PURPOSE: Vascularized composite allografts (VCA) can enhance the quality of life of patients with severe facial or extremity injuries, and the induction of tolerance would avoid the risk of immunosuppression and increase application of VCA. The purpose of this study is to investigate strategies for tolerance induction in a large animal model.

METHODS: Heterotopic osteomyocutaneous hind limb transplantation was performed in 19 MGH miniature swine across full swine leukocyte antigen mismatch. All animals received non-myeloablative conditioning with 50cGy total body and 350cGy thymic irradiation for induction. Group I was treated with high-dose tacrolimus (15-20ng/ml) maintenance therapy. Group II was treated with low-dose tacrolimus (4-6ng/ml). Group III received low-dose tacrolimus and 20 mg/kg of CTLA4-Ig administered on POD2, 7, 14, 30, 60, 90, and 120. Group IV received transient high-dose tacrolimus until POD60. Group V received transient high-dose tacrolimus until POD60 and was switched to CTLA4-Ig administered on POD60, 85, 100, 120 and 150. Graft rejection was monitored by clinical assessment and protocoled skin biopsies. Alloreactivity against donor antigens was assessed using an optimized CFSE-based mixed lymphocyte reaction (MLR).

RESULTS: Prolonged high-dose tacrolimus led to maintenance of VCA in 3/3 animals but was associated with major infectious complications. 2/3 animals in group II rejected their grafts by POD46 and 217. In group III, 2/5 animals demonstrated rejection prior to POD150, while 3/5 animals achieved long-term survival of their VCA beyond POD300. However, 3/3 animals in group IV and 5/5 animals in group V achieved indefinite graft survival (beyond POD200) despite weaning of all immunosuppression. Donor specific unresponsiveness was confirmed in long-term survivors in vitro by CFSE-MLR.

CONCLUSIONS: Tolerance of VCA containing vascularized bone marrow can be achieved with a regimen of peritransplant high-dose tacrolimus without myeloablative conditioning. These findings describe a potential induction regimen to eliminate the need for long-term immunosuppression after reconstructive transplantation.

CITATION INFORMATION: Wang H, Swanson E, Cheng H.-T, Walch J, Alonso-Esclante J, Kolegraff K, Lopez J, Furtmuller G, Oh B, Quan A, Budihardjo J, AlFadil S, Mulla S, Akre P, Sacks J, Bonawitz S, Raimondi G, Shores J, Cooney D, Lee W, Brandacher G. Vascularized Composite Allograft Tolerance with Transient High-Dose Tacrolimus Across a Full MHC Mismatch in a Large Animal Model. Am J Transplant. 2016;16 (suppl 3).

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