Long-term composite tissue allograft survival in a porcine model with cyclosporine/mycophenolate mofetil therapy

Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct cl inical application, we developed a large-animal extremity composite tissue: allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/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 10 pigs received a once-daily oral CsA/MMF/prednisone regimen. Rejection was assessed by visual inspection of flap skin and correlated with serial histopathologic examination of skin b iopsies. Results. In all control pigs, the flap was completely rejected on day 7, Of the 10 pigs receiving treatment, one died from pneumonia and an another fr om an anesthetic complication on days 19 and 30, respectively, without sign s of rejection. Two flaps were lost on days 25 and 29 from severe rejection , Three pigs were free of rejection at the end of the 90-day follow-up peri od, and three had stable mild-to-moderate rejection at 90 days (P = 0.0007 vs, controls). White blood cell and platelet counts, serum creatinine value s, and liver function tests remained normal in all animals receiving immuno suppressive therapy. Conclusions. Our results, to our knowledge, demonstrate for the first time that rejection can be significantly delayed in a large-animal composite tis sue allograft model including skin using only orally administered agents do sed according to clinically relevant strategies without significant drug-sp ecific systemic side effects.