Jolicoeur E Marc, Qi Shijie, Xu Dasheng, Dumont Louis, Daloze Pierre, Chen Huifang
Laboratory of Experimental Surgery, Research Center of CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
Transplantation. 2003 Jan 15;75(1):54-9. doi: 10.1097/00007890-200301150-00010.
Chronic rejection is the leading cause of long-term allograft loss. Until now, no therapy has been recognized as being efficient in its prevention. In addition to their immunosuppressive activity, mycophenolate mofetil (MMF) and rapamycin (RAPA) show diverse properties against vascular smooth muscle cell activity, cell-adhesion molecule expression, and ischemia-reperfusion injury. The combination effect of MMF and RAPA was tested to prevent chronic renal allograft rejection in the rat in this study.
Nephrectomized Lewis recipients underwent orthotopic transplantation with Fisher (F344) kidneys (allograft groups) or Lewis kidneys (isograft control). The initial episode of acute rejection was controlled with a short course of cyclosporine A (CsA) (1.5 mg/kg/day for 10 days). From weeks 4 to 20, animals were thereafter treated every other day either with vehicle, MMF (20 mg/kg), RAPA (0.8 mg/kg), or MMF (20 mg/kg) plus RAPA (0.8 mg/kg) in combination. Animals were sequentially killed at serial intervals over a follow-up of 50 weeks, and histologic study was performed on harvested kidneys according to the Banff working classification for allograft pathology.
Animals treated with MMF or RAPA alone showed a Banff sum score similar to the allograft control group (6.31+/-1.01 and 7.27+/-1.14 vs. 7.21+/-1.14, respectively; P>0.05). When the recipient rats were treated with MMF and RAPA in combination, it resulted in a clinically and statistically significant reduction of Banff sum score (4.21+/-0.79, P<0.01), with specific inhibition of vascular fibrous intimal thickening, allograft glomerulopathy, and interstitial fibrosis.
Over a 50-week study, concomitant therapy of MMF and RAPA prevents chronic renal allograft rejection, probably through reduction of ischemic and cytotoxic degenerative changes. These results warrant further investigation in the combination of MMF and RAPA as anti-chronic rejection therapy in clinical transplantation.
慢性排斥是同种异体移植长期失功的主要原因。到目前为止，尚无被认可的有效预防疗法。霉酚酸酯（MMF）和雷帕霉素（RAPA）除具有免疫抑制活性外，还对血管平滑肌细胞活性、细胞黏附分子表达及缺血再灌注损伤表现出多种作用。本研究检测了MMF与RAPA联合应用预防大鼠慢性肾移植排斥的效果。
行肾切除的Lewis受体接受Fisher（F344）肾原位移植（同种异体移植组）或Lewis肾原位移植（同基因移植对照组）。急性排斥反应的初始阶段用短疗程环孢素A（CsA）（1.5mg/kg/天，共10天）控制。从第4周开始至第20周，此后动物每隔一天分别接受溶媒、MMF（20mg/kg）、RAPA（0.8mg/kg）或MMF（20mg/kg）加RAPA（0.8mg/kg）联合治疗。在50周的随访期间按顺序间隔处死动物，根据移植肾病理的Banff工作分类法对摘取的肾脏进行组织学研究。
单独使用MMF或RAPA治疗的动物Banff总分与同种异体移植对照组相似（分别为6.31±1.01和7.27±1.14，而对照组为7.21±1.14；P>0.05）。当受体大鼠接受MMF与RAPA联合治疗时，Banff总分在临床和统计学上均显著降低（4.21±0.79，P<0.01），对血管纤维内膜增厚、移植肾肾小球病和间质纤维化有特异性抑制作用。
在一项为期50周的研究中，MMF与RAPA联合治疗可预防慢性肾移植排斥，可能是通过减少缺血性和细胞毒性退行性改变实现的。这些结果值得进一步研究MMF与RAPA联合作为临床移植中抗慢性排斥治疗的应用。
