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21437870
Calcium signaling in systemic lupus erythematosus T cells: a treatment target.

Arthritis Rheum, 2011/7;63(7):2058-66.

Kyttaris VC[1], Zhang Z, Kampagianni O, Tsokos GC

Affiliations

PMID: 21437870DOI: 10.1002/art.30353

Abstract
objective: Systemic lupus erythematosus (SLE) T cells display a hyperactive calcineurin/NF-AT pathway. The aim of this study was to determine whether this pathway is responsible for the aberrant SLE T cell function and to test the effectiveness of the recently recognized calcineurin inhibitor dipyridamole in limiting SLE-related pathology.
methods: T cells and mononuclear cells were isolated from the peripheral blood of SLE patients and healthy individuals. Murine cells were isolated from the spleens and lymph nodes of lupus-prone MRL/lpr mice and control MRL/MpJ mice. Cells were treated in vitro with tacrolimus, dipyridamole, or control. MRL/lpr mice were injected intraperitoneally with 50 mg/kg of dipyridamole 3 times a week for 3 weeks.
results: MRL/lpr T cells, especially CD3+CD4-CD8- cells, displayed a robust calcium influx upon activation and increased levels of NF-ATc1. MRL/lpr T cells (both CD4+ and CD3+CD4-CD8- cells) provided help to B cells to produce immunoglobulin in a calcineurin-dependent manner. Dipyridamole treatment of SLE T cells significantly inhibited CD154 expression, interferon-γ, interleukin-17 (IL-17), and IL-6 production, and T cell-dependent B cell immunoglobulin secretion. Treatment of MRL/lpr mice with dipyridamole alleviated lupus nephritis and prevented the appearance of skin ulcers.
conclusion: NF-AT activation is a key step in the activation of SLE T cells and the production of immunoglobulin. Dipyridamole inhibits SLE T cell function and improves pathologic changes of the disease in lupus-prone mice. We propose that dipyridamole can be used in treatment regimens for patients with SLE.
MeSH terms
Adult; Animals; B-Lymphocytes; Blotting, Western; Calcium; Calcium Signaling; Cell Proliferation; Cytokines; Dipyridamole; Female; Humans; Lupus Erythematosus, Systemic; Male; Mice; Middle Aged; Phosphodiesterase Inhibitors; T-Lymphocytes
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