Synergistic effect of FK506 and calcium antagonist on small intestinal transplantation

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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.