Jw. Jones et al., Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy, SURGERY, 126(2), 1999, pp. 384-388
Background. High-dose tacrolimus (FK506) monotherapy has significantly prol
onged rat hindlimb allograft survival. With an eye toward direct clinical a
pplication, we used a large-animal extremity composite tissue allograft mod
el to assess the antirejection efficacy and systemic toxicity of combinatio
n 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 8
3 without signs of rejection and another died from gastric rupture on day 4
2 with persistent mild rejection. The remaining 5 animals were free of reje
ction at the end of the 90-day follow-up period (P < 0.005 vs controls). Ov
erall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 dia
rrhea and decreased weight gain.
Conclusions. Combination oral FK506-MMF treatment provided a superior antir
ejection effect but more produced more toxicity than that previously demons
trated with cyclosporin A-MMF therapy in our model. Our results suggest tha
t reduction of FK506 or MMF doses might decrease both infectious and drug-s
pecific side effects while still providing adequate prophylaxis against rej
ection.