71 In order to proceed with clinical hand transplantation, it was necessary to demonstrate that rejection could be effectively suppressed in a large-animal CTA model with acceptable morbidity. We therefore developed a porcine brachial artery-based radial forearm osteomyocutaneous flap allograft model to assess the antirejection efficacy of combination cyclosporine (CSA)/mycophenolate mofetil (MMF) and tacrolimus (FK)/MMF treatment. Once-daily oral CSA/MMF/prednisone (pred) and FK/MMF/pred regimens were used. Initial CSA and FK506 doses were 40 and 1.5 mg/kg/d, adjusted to maintain 24 hr trough levels between 100-300 and 3-8 ng/ml, respectively; MMF dose was 0.5 g/d; and pred was tapered from 2.0 to 0.1 mg/kg/d over 30 days. Drug doses were not adjusted based on the clinical course. Graft skin biopsies were performed at 0, 2, 4, 7, 10, 14, 21, 30, 45, 60, and 90 days posttransplant. Visual and histologic scoring systems for grading of skin rejection were developed. In 5 control pigs, the flap was completely rejected on day 7. Of the 10 pigs receiving CSA, 1 died from pneumonia and an another from an anesthetic complication on days 19 and 30 without rejection. 2 flaps were lost on days 25 and 29 from severe rejection. 6 flaps survived 90 days, 5 with persistent mild to severe rejection. Of the 9 pigs receiving FK, 3 died from pneumonia on days 29, 30, and 83 without rejection and an another from gastric rupture on day 42 with mild rejection. The remaining 5 pigs were free of rejection at 90 days (p < 0.01 vs controls for both groups). Our results demonstrated for the first time that rejection can be significantly delayed in a large-animal CTA model including skin using only orally-administered agents dosed according to a clinically-relevant strategy without antibody induction and led to clinical trials. We assessed the risk/benefit ratio for a human hand transplant using risk analysis as an epidemiologic tool to measure quality of life values. The development of a clinical program was done as a transparent process, inviting public and medical commentary prior to the procedure. Ethics committee and institutional review board presentations led to final approval. Patient selection involved medical, surgical, psychiatric, and social services input. The protocol included HLA and blood group testing, as well as flow cytometric and CDC crossmatching. The heartbeating cadaver donor was matched by bone size (± 20%), gender, and color, and the donor hand was flushed with UW solution and cold-stored until blood flow was reestablished. The recipient received basilixamab 20 mg IV on days 0 and 4, FK (target trough level 15-20 ng/ml), MMF 1g bid, and pred (2 mg/kg/d tapered to 10 mg/d by 90 days). Protocol skin biopsies were performed on days 0, 5, 7, 10, 14, 21, and 28. Physical therapy and bracing started on day 3 and continued daily. No visual signs of skin rejection were apparent during the first month, with mild perivascular infiltrates seen on biopsy. Function is equivalent to that of the replanted autologous hand. No drug-specific toxicity or infectious complications were observed. We conclude that early success in clinical hand transplantation is achievable using currently available immunosuppressants.