Chen H, Wu J, Xu D, Luo H, Daloze P M
Laboratories of Experimental Surgery and Transplantation Immunology, Notre-Dame Hospital, University of Montreal, Quebec, Canada.
Transplantation. 1993 Sep;56(3):661-6. doi: 10.1097/00007890-199309000-00031.
Rapamycin was examined for its effects on reversal of ongoing rejection of heart, kidney, and pancreas allografts and on suppression of accelerated heart allograft rejection in the rat. A 14-day continuous intravenous infusion of RAPA by an osmotic pump at 0.02, 0.08, and 0.8 mg/kg/day to WFu recipients, starting 4 days postoperation, significantly protected the BUF heart allografts with a mean survival time (MST) +/- 1 SD of 33.2 +/- 19.8 (p < 0.001), 48.2 +/- 14.8 (p < 0.001), and 107.0 +/- 86.3 (p < 0.001) days, respectively, as compared with 7.2 +/- 0.8 days in vehicle-treated controls. Combination of low dose RAPA (0.02 mg/kg or 0.08 mg/kg) and low dose CsA (2 mg/kg) achieved significantly longer cardiac allograft survival than RAPA or CsA alone. RAPA's effect in reversing ongoing rejection of renal and pancreatic allografts was also significant. The BUF kidney and pancreas in WFu recipients treated with a 14-day course of RAPA (0.8 mg/kg/day starting 4 days postoperation) had an MST of 44.7 +/- 15.9 (p < 0.001) and 46.4 +/- 12.5 (p < 0.001), while in vehicle-treated controls, the grafts were rejected within 10 days. RAPA could also suppress accelerated cardiac allograft rejection. Hyperimmunized WFu recipients were treated with two 14-day courses of continuous i.v. RAPA at 0.8 mg/kg/day before and after BUF heart allografting. Significantly longer survival of the grafts (25.5 +/- 3.7 days, p < 0.001) was achieved compared with that of the vehicle-treated controls (3.8 +/- 1.0 days). One-course RAPA treatment before or after heart transplantation was considerably less effective. RAPA was also shown to prevent the increase of serum IgG levels and to inhibit the production of specific cytotoxic Ab in the rat receiving repetitive immunizations. Such effects presumably contribute to the inhibition of the accelerated rejection. The results of this study suggest that RAPA is potentially useful in treatment of ongoing as well as accelerated allograft rejection.
研究了雷帕霉素对逆转大鼠心脏、肾脏和胰腺同种异体移植正在进行的排斥反应以及抑制心脏同种异体移植加速排斥反应的作用。从术后4天开始，通过渗透泵以0.02、0.08和0.8mg/kg/天的剂量对WFu受体进行14天的雷帕霉素持续静脉输注，与接受载体治疗的对照组相比，显著保护了BUF心脏同种异体移植，其平均存活时间（MST）±1标准差分别为33.2±19.8（p<0.001）、48.2±14.8（p<0.001）和107.0±86.3（p<0.001）天，而载体治疗对照组的平均存活时间为7.2±0.8天。低剂量雷帕霉素（0.02mg/kg或0.08mg/kg）与低剂量环孢素A（2mg/kg）联合使用，使心脏同种异体移植的存活时间显著长于单独使用雷帕霉素或环孢素A。雷帕霉素在逆转肾脏和胰腺同种异体移植正在进行的排斥反应方面的作用也很显著。接受14天疗程雷帕霉素（术后4天开始，0.8mg/kg/天）治疗的WFu受体中的BUF肾脏和胰腺，其MST分别为44.7±15.9（p<0.001）和46.4±12.5（p<0.001），而在接受载体治疗的对照组中，移植物在10天内被排斥。雷帕霉素还可以抑制心脏同种异体移植的加速排斥反应。对高度免疫的WFu受体在BUF心脏同种异体移植前后分别进行两个14天疗程的0.8mg/kg/天雷帕霉素持续静脉输注。与接受载体治疗的对照组（3.8±1.0天）相比，移植物的存活时间显著延长（25.5±3.7天，p<0.001）。心脏移植前或后的一个疗程雷帕霉素治疗效果明显较差。雷帕霉素还被证明可以防止接受重复免疫的大鼠血清IgG水平升高，并抑制特异性细胞毒性抗体的产生。这些作用可能有助于抑制加速排斥反应。本研究结果表明，雷帕霉素在治疗正在进行的以及加速的同种异体移植排斥反应方面可能具有潜在用途。
