
Calcium signaling in systemic lupus erythematosus T cells: A treatment target
Author(s) -
Kyttaris Vasileios C.,
Zhang Zheng,
Kampagianni Ourania,
Tsokos George C.
Publication year - 2011
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.30353
Subject(s) - medicine , dipyridamole , calcineurin , immunology , t cell , systemic lupus erythematosus , cd8 , lupus erythematosus , endocrinology , antibody , cd3 , immune system , transplantation , disease
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.