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 nonrelated out-bred pigs, we compared the effects of two immunosuppressive regimens—one with FK506, the other with cyclosporine (CsA) and pig antithymocyte globulin (ATG)—on incidence and severity of rejection in the early, critical posttransplant period. Group A (n=14) was nonimmunosuppressed (controls). Group В (n=17) received pig ATG (10 mg/kg/day ×IO days), CsA (3 mg/kg/day), prednisolone (2 mg/kg/day), and aza-thioprine (2.5 mg/kg/day); prednisolone and azathio-prine were each reduced by 50% at 8 and 15 days posttransplant. Trough CsA whole-blood concentrations were ≥400 ng/ml for the first 7 days, ≥200 ng/ml thereafter. Group С (n=13) received FK506 (0.2 mg/kg/day) and prednisolone (2 mg/kg/day); prednisolone was reduced by 50% at 8 and 15 days. FK506 whole-blood concentrations were ≥20 ng/ml. All immunosuppression in groups В and С was given intravenously. We performed orthotopic small bowel transplants with systemic venous drainage. Recipient bowel was resected distal to the second portion of the duodenum and proximal to the rectum at transplant; bowel continuity was restored by duodenojejunostomy; ileostomy was created distally to allow access for daily biopsies. We graded interstitial and vascular rejection separately, according to a scoring system (no, mild, moderate, and severe rejection). Rejection-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%, 91%, and 82% in group С (P<O.OOl). Comparing rejection in the immunosuppressed groups, group С (FK506) had a stronger tendency toward rejection than group В (CsA-ATG); significant differences between groups В and С were, however, noted only on individual days posttransplant, not over time. The death rate due to irreversible rejection was not significantly different in groups В and С (P=0.8), but was significantly better in both of these immunosuppressed groups than in group A (P<O.OOl). Pig survival was significantly longer in group С than in В (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. Graft-versus-host reaction was noted only in the skin in 29% of group A, 73% of group В, and 77% of group С pigs; liver and native bowel were not involved. We conclude that high-dose intravenous immunosuppressive regimens— whether FK506 or CsA-ATG—can effectively prevent moderate and severe interstitial rejection in the early period after bowel transplantation.