Efficacy of malononitrilamide FK778 in a preclinical model of small bowel transplantation.
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.
Alessiani
M
M
Department of Surgery, University of Pavia School of Medicine, I.R.C.C.S. Policlinico San Matteo Hospital, Pavia, Italy. mario.alessiani@unipv.it
Zonta
S
S
Abbiati
F
F
Cobianchi
L
L
Bardone
M
M
Zitelli
E
E
Doni
M
M
Viganò
J
J
Mazzilli
M
M
Lovisetto
F
F
Dominioni
T
T
Dionigi
B
B
Lusona
B
B
Morbini
P
P
Molinaro
M D
MD
Dionigi
P
P
D000480:Alkynes; D000818:Animals; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007421:Intestine, Small / Q000637:transplantation*; D007555:Isoxazoles / Q000627:therapeutic use*; D023421:Models, Animal; D009570:Nitriles; D016019:Survival Analysis; D013552:Swine; D014184:Transplantation, Homologous / Q000276:immunology / Q000401:mortality
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide