title: Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.
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.
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Standifer
authors.forename: Philippe
authors.initials: P
authors.lastname: Azam
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Mullen
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.forename: Aaron
authors.initials: A
authors.lastname: Kolski-Andreaco
authors.forename: Eric
authors.initials: E
authors.lastname: Wei
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grino
authors.forename: Debra R
authors.initials: DR
authors.lastname: Counts
authors.forename: Ping H
authors.initials: PH
authors.lastname: Wang
authors.forename: Christine J
authors.initials: CJ
authors.lastname: LeeHealey
authors.forename: Brian
authors.initials: B
authors.lastname: S Andrews
authors.forename: Ananthakrishnan
authors.initials: A
authors.lastname: Sankaranarayanan
authors.forename: Daniel
authors.initials: D
authors.lastname: Homerick
authors.forename: Werner W
authors.initials: WW
authors.lastname: Roeck
authors.forename: Jamshid
authors.initials: J
authors.lastname: Tehranzadeh
authors.forename: Kimber L
authors.initials: KL
authors.lastname: Stanhope
authors.forename: Pavel
authors.initials: P
authors.lastname: Zimin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
authors.forename: Stephen
authors.initials: S
authors.lastname: Griffey
authors.forename: Hans-Guenther
authors.initials: HG
authors.lastname: Knaus
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.forename: George A
authors.initials: GA
authors.lastname: Gutman
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: C515370:CCR7 protein, human; C515372:Ccr7 protein, rat; D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers; C000612141:REG3A protein, human; D054400:Receptors, CCR7; D019707:Receptors, Chemokine