Comparison of long-term immunosuppression for limb transplantation using cyclosporine, tacrolimus, and mycophenolate mofetil: Implications for clinical composite tissue transplantation

This study compared the efficacy of long-term intermittent immunosuppressio n in preventing the rejection of a limb transplant across the strongest his tocompatibility barrier in ACI --> Lewis rats using the conventional immuno suppressive agent cyclosporine-A and the newer immunosuppressive agents FK- 506 (tacrolimus) and RS-61443 (mycophenolate mofetil). The recipient animal s were immunosuppressed daily for 14 days postoperatively, followed by long -term intermittent, twice-weekly immunosuppression using cyclosporine 25 mg /kg, RS-61443 30 mg/kg, or FK-506 2 mg/kg. All three immunosuppressive agen ts were able to prolong the rejection of the skin component of a limb trans plant compared with nonimmunosuppressed controls. Eight of nine animals rec eiving cyclosporine immunosuppression showed signs of rejection of the skin component of the limb transplant while continuing to receive long-term imm unosuppression and had a mean rejection time of 61.6 days. Seven of 10 anim als immunosuppressed with RS-61443 also showed signs of rejection while sti ll receiving immunosuppression, with a mean rejection time of 43.6 days. Ni ne of 10 animals receiving FK-506 immunosuppression showed no signs of skin rejection, but died of bacterial pneumonia between 273 and 334 days after transplantation, with a mean rejection time of 296.1 days. There was no sta tistically significant difference between intermittent immunosuppression wi th cyclosporine and RS-61443, but FK-506 was significantly superior to both cyclosporine and RS-61443. The implication of this study is that FK-506, b ut not cyclosporine or RS-61443, is probably the only single immunosuppress ive agent capable of preventing rejection of the skin component of a compos ite tissue transplant. Combination immunosuppression with FK-506 and RS-614 43, therefore, may be required to allow composite tissue transplantation to become a predictable clinical reality in the future.