Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases

Christine Beeton, Heike Wulff, Nathan E. Standifer, Philippe Azam, Katherine M. Mullen, Michael W. Pennington, Aaron Kolski-Andreaco, Eric Wei, Alexandra Grino, Debra R. Counts, Ping H. Wang, Christine J. LeeHealey, Brian S. Andrews, Ananthakrishnan Sankaranarayanan, Daniel Homerick, Werner W. Roeck, Jamshid Tehranzadeh, Kimber Stanhope, Pavel Zimin, Peter J HavelStephen M Griffey, Hans Guenther Knaus, Gerald T. Nepom, George A. Gutman, Peter A. Calabresi, K. George Chandy

Research output: Contribution to journalArticlepeer-review

386 Scopus citations

Abstract

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+CCR7-CD45RA- effector memory T cells (TEM cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T CM) cells. In TEM cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56lck, and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific TEM cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

Original languageEnglish (US)
Pages (from-to)17414-17419
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number46
DOIs
StatePublished - Nov 14 2006

Keywords

  • Effector memory T cell
  • Rheumatoid arthritis
  • Type-1 diabetes mellitus

ASJC Scopus subject areas

  • Genetics
  • General

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