FK778 and Tacrolimus Combination Therapy to Control Acute Rejection After Pig Intestinal Transplantation

• Published in: Transplantation proceedings Vol. 38; no. 6; pp. 1809 - 1811
• Main Authors: Alessiani, M., Abbiati, F., Zonta, S., Zitelli, E., Bardone, M., Cobianchi, L., Viganò, J., Doni, M., Mazzilli, M., Dominioni, T., Kabiri, D., Bottazzi, A., Morbini, P., Molinaro, M.D., Dionigi, P.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01-07-2006; Elsevier Science
• Subjects: Alkynes; Animals; Biological and medical sciences; Drug Therapy, Combination; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Graft Rejection - immunology; Graft Survival - drug effects; Graft Survival - immunology; Intestine, Small - transplantation; Isoxazoles - therapeutic use; Medical sciences; Miscellaneous; Models, Animal; Nitriles; Public health. Hygiene; Public health. Hygiene-occupational medicine; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Survival Analysis; Swine; Tacrolimus - therapeutic use; Tissue, organ and graft immunology; Trypsin Inhibitors - therapeutic use; Graft(material); Calcineurin inhibitor; Transplantation; Homotransplantation; Small intestine; Surgery; Graft; Protein synthesis inhibitor; Sanitary surveillance; Ungulata; Drug combination; Digestive system; Acute; Lactone; Macrolide; Pig; Immunomodulator; Medicine; Rejection; Vertebrata; Mammalia; Tacrolimus; Animal; Combined treatment; Artiodactyla; Immunosuppressive agent; Antibacterial agent
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2006.05.042

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.