title: Calcium signaling in systemic lupus erythematosus T cells: a treatment target.
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.
  
  
  CONCLUSIONS
  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.
authors: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. vkyttari@bidmc.harvard.edu
authors: Vasileios C
authors: VC
authors: Kyttaris
authors: Zheng
authors: Z
authors: Zhang
authors: Ourania
authors: O
authors: Kampagianni
authors: George C
authors: GC
authors: Tsokos
mesh_terms: D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004176:Dipyridamole / Q000494:pharmacology; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D010726:Phosphodiesterase Inhibitors; D004176:Dipyridamole; D002118:Calcium