The in vivo induction of lymphocyte apoptosis in MRL-lpr/lpr mice treated with FTY720

The in vitro treatment of lpr thymocytes with FTY720 resulted in a dose-dependent reduction in cell viability due to apoptosis. In order to study the effect of FTY720 in vivo, lpr mice received an oral daily dose of 1 mg/kg FTY720 for 14 days, beginning at 16 weeks of age which was when the animals were developing massive lymphoadenopathy. Compared with untreated lpr mice, FTY720-treated lpr mice had significantly prolonged lives. At 24 weeks of age, treated mice demonstrated markedly reduced weights of the spleen and lymph nodes, and the proportion of CD3⁺B220⁺ and CD4⁻CD8⁻ cells in the thymus, spleen and lymph nodes decreased markedly. In addition, in these mice the percentage of CD4⁺CD8⁺ and CD3⁻B220⁻ cells in the thymus and the percentage of CD4⁺CD8⁻, CD4⁻CD8⁺, CD3⁺B220⁻ and CD3⁻B220⁺ cells in the spleen returned to almost the normal values observed in wild-type mice. Histological observation 1 day after the final administration of FTY720 revealed a remarkable infiltration of neutrophils in the lymphoid organs. Apoptotic cells were detected in all the lymphoid organs using in situDNA nick-end labelling. Electron microscopy showed that the apoptotic cells were ingested by phagocytes. FTY720 therapy is thus highly effective in Fas-mutant animals with abnormally expanding lymphocytes.