PubMed 17088564

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

Authors: 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 Havel, Stephen Griffey, Hans-Guenther Knaus, Gerald T Nepom, George A Gutman, Peter A Calabresi, K George Chandy

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2006 Nov 14 , 103, 17414-9

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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.