A PROSPECTIVE-STUDY OF FK506 VERSUS CSA AND PIG ATG IN A PORCINE MODEL OF SMALL-BOWEL TRANSPLANTATION

Rejection remains a major barrier to successful bowel transplantation, and immunosuppressive protocols are far from standardized, In 88 nonr elated outbred pigs, we compared the effects of two immunosuppressive regimens - one with FK506, the other with cyclosporine (CsA) and pig a ntithymocyte globulin (ATG) on incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 14) was nonimm unosuppressed (controls), Group B (n = 17) received pig ATG (10 mg/kg/ day x 10 days), CsA (3 mg/kg/day), prednisolone (2 mg/kg/day), and aza thioprine (2.5 mg/kg/day); prednisolone and azathioprine were each red uced by 50% at 8 and 15 days posttransplant, Trough CsA whole-blood co ncentrations were greater than or equal to 400 ng/ml for the first 7 d ays, greater than or equal to 200 ng/ml thereafter, Group C (n = 13) r eceived FK506 (0.2 mg/kg/day) and prednisolone (2 mg/kg/day); predniso lone was reduced by 50% at 8 and 15 days, FK506 whole-blood concentrat ions were greater than or equal to 20 ng/ml. All immunosuppression in groups B and C was given intravenously. We performed orthotopic small bowel transplants with systemic venous drainage, Recipient bowel was r esected distal to the second portion of the duodenum and proximal to t he rectum at transplant; bowel continuity was restored by duodenojejun ostomy; ileostomy was created distally to allow access for daily biops ies, We graded interstitial and vascular rejection separately, accordi ng to a scoring system (no, mild, moderate, and severe rejection), Rej ection-free graft survivals at 7, 14, and 21 days posttransplant were 38%, 19%, and 0% in group A; 93%, 93%, and 62% in group B; and 100%, 9 1%, and 82% in group C (P < 0.001). Comparing rejection in the immunos uppressed groups, group C (FK506) had a stronger tendency toward rejec tion than group B (CsA-ATG); significant differences between groups B and C were, however, noted only on individual days posttransplant, not over time, The death rate due to irreversible rejection was not signi ficantly different in groups B and C (P = 0.8), but was significantly better in both of these immunosuppressed groups than in group A (P < 0 .001), Pig survival was significantly longer in group C than in B (P = 0.001) due to a lower infection rate in group C, Posttransplant serum interleukin 2 and 7 levels did not correlate with rejection grades. G raft-versus-host reaction was noted only in the skin in 29% of group A , 73% of group B, and 77% of group C pigs; liver and native bowel were not involved. We conclude that high-dose intravenous immunosuppressiv e regimens-whether FK506 or CsA-ATG - can effectively prevent moderate and severe interstitial rejection in the early period after bowel tra nsplantation.