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

Christine Beeton(University of California, Irvine), Heike Wulff(University of California, Davis), Nathan Standifer(Virginia Mason Medical Center), Philippe Azam(University of California, Davis), Katherine M. Mullen(Johns Hopkins Hospital), Michael W. Pennington(BioChem Technology (United States)), Aaron Kolski‐Andreaco(University of California, Irvine), Eric Wei(University of California, Irvine), Alexandra Grino(University of California, Irvine), Debra Counts(University of Maryland, Baltimore), Ping H. Wang(University of California, Irvine), Christine J. LeeHealey(University of California, Irvine), Brian S. Andrews(University of California, Irvine), Ananthakrishnan Sankaranarayanan(University of California, Davis), Daniel Homerick(University of California, Davis), Werner W. Roeck(University of California, Irvine), Jamshid Tehranzadeh(University of California, Irvine), Kimber L. Stanhope(University of California, Davis), Pavel I. Zimin(University of California, Davis), Peter J. Havel(University of California, Davis), Stephen M. Griffey(University of California, Davis), Hans-Guenther Knaus(Innsbruck Medical University), Gerald T. Nepom(Virginia Mason Medical Center), George A. Gutman(University of California, Irvine), Peter A. Calabresi(Johns Hopkins Hospital), K. George Chandy(University of California, Irvine)
Proceedings of the National Academy of Sciences
November 7, 2006
10.1073/pnas.0605136103
Cited by 535

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 (T(EM) 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 T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvbeta2, SAP97, ZIP, p56(lck), 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 T(EM) 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.

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