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
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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