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 L. Stanhope, Pavel Zimin, Peter J. HavelStephen Griffey, Hans Guenther Knaus, Gerald T. Nepom, George A. Gutman, Peter A. Calabresi, K. George Chandy

Research output: Contribution to journalArticlepeer-review

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

  • General

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