Dr. Tsokos has received consulting fees, speaking fees, and/or honoraria from Millennium Pharmaceuticals, Merck, MedImmune, Genentech, and Eli Lilly (less than $10,000 each) and has performed editorial work for Elsevier.
Systemic Lupus Erythematosus
Calcium signaling in systemic lupus erythematosus T cells: A treatment target
Article first published online: 29 JUN 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 7, pages 2058–2066, July 2011
How to Cite
Kyttaris, V. C., Zhang, Z., Kampagianni, O. and Tsokos, G. C. (2011), Calcium signaling in systemic lupus erythematosus T cells: A treatment target. Arthritis & Rheumatism, 63: 2058–2066. doi: 10.1002/art.30353
- Issue published online: 29 JUN 2011
- Article first published online: 29 JUN 2011
- Accepted manuscript online: 24 MAR 2011 01:50PM EST
- Manuscript Accepted: 10 MAR 2011
- Manuscript Received: 22 OCT 2010
- NIH. Grant Numbers: K23-AR-055672, R01-AI-42269, R01-AI-49954
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.
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.
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.
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.