Li X K, Tamura A, Fujino M, Guo L, Kakefuda T, Funeshima N, Enosawa S, Amari M, Naoe S, Amemiya H, Suzuki S
Department of Experimental Surgery & Bioengineering, National Children's Medical Research Centre, Tokyo, Japan.
Clin Exp Immunol. 2001 Feb;123(2):331-9. doi: 10.1046/j.1365-2249.2001.01434.x.
The action mechanism of FTY720, a novel immunosuppressant, is completely different from conventional immunosuppressants. The drug, which triggers apoptosis in murine and human lymphocytes, has a potent immunosuppressive activity to prevent allograft rejection without any severe side-effect. The present study was designed to determine whether FTY720 induces apoptotic cell death in activated lymphocytes infiltrated into liver grafts with ongoing rejection. FTY720 was orally administered at 5 mg/kg to the recipients on day 3 and day 4 after grafting, when the graft rejection was histologically confirmed. The intragraft patterns of IL-2, interferon-gamma (IFN-gamma), perforin, and granzyme B gene expression were detected by reverse transcriptase-polymerase chain reaction. The treatment reversed ongoing rejection and significantly prolonged recipient survival time compared with the control group. Light microscopic observation of the graft sections stained with the DNA nick-end labelling method showed that the apoptosis in the control allografts was mainly induced in hepatocytes, while that in the FTY720-treated allografts was in infiltrated lymphocytes. The rejection therapy with FTY720 did not alter the expression of IL-2, IFN-gamma, and perforin mRNAs, but slightly decreased granzyme B expression. Our results suggest that FTY720 does not alter the intrinsic lymphocyte function to produce the rejection-related cytokines, but strongly induces apoptotic cell death in the activated lymphocytes. Thus, FTY720 affords new insight into the mechanisms underlying improvements in immunosuppressive treatments.
新型免疫抑制剂FTY720的作用机制与传统免疫抑制剂完全不同。该药物可诱导鼠类和人类淋巴细胞凋亡，具有强大的免疫抑制活性，可预防同种异体移植排斥反应，且无任何严重副作用。本研究旨在确定FTY720是否能诱导浸润到正在发生排斥反应的肝移植组织中的活化淋巴细胞发生凋亡性细胞死亡。在移植后第3天和第4天，当组织学确认发生移植排斥反应时，给受体口服5mg/kg的FTY720。通过逆转录-聚合酶链反应检测移植组织内白细胞介素-2（IL-2）、干扰素-γ（IFN-γ）、穿孔素和颗粒酶B基因表达模式。与对照组相比，该治疗逆转了正在发生的排斥反应，并显著延长了受体存活时间。用DNA缺口末端标记法染色的移植组织切片的光学显微镜观察显示，对照同种异体移植中的凋亡主要在肝细胞中诱导，而FTY720处理的同种异体移植中的凋亡则发生在浸润的淋巴细胞中。FTY720的排斥治疗并未改变IL-2、IFN-γ和穿孔素mRNA的表达，但略微降低了颗粒酶B的表达。我们的结果表明，FTY720不会改变淋巴细胞产生排斥相关细胞因子的内在功能，但能强烈诱导活化淋巴细胞发生凋亡性细胞死亡。因此，FTY720为免疫抑制治疗改善的潜在机制提供了新的见解。
