Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis.
Adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), a disease resembling multiple sclerosis, is induced in rats by myelin basic protein (MBP)-activated CD4(+) T lymphocytes. By patch-clamp analysis, encephalitogenic rat T cells stimulated repeatedly in vitro expressed a unique channel phenotype ("chronically activated") with large numbers of Kv1.3 voltage-gated channels (approximately 1500 per cell) and small numbers of IKCa1 Ca(2+)-activated K(+) channels (approximately 50-120 per cell). In contrast, resting T cells displayed 0-10 Kv1.3 and 10-20 IKCa1 channels per cell ("quiescent" phenotype), whereas T cells stimulated once or twice expressed approximately 200 Kv1.3 and approximately 350 IKCa1 channels per cell ("acutely activated" phenotype). Consistent with their channel phenotype, [(3)H]thymidine incorporation by MBP-stimulated chronically activated T cells was suppressed 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 selective IKCa1 blocker (TRAM-34). The combination of ShK-Dap(22) and TRAM-34 enhanced the suppression of MBP-stimulated T cell proliferation. Based on these 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 by a combination of ShK-Dap(22) plus TRAM-34 prevented lethal AT-EAE. Blockade 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 combination 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 for multiple sclerosis.
Beeton
C
C
Laboratoire d'Immunologie, Faculté de Médecine, 13385 Marseille, France.
Wulff
H
H
Barbaria
J
J
Clot-Faybesse
O
O
Pennington
M
M
Bernard
D
D
Cahalan
M D
MD
Chandy
K G
KG
Béraud
E
E
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D002478:Cells, Cultured; D003064:Cnidarian Venoms / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D006168:Guinea Pigs; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D007553:Isotope Labeling; D051664:Kv1.3 Potassium Channel; D009103:Multiple Sclerosis / Q000378:metabolism / Q000517:prevention & control*; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013936:Thymidine / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
D002121:Calcium Channel Blockers; D003064:Cnidarian Venoms; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496975:Kcna3 protein, rat; C491575:Kcnn4 protein, rat; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011720:Pyrazoles; C095391:ShK neurotoxin; C411671:TRAM 34; D014316:Tritium; D013936:Thymidine