QUADRUPLE IMMUNOSUPPRESSION IN A PIG MODEL OF SMALL-BOWEL TRANSPLANTATION

Rejection remains a major obstacle to successful small bowel transplan tation in humans, irrespective of the immunosuppressants, Previous lar ge animal studies have not used quadruple immunosuppression (with high -dose intravenous cyclosporine A [CSA]) for induction, followed by tri ple immunosuppression for maintenance therapy. Nor have immunosuppress ive doses been comparable to clinical solid organ transplants. We stud ied, in 78 nonrelated outbred pigs, the effect of quadruple immunosupp ression (including horse anti-pig thymocyte globulin [ATG] and high-do se intravenous CSA) on the incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 19) pigs were noni mmunosuppressed. Group B (n = 20) received quadruple immunosuppression : pig ATG (10 mg/kg/day x 10 days), intravenous CSA (3.0 mg/kg/day), p rednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisol one and azathioprine were each reduced by 50% on posttransplant Days 8 and 15. Trough CSA levels were greater than or equal to 400 ng/ml for the first 7 days posttransplant, >200 ng/ml thereafter. Recipient pig s underwent resection of large and small bowel; orthotopic transplants (proximal duodenojejunostomy, distal ileostomy) were done with system ic vein drainage. We developed a scoring system (no, mild, moderate, s evere rejection) to grade the extent of both interstitial and vascular rejection; biopsies were obtained daily from the ileostomy. Rejection -free graft survival at posttransplant Days 7, 10, and 14 was 32, 26, and 16% in the nonimmunosuppressed group versus 95, 90, and 85% in the immunosuppressed group (P < 0.0001). Rejection grades were significan tly better over the whole observation period in immunosuppressed pigs: interstitial rejection was not present in up to 67% of all daily biop sy specimens, Rejection was present in all specimens of nonimmunosuppr essed pigs. Vascular rejection was uncommon (incidence < 10%) in both groups, Isolated vascular rejection without interstitial rejection was not found. Graft-versus-host reaction was noted in both groups in the skin only; liver and native bowel were not involved, We conclude that quadruple immunosuppression with pig ATG and high-dose intravenous CS A for induction effectively prevents moderate and severe rejection in this model. Since clinical transplant complications (rejection, lympho mas) have persisted under FK 506 treatment, our immunosuppressive regi men should be considered an alternative for bowel transplantation in h umans to prevent early rejection. (C) 1996 Academic Press, Inc.