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Vascularized Composite Allograft Tolerance with Costimulatory Blockade and Transient Tacrolimus in a Large Animal Model
Howard D. Wang, MD, Edward W. Swanson, MD, Hsu-Tang Cheng, MD, Keli Kolegraff, MD, PhD, Joseph Lopez, MD, MBA, Georg Furtmuller, MD, Byoungchoi Oh, DVM, PhD, Jose C. Alonso, BS, Amy Quan, BS, Jeffrey M. Walch, MD, PhD, Joshua D. Budihardjo, BS, Sara AlFadil, MBBS, Paul J. Akre, BA, MS, Sara Mermulla, MBBS, Justin M. Sacks, MD, Steven C. Bonawitz, MD, Jaimie T. Shores, MD, Damon S. Cooney, MD, PhD, W.P. Andrew Lee, MD, Gerald Brandacher, MD.
Johns Hopkins Hospital: Department of Plastic and Reconstructive Surgery, Baltimore, MD, USA.

PURPOSE:
Costimulatory blockade with belatacept, a Cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin (CTLA4-Ig), has shown promise in solid organ transplantation. The aim of this study was to investigate the efficacy of belatacept to reduce the requirement for conventional immunosuppression such as calcineurin inhibitors (CNI) in maintaining vascularized composite allograft (VCA) survival in a large animal model.
METHODS:
Heterotopic osteomyocutaneous hind limb transplantation was performed in 16 MGH miniature swine across full swine leukocyte antigen mismatch. All animals received non-myeloablative conditioning with 50cGy total body and 300cGy thymic irradiation pre-transplant. Experimental groups and treatment regimens are outlined in Table 1.
RESULTS:
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 graft by POD46 and 217. In group III, 2/5 animals demonstrated rejection prior to POD150, while 3/5 animals achieved tolerance of their VCA with graft survival beyond POD300. 5/5 animals in group IV has maintained graft survival beyond POD170 without rejection.
CONCLUSION:
Previously, VCA tolerance in large animal models have required establishment of chimerism by either donor bone marrow infusion or hematopoietic stem cell transplantation. The results of this study suggest that tolerance of VCA containing vascularized bone marrow can be achieved with our conditioning regimen of belatacept and peritransplant tacrolimus without the requirement for myeloablative conditioning.
Table 1. Treatment groups and rationale
GroupNProtocolRationale
I3High-dose TAC (15-20 ng/ml) maintenance to POD150Control Group: therapeutic (CNI)
II3Low-dose TAC (4-6 ng/ml) maintenance to POD150Control Group: sub-therapeutic CNI
III5Low-dose TAC (4-6 ng/ml) + CTLA4-Ig maintenance to POD150Experimental Group: Tests role of CTLA4-Ig to achieve graft survival with minimal CNI
IV5Transient high-dose TAC (15-20 ng/ml) to POD60 + CTLA4-Ig Maintenance to POD150Experimental Group: Tests role of CTLA4-Ig to achieve graft survival with transient CNI


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