Synergistic effect of FK506 and calcium antagonist on small intestinal transplantation

小肠移植的主要障碍之一是免疫抑制。FK506是最有效的免疫抑制剂之一，已被证明在肝移植中比环孢素更有效。匹兹堡小组已经临床试验了大约60例使用FK506的小肠移植。但移植物2年存活率不到50%。由于FK506是一种钙依赖的免疫抑制剂，与钙拮抗剂有望产生协同作用。以WKAM(RT1^u)为供体，Lewis(RT1^1)为受体，进行大鼠全同种异体移植。移植物存活需给予FK506 0.5 mg/kg/d或以上。FK506 0.3 mg/kg不能抑制移植物排斥反应。联合应用FK506 0.3 mg/kg和TFP 3 mg/kg可避免移植物排斥反应。术后10d，FK506 0.3 mg组和TFP 3 mg组的组织学改变与FK506 0.5 mg组基本一致。经FK506 0.3 mg处理的移植物组织学显示排斥反应。受者因食欲减退或呼吸功能不全而不能耐受超过3 mg/kg/d的TFP。综上所述，本实验揭示了FK506和TFP的协同作用。这一组合有望为临床小肠移植带来成功的希望。

One of the major obstacles for small intestinal transplabtation is the immunosuppression. FK506 is one of the most powerful immunosuppressive agents which has been shown to be more effective than ciclosporine in liver transplantation. Pittsburg group has tried about 60 cases of small bowel transplantation clinically using FK506. However, the graft survival for 2 years was less than 50%. Because FK506 is a calcium dependent immunosuppres-sive agent, synergistic effect with calcium antagonist is expected. Therefore, combination FK506 and Trifluoperazine (TFP : calmodulin inhibitor) was examined using rat model.Fully allogeneic rat transplanation was done using combination of WKAM (RT1^u) as a donor and Lewis(RT1^1) as a recipient. For graft survival, administration of FK506 0.5mg/kg/day or more was necessary. FK506 0.3mg/kg did not inhibit graft rejection. On the other hand, combination FK506 0.3mg/kg and TFP 3mg/kg were able to avoid graft rejection. The histological findings of the graft treated by FK506 0.3mg and TFP 3mg at 10 days after operation was almost same as those of the graft treated by FK506 0.5mg. The graft treated by FK506 0.3mg was shown to be rejected histologically. Recipients could not tolerate the administration of TFP more than 3mg/kg/day, because of appetite loss or respiratory insufficiency.In summary, synergistic effect of FK506 and TFP was revealed in this experiment. This combination will be hopeful for successful clinical small bowel transplantation.