Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy

Abstract

Background: High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment.

Methods: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens.

Results: In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain.

Conclusions: Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.