Synergistic effect of FK506 and calcium antagonist on small intestinal transplantation

FK506与钙拮抗剂对小肠移植的协同作用

基本信息

批准号：
02670581
负责人：
TAGUCHI Tomoaki
金额：
$ 1.41万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02670581/
关键词：
small intestine allogeneic transplantation rejection FK506 calcium antagonist orthotopic heterotopic histology 小腸移植同種移植 KF506

项目摘要

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.

小肠移植的主要障碍之一是免疫抑制。 FK506是最强大的免疫抑制剂之一，在肝移植中已显示出比ciclosporine更有效。匹兹堡集团使用FK506在临床上尝试了大约60例小肠移植。但是，移植2年的存活率小于50％。由于FK506是钙依赖性的免疫植物剂，因此预计会与钙拮抗剂具有协同作用。因此，使用大鼠模型检查了FK506和三氟甲嗪（TFP：钙调蛋白抑制剂）的组合。使用WKAM（RT1^U）作为供体和Lewis（RT1^1）的组合进行同种异体大鼠移植。对于移植生存，需要给予FK506 0.5mg/kg/天或更多。 FK506 0.3mg/kg没有抑制移植物排斥。另一方面，FK506组合0.3mg/kg和TFP 3mg/kg能够避免移植排斥。手术后10天，FK506 0.3mg和TFP 3mg处理的移植物的组织学发现几乎与FK506 0.5mg处理的移植物相同。通过FK506 0.3mg处理的移植物在组织学上被拒绝。由于食欲丧失或呼吸不足，受体无法忍受TFP超过3mg/kg/天的给药。总而言之，FK506和TFP的协同作用在本实验中揭示了。这种组合将对成功的临床小肠移植有希望。