Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation.
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 Ca(2+) 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.
Beeton
C
C
Laboratoire d'Immunologie, Faculté de Médecine, Université de la Méditerranée, Unité de Formation et de Recherche de Médecine, Université de la Méditerranée, 13385 Marseille Cedex 5, France.
Barbaria
J
J
Giraud
P
P
Devaux
J
J
Benoliel
A M
AM
Gola
M
M
Sabatier
J M
JM
Bernard
D
D
Crest
M
M
Béraud
E
E
D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects* / Q000276:immunology; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D004676:Myelin Basic Protein / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000096:biosynthesis / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D012604:Scorpion Venoms / Q000008:administration & dosage / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000941:Antigens; D018984:Epitopes, T-Lymphocyte; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C496973:KCNA3 protein, human; C496974:Kcna3 protein, mouse; C496975:Kcna3 protein, rat; D051664:Kv1.3 Potassium Channel; D004676:Myelin Basic Protein; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D012604:Scorpion Venoms; D014409:Tumor Necrosis Factor-alpha; C072276:kaliotoxin; D002118:Calcium