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

Christine Beeton, Heike Wulff, Jocelyne Barbaria, Olivier Clot-Faybesse, Michael Pennington, Dominique Bernard, Michael D. Cahalan, K. George Chandy, Evelyne Béraud

Research output: Contribution to journalArticle

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Abstract

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 (≈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-Dap22 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-Dap22 plus 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-Dap22 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.

Original languageEnglish (US)
Pages (from-to)13942-13947
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number24
DOIs
StatePublished - Nov 20 2001

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Autoimmune Experimental Encephalomyelitis
Multiple Sclerosis
Adoptive Transfer
T-Lymphocytes
Phenotype
Myelin Basic Protein
Calcium-Activated Potassium Channels
Thymidine
Cell Count
Cell Proliferation
TRAM 34
Peptides

ASJC Scopus subject areas

  • Genetics
  • General

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Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. / Beeton, Christine; Wulff, Heike; Barbaria, Jocelyne; Clot-Faybesse, Olivier; Pennington, Michael; Bernard, Dominique; Cahalan, Michael D.; Chandy, K. George; Béraud, Evelyne.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 24, 20.11.2001, p. 13942-13947.

Research output: Contribution to journalArticle

Beeton, Christine ; Wulff, Heike ; Barbaria, Jocelyne ; Clot-Faybesse, Olivier ; Pennington, Michael ; Bernard, Dominique ; Cahalan, Michael D. ; Chandy, K. George ; Béraud, Evelyne. / Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 24. pp. 13942-13947.
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AU - Clot-Faybesse, Olivier

AU - Pennington, Michael

AU - Bernard, Dominique

AU - Cahalan, Michael D.

AU - Chandy, K. George

AU - Béraud, Evelyne

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