Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus.

OBJECTIVE To examine the effects of a novel immunosuppressant, FTY720, on hematolymphoid cells and the clinical course of MRL-lpr/lpr (MRL/lpr) mice genetically predisposed to systemic lupus erythematosus (SLE). METHODS: Apoptosis of hematolymphoid cells was determined in vitro by FACScan after staining with propidium iodide or merocyanine 540. From 4 months of age, 15 female MRL/lpr mice received oral administration of 2 mg/kg each of FTY720, methylprednisolone (mPSL), or vehicle, 3 times per week. Therapeutic efficacy was evaluated by levels of anti-dsDNA antibodies in serum and the survival rate. In parallel, T cell proliferation and secretion of interleukin 2 (IL-2) induced by anti-CD3, phenotypes of the spleen, lymph node and bone marrow cells, as well as immunohistochemistry of the kidney, were examined in vitro. RESULTS: FTY720 at 2 microM induced apoptosis in more than 70% of double negative (CD4-/CD8-) T cells from the spleen of MRL/lpr mice in vitro. Oral FTY720 was tolerated well with no apparent side effects. FTY720 treated and control mice gained weight at an identical pace through to 9 months of age. FTY720 significantly suppressed the production of anti-dsDNA antibodies (FTY720 vs control: 1739 +/- 898 U/ml vs 410 +/- 356 U/ml at 8 months of age; p