{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:41:22Z","timestamp":1792514482640,"version":"4.5.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"46","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,11,14]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    CCR7\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD45RA\n                    <jats:sup>\u2212<\/jats:sup>\n                    effector memory T cells (T\n                    <jats:sub>EM<\/jats:sub>\n                    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 na\u00efve or central-memory (T\n                    <jats:sub>CM<\/jats:sub>\n                    ) cells. In T\n                    <jats:sub>EM<\/jats:sub>\n                    cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kv\u03b22, SAP97, ZIP, p56\n                    <jats:sup>lck<\/jats:sup>\n                    , and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -signaling, cytokine production, and proliferation of autoantigen-specific T\n                    <jats:sub>EM<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0605136103","type":"journal-article","created":{"date-parts":[[2006,11,6]],"date-time":"2006-11-06T20:54:23Z","timestamp":1162846463000},"page":"17414-17419","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":491,"title":["Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases"],"prefix":"10.1073","volume":"103","author":[{"given":"Christine","family":"Beeton","sequence":"first","affiliation":[{"name":"*Departments of Physiology and Biophysics, Microbiology and Molecular Genetics, Medicine, and Radiological Sciences, University of California, Irvine, CA 92697;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Wulff","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Toxicology, Department of Nutrition, and Comparative Pathology Laboratory, University of California, Davis, CA 95616;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan E.","family":"Standifer","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Azam","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Toxicology, Department of Nutrition, and Comparative Pathology Laboratory, University of California, Davis, CA 95616;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M.","family":"Mullen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins Hospital, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Pennington","sequence":"additional","affiliation":[{"name":"Bachem Bioscience, Inc., King of Prussia, PA 19406;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Kolski-Andreaco","sequence":"additional","affiliation":[{"name":"*Departments of Physiology and Biophysics, Microbiology and Molecular Genetics, Medicine, and Radiological Sciences, University of California, Irvine, CA 92697;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Wei","sequence":"additional","affiliation":[{"name":"*Departments of Physiology and Biophysics, Microbiology and Molecular Genetics, Medicine, and Radiological Sciences, University of California, Irvine, CA 92697;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Grino","sequence":"additional","affiliation":[{"name":"*Departments of Physiology and Biophysics, Microbiology and Molecular Genetics, Medicine, and Radiological Sciences, University of California, Irvine, CA 92697;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra R.","family":"Counts","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Maryland, Baltimore, MD 21201; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping H.","family":"Wang","sequence":"additional","affiliation":[{"name":"*Departments of Physiology and Biophysics, Microbiology and Molecular Genetics, Medicine, and Radiological Sciences, University of California, Irvine, CA 92697;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine J.","family":"LeeHealey","sequence":"additional","affiliation":[{"name":"*Departments of Physiology and Biophysics, Microbiology and Molecular Genetics, Medicine, and Radiological Sciences, University of California, Irvine, CA 92697;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"S. 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