2523: Vascularized composite allograft tolerance with transient high-dose tacrolimus across a full MHC mismatch in a large animal model

2523: Vascularized composite allograft tolerance with transient high-dose tacrolimus across a full MHC mismatch in a large animal model Howard D. Wang, MD, Edward W. Swanson, MD, Hsu-Tang Cheng, MD, Jeffrey Walch, MD, PhD, Jose C. Alonso-Escalante, MD, Keli Kolegraff, MD, PhD, Joseph Lopez, MD, MBA, Georg Furtmuller, MD, Byoung Chol Oh, DVM, PhD, Amy Quan, MPH, Joshua Budihardjo, Sara AlFadil, MD, Sara Mulla, MD, Samuel Fidder, MD, Paul Akre, MS, Justin M. Sacks, MD, Steven C. Bonawitz, MD, Giorgio Raimondi, PhD, Jaimie T. Shores, MD, Damon S. Cooney, MD, PhD, W. P. Andrew Lee, MD, and Gerald Brandacher, MD Johns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA Background Vascularized composite allografts (VCA) can enhance the quality of life for patients with severe facial or extremity injuries, and 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 MGHminiature 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 (15–20 ng/ml) maintenance therapy Group II was treated with low-dose tacrolimus (4–6 ng/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 highdose 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 protocol 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 3/3 animals in group IV and 4/5 animals in group V achieved indefinite graft survival beyond POD300 despite weaning of all immunosuppression The one animal in group V that rejected its graft began to show evidence of rejection on POD277 Donor specific unresponsiveness was confirmed in all 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. CONTACT Howard D. Wang, MD hdwang86@gmail.com © 2016 Howard D. Wang, Edward W. Swanson, Hsu-Tang Cheng, Jeffrey Walch, Jose C. Alonso-Escalante, Keli Kolegraff, Joseph Lopez, Georg Furtmuller, Byoung Chol Oh, Amy Quan, Joshua Budihardjo, Sara AlFadil, Sara Mulla, Samuel Fidder, Paul Akre, Justin M. Sacks, Steven C. Bonawitz, Giorgio Raimondi, Jaimie T. Shores, Damon S. Cooney, W. P. Andrew Lee, and Gerald Brandacher. Published with license by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. VASCULARIZED COMPOSITE ALLOTRANSPLANTATION 2016, VOL. 3, NOS. 1–2, 8 http://dx.doi.org/10.1080/23723505.2016.1232941