell function such as the delayed-type hypersensitivity. Lastly, the administration of this blocker of neuronal and lymphocyte channels to Lewis rats improved the symptoms of EAE. We conclude that KTX is a potent immunosuppressive agent with beneficial effects on the neurological symptoms of EAE.

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].…”

“…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].…”

The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

“…KCa3.1 channels are transcriptionally up-regulated in naive [CD45RA ϩ ͞chemokine receptor 7-positive (CCR7 ϩ )] and T CM (CD45RA Ϫ ͞CCR7 ϩ ) cells after activation (10 3 500 per cell) and become the predominant functional K ϩ channel in these cells over the ensuing days and weeks of activation (10)(11)(12). In contrast, Kv1.3 is up-regulated to 1,500-2,000 channels per cell in activated T EM cells (CD45RA Ϫ ͞CCR7 Ϫ ) and takes over as the dominant functional K channel (11,13). Kv1.3 blockers preferentially suppress proliferation of T EM cells, whereas naive͞T CM cells escape inhibition by augmenting KCa3.1 expression (14).…”

“…The availability of highly specific Kv1.3 inhibitors and the important role of the channel in T EM cells make Kv1.3 an interesting therapeutic target in autoimmune disease in which memory T cells of multiple antigenic specificities exist at low levels in the blood and presumably become concentrated in the target organ (10,14,15). Indeed, several Kv1.3 antagonists have been shown to be effective in ameliorating experimental allergic encephalomyelitis (EAE) (13,14,16,17).…”