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 situ DNA 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.