A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation
A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation
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DOI：
10.1097/00007890-199601270-00006
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发表时间：
1996-01-27
期刊：
影响因子：
6.2
通讯作者：
Chiba, K
中科院分区：
文献类型：
--
作者：
Suzuki, S;Enosawa, S;Chiba, K
从辛氏棒束孢菌培养液中分离纯化了一种具有免疫抑制作用的新化合物，并对其进行化学修饰，得到FTY 720。用FTY 720孵育的大鼠脾细胞通过电子显微镜观察显示出细胞凋亡的特征，例如表面微绒毛的缺失、染色质浓缩和凋亡小体的形成，并通过琼脂糖凝胶电泳观察到基因组DNA片段化。当从移植后第1天至第14天以0.5mg/kg的剂量向肝同种异体移植大鼠施用FTY 720时，受体的存活时间显著长于对照组。移植前一天和移植当天用5 mg/kg FTY 720进行移植前处理诱导受体存活显著延长，10个受体中有3个存活超过50天。此外，在移植后第3天和第4天以5 mg/kg施用FTY 720也延长了存活。在犬肾同种异体移植中，移植前2天疗程的FTY 720以5 mg/kg延长移植物存活。FTY 720与CsA联合每日给药导致移植物存活以协同方式显著延长。此外，FTY 720似乎在犬受体中无毒。这些结果表明，FTY 720具有独特的作用机制，在大鼠和犬同种异体移植中诱导长期移植物接受。
A new compound with an immunosuppressive property was purified from culture filtrates of Isaria sinclairii and was chemically modified to FTY720. Rat spleen cells incubated with FTY720 demonstrated features characteristic of apoptosis-such as the absence of surface microvilli, chromatin condensation, and the formation of apoptotic bodies-by electron microscopy, and genemic DNA fragmentation by agarose gel electrophoresis. When FTY720 was administered in liver-allografted rats at a dose of 0.5 mg/kg from day 1 to day 14 after transplantation, the recipients survived significantly longer than the control group. Pretransplant treatment with 5 mg/kg of FTY720 one day before and on the day of grafting induced a remarkable prolongation of recipient survival, and three of 10 recipients survived for longer than 50 days. Furthermore, administration of FTY720 at 5 mg/kg on days 3 and day 4 after grafting also prolonged survival. In canine kidney allografting, a pretransplant 2-day course of FTY720 at 5 mg/kg prolonged graft survival. Daily administration of FTY720 in combination with CsA resulted in a significant prolongation of graft survival in a synergistic manner. In addition, FTY720 appeared to be nontoxic in canine recipients. These results demonstrated that FTY720, having a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation.