Combined immunosuppressive therapy with tacrolimus and mycophenolate mofetil for small bowel transplantation in pigs.
In a swine model of orthotopic small bowel transplantation, we assessed the efficacy of combined therapy with a low dose of tacrolimus plus mycophenolate mofetil, compared with high-dose tacrolimus monotherapy. The bowel was replaced in 25 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 10), tacrolimus, 0.3 mg/kg daily i.m. for 7 days, followed by b.i.d. oral doses to maintain blood levels of 15-25 ng/ml; and group 3 (n = 10), tacrolimus, 0.1 mg/kg i.m., in a single dose on day 0 and thereafter oral doses to maintain blood levels of 5-15 ng/ml, plus oral mycophenolate mofetil (10 mg/kg twice daily). Follow-up time was limited to 60 days. Median survival time as 11, 27, and > 60 days in groups 1, 2, and 3, respectively (P = 0.001). Survival rates were 0%, 40%, and 80% at 30 days and 0%, 0%, and 70% at 60 days in groups 1, 2, and 3, respectively (P = 0.03), group 1 vs. group 2; P = 0.003, group 1 vs. group 3; P = 0.02, group 2 vs. group 3). One animal in group 1 (20%) and two animals each in groups 2 and 3 (20%) died of technical complications. Rejection was the cause of death of 80% of animals of group 1 and of no animals in either group 2 or 3. None of the immunosuppressed animals developed clinical or histopathological evidence of graft-versus-host disease. Sixty percent of animals in group 2 (n = 6) and 10% in group 3 (n = 1) died from infections; two other animals in group 2 died of emaciation. The seven animals of group 3 that were alive at 60 days had immunosuppression stopped at that time. All died of rejection within 1 month. In conclusion, double-drug therapy with tacrolimus and mycophenolate mofetil consistently allowed extended survival after small bowel transplantation in swine, preventing or controlling acute cellular rejection without a high incidence of lethal complications related to overimmunosuppression.
Alessiani
M
M
Department of Surgery, University of Pavia, Italy.
Spada
M
M
Dionigi
P
P
Arbustini
E
E
Regazzi
M
M
Fossati
G S
GS
Zonta
A
A
D000818:Animals; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D006086:Graft vs Host Disease / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011446:Prospective Studies; D011897:Random Allocation; D013552:Swine; D016559:Tacrolimus / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus