Malononitrilamide 715 (
FK778) is a new class of
immunosuppressant, derived from the active metabolite of
leflunomide A77 1726. We investigated the efficacy of two different immunosuppressive induction protocols with
tacrolimus plus
FK778 followed by
FK778 monotherapy. In a swine model of small bowel
transplantation, we observed three groups, divided by different
therapy regimens: group 1 (n = 5): no
immunosuppressant (control group); group 2 (n = 10): oral
tacrolimus (from postoperative day [POD] 0 to 30) and
FK778 (from POD 0 to 60); group 3 (n = 8): oral
tacrolimus, as group 2, and
FK778 (from POD 7 to POD 60). Median survival was 11, 60, and 21 days in groups 1, 2, and 3, respectively. In group 1 all animals died of acute rejection; in group 2 the causes of death were technical complication (n = 1) and
sepsis (n = 1); in group 3, one animal died from obstruction, two from
pneumonia, one from
peritonitis, one from
sepsis. Group 2 accounted for 0.5
infection episode/animal versus 0.62 in group 3 (P < .05). Acute rejection was absent or mild in 66% and 75% of group 3 and 2 biopsies, respectively (P < .05). The
D-xylose absorption curves from groups 2 and 3 were similar to those of the nontransplanted healthy animals. In conclusion,
FK778 monotherapy after a consistent induction period with
tacrolimus combined immunosuppression is able to extend survival and preserve optimal absorptive capacity of the small bowel allograft in our pig model. The association of
tacrolimus and
FK778 from day 1, compared to the delayed administration of
FK778 from day 7, results in a significant reduction of
infections and postoperative complications.