FK778 and tacrolimus combination therapy to control acute rejection after pig intestinal transplantation.
Malononitrilamide 715 (FK778) is a new class of low molecular weight immunosuppressant. Experimental studies in heart, liver, and kidney transplantation have shown a strong synergism when FK778 is used in combination with tacrolimus and when its administration is delayed by 7 days after the transplant. Following this indication, in a swine model of orthotopic small bowel transplantation (SBT), we assessed the efficacy of combined low dose tacrolimus and FK778 administered from day 0 or day 7. The entire small bowel was replaced in 16 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 6) oral tacrolimus to maintain whole blood trough levels between 5 and 15 ng/mL plus FK778 4 mg/kg per day; group 3 (n = 6) oral tacrolimus as in group 2 plus FK778 4 mg/kg per day administered after a 7-day delay posttransplant. The median survival was 8 days in group 1, 60 days in group 2, and 13 days in group 3. The differences between group 2 and 1 and between group 2 and 3 are statistically significant. Three episodes of major bacterial infection were detected in both group 2 and 3 (0.5 episode/animal). The infectious-related mortality was 0% in group 2 and 50% in group 3 (P < .05). Acute cellular rejection was absent or mild in all group 2 and 3 stomal biopsies. In conclusion, combining tacrolimus and FK778 allowed prolonged survival after SBT in swine when FK778 was started at the time of SBT. The delayed administration of FK778 resulted in a high incidence of lethal infectious complications.
Alessiani
M
M
Department of Surgery, University of Pavia School of Medicine and I.R.C.C.S. Policlinico San Matteo Hospital, Piazzale Golgi 2, 27100 Pavia, Italy. mario.alessiani@unipv.it
Abbiati
F
F
Zonta
S
S
Zitelli
E
E
Bardone
M
M
Cobianchi
L
L
Viganò
J
J
Doni
M
M
Mazzilli
M
M
Dominioni
T
T
Kabiri
D
D
Bottazzi
A
A
Morbini
P
P
Molinaro
M D
MD
Dionigi
P
P
D000480:Alkynes; D000818:Animals; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007421:Intestine, Small / Q000637:transplantation*; D007555:Isoxazoles / Q000627:therapeutic use*; D023421:Models, Animal; D009570:Nitriles; D016019:Survival Analysis; D013552:Swine; D016559:Tacrolimus / Q000627:therapeutic use*; D014361:Trypsin Inhibitors / Q000627:therapeutic use
D000480:Alkynes; D007555:Isoxazoles; D009570:Nitriles; D014361:Trypsin Inhibitors; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016559:Tacrolimus