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

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