Suzuki S, Li X K, Shinomiya T, Enosawa S, Amemiya H, Amari M, Naoe S
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan.
Clin Exp Immunol. 1997 Jan;107(1):103-11. doi: 10.1046/j.1365-2249.1997.d01-885.x.
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.
用FTY720对lpr胸腺细胞进行体外处理，由于凋亡导致细胞活力呈剂量依赖性降低。为了研究FTY720在体内的作用，lpr小鼠从16周龄开始（此时动物正出现大量淋巴结病），每天口服1 mg/kg FTY720，持续14天。与未治疗的lpr小鼠相比，经FTY720治疗的lpr小鼠寿命显著延长。在24周龄时，治疗组小鼠的脾脏和淋巴结重量明显减轻，胸腺、脾脏和淋巴结中CD3+B220+和CD4 - CD8 - 细胞的比例显著降低。此外，在这些小鼠中，胸腺中CD4+CD8+和CD3 - B220 - 细胞的百分比以及脾脏中CD4+CD8 - 、CD4 - CD8+、CD3+B220 - 和CD3 - B220+细胞的百分比几乎恢复到野生型小鼠中观察到的正常水平。在最后一次给予FTY720后1天进行的组织学观察显示，淋巴器官中有大量中性粒细胞浸润。使用原位DNA缺口末端标记在所有淋巴器官中检测到凋亡细胞。电子显微镜显示凋亡细胞被吞噬细胞吞噬。因此，FTY720疗法对淋巴细胞异常扩增的Fas突变动物非常有效。
