Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases
Autor: | Heike Wulff, Christine Beeton, Jamshid Tehranzadeh, Nathan Standifer, Stephen M Griffey, Werner W. Roeck, Christine J. LeeHealey, Philippe Azam, Brian S. Andrews, Alexandra Grino, Debra Counts, K. George Chandy, George A. Gutman, Kimber L. Stanhope, Ananthakrishnan Sankaranarayanan, Ping H. Wang, Katherine M. Mullen, Daniel Homerick, Pavel I. Zimin, Peter J. Havel, Michael W. Pennington, Aaron Kolski-Andreaco, Eric Wei, Peter A. Calabresi, Gerald T. Nepom, Hans Guenther Knaus |
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Rok vydání: | 2006 |
Předmět: |
rheumatoid arthritis
type-1 diabetes mellitus Patch-Clamp Techniques T-Lymphocytes Pancreatitis-Associated Proteins Arthritis Rheumatoid Interleukin 21 Rheumatoid Receptors 2.1 Biological and endogenous factors Medicine Cytotoxic T cell IL-2 receptor Aetiology Kv1.3 Potassium Channel Multidisciplinary Biological Sciences Natural killer T cell Electrophysiology medicine.anatomical_structure Chemokine 5.1 Pharmaceuticals Interleukin 12 Receptors Chemokine Female Development of treatments and therapeutic interventions Type 1 Receptors CCR7 T cell Autoimmune Disease Antigen effector memory T cell MD Multidisciplinary Diabetes Mellitus Potassium Channel Blockers Animals Humans Animal business.industry Arthritis Inflammatory and immune system Rats Disease Models Animal Diabetes Mellitus Type 1 CTLA-4 Disease Models Immunology business CCR7 |
Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 103, iss 46 Beeton, Christine; Wulff, Heike; Standifer, Nathan E; Azam, Philippe; Mullen, Katherine M; Pennington, Michael W; et al.(2006). Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.. Proceedings of the National Academy of Sciences of the United States of America, 103(46), 17414-17419. doi: 10.1073/pnas.0605136103. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/2647b9c5 |
ISSN: | 1091-6490 0027-8424 |
Popis: | 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 (TEMcells) 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 (TCM) cells. In TEMcells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56lck, 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 TEMcells 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. |
Databáze: | OpenAIRE |
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