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Abstract: The intestine is a highly immunogenic organ that requires heavy immunosuppression (IS); therefore corticosteroid withdrawal after clinical small bowel transplantation (SBT) has not been standardized. In this study, we compared different immunosuppressive regimens (none with steroid or induction treatment) in a SBT pig model. Large White unrelated piglets were transplanted and divided into four groups as follow: group 1 (n = 3): no IS; group 2 (n = 10): IS with tacrolimus only; group 3 (n = 10): IS with tacrolimus and mycophenolate mofetil; group 4 (n = 5): IS with tacrolimus and rapamycin. Follow-up time was 30 days. All IS drugs were given orally; tacrolimus whole blood levels ranged between 5 and 15 ng/mL in all groups except for group 2 whose tacrolimus whole blood levels ranged between 15 and 25 ng/mL. Group 1 pigs died of graft acute rejection (ACR) after a median of 12 days. Overall survival in groups 2, 3, and 4 at day 30 was 40%, 80%, and 60%, respectively. Biochemical parameters, including glycemia and cholesterol, were into the normal range with no significant differences between groups. At the end of the study, one animal in group 2 and another one in group 4 showed histological signs of moderate to severe ACR. The incidence of infection was higher in group 2 (2.1 episodes/pig) compared to group 3 (1.25) and group 4 (1.6). This large-animal study demonstrates that tacrolimus-based IS without corticosteroids allows, in the early postoperative period (30 days) after SBT, good survival rates without an increased risk in the incidence of rejection. [Copyright &y& Elsevier]

Abstract: In a swine model of orthotopic small bowel transplantation, we assessed the efficacy of combined immunosuppressive therapy with low-dose tacrolimus plus FK778, compared with high-dose tacrolimus monotherapy. The small bowel was replaced in 23 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 12), oral tacrolimus to maintain whole blood trough levels between 15 and 25 ng/mL; and group 3 (n = 6), oral FK778 4 mg/kg/d, plus oral tacrolimus to maintain whole blood trough levels between 5 and 15 ng/mL. Follow-up time was limited to 60 days. Overall survival rates at 30 and 60 days were 0% and 0% in group 1, 30% and 0% in group 2, and 66% and 66% in group 3, respectively. The median survival time was 11 days in group 1, 28 days in group 2, and more than 60 days in group 3. The differences between groups 3 and 1 and between groups 3 and 2 were statistically significant. The numbers of major bacterial infections were 19 in group 2 (1.9 episodes per animal) and 3 in group 3 (0.75 episodes per animal). The infectious-related mortality rate was 70% in group 2 (7 cases) and 0% in group 3 (P < .05). Acute cellular rejection was absent or mild in 85% of group 2 stomal biopsy specimens and in 100% of group 3 biopsy specimens. In conclusion, combination therapy of low-dose tacrolimus is potentiated by FK778 to prevent acute cellular rejection and prolong small bowel transplant survival in pigs. [Copyright &y& Elsevier]