Selective blockade of T lymphocyte K+channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis
| Autor: | Olivier Clot-Faybesse, Jocelyne Barbaria, Evelyne Beraud, Michael W. Pennington, Heike Wulff, Dominique Bernard, Christine Beeton, K. George Chandy, Michael D. Cahalan |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
CD4-Positive T-Lymphocytes
medicine.medical_specialty Adoptive cell transfer Encephalomyelitis Autoimmune Experimental Multiple Sclerosis Potassium Channels T cell Guinea Pigs Biology Pharmacology Tritium Cnidarian Venoms Internal medicine Potassium Channel Blockers medicine Animals Channel blocker Cells Cultured Kv1.3 Potassium Channel Multidisciplinary Voltage-gated ion channel Experimental autoimmune encephalomyelitis Potassium channel blocker T lymphocyte Biological Sciences Calcium Channel Blockers Intermediate-Conductance Calcium-Activated Potassium Channels medicine.disease Potassium channel Rats Disease Models Animal Phenotype Endocrinology medicine.anatomical_structure Potassium Channels Voltage-Gated Rats Inbred Lew Isotope Labeling Pyrazoles Female Thymidine medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 98:13942-13947 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 repeatedlyin vitroexpressed a unique channel phenotype (“chronically activated”) with large numbers of Kv1.3 voltage-gated channels (≈1500 per cell) and small numbers of IKCa1 Ca2+-activated K+channels (≈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 ≈200 Kv1.3 and ≈350 IKCa1 channels per cell (“acutely activated” phenotype). Consistent with their channel phenotype, [3H]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-Dap22) engineered to be highly specific for Kv1.3, but not by a selective IKCa1 blocker (TRAM-34). The combination of ShK-Dap22and TRAM-34 enhanced the suppression of MBP-stimulated T cell proliferation. Based on thesein vitroresults, 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-Dap22plus TRAM-34 prevented lethal AT-EAE. Blockade of Kv1.3 alone with ShK-Dap22, but not of IKCa1 with TRAM-34, was also effective. When administered after the onset of symptoms, ShK or the combination of ShK-Dap22plus 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|