Vascularized Composite Allograft Tolerance Across A Full MHC Mismatch Is Possible With Transient High Dose Tacrolimus
Angelo A. Leto Barone*, MD, Howard D. Wang*, MD, Edward W. Swanson, MD, Keli Kolegraff, MD, PhD, Joseph Lopez, MD, MBA, Georg Furtmüller, MD, Byoungchol Oh, PhD, Sara AlFadil, MD, 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, Gerald Brandacher, MD.
Johns Hopkins, Baltimore, MD, USA.
Purpose: The achievement of tolerance induction in Vascularized composite allografts (VCA) could potentially enhance the quality of life for patients with severe facial or extremity injuries while avoiding the risk of immunosuppression. The achievement of tolerance would help transitioning VCA from an experimental to a routine practice worldwide. The purpose of this study was to investigate strategies for tolerance induction in a large animal model and to assess whether current VCA recipients could potentially be weaned off of immunosuppression while maintaining their intact graft using only a co-stimulation blockade agent.
Methods: A total of 19 MGH miniature swine underwent heterotopic osteomyocutaneous hind limb transplantation 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 protocol skin biopsies. Alloreactivity against donor antigens was assessed using a lymphocyte reaction (MLR).
Results: Prolonged high-dose tacrolimus led to maintenance of VCA in 3/3 animals but was associated with major infectious complications and death of animals with intact grafts. 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. One animal in group V rejected its graft on POD277. Donor specific unresponsiveness was confirmed in all long-term survivors in vitro by CFSE-MLR. The addition of CTLA4-Ig to subtherapeutic (low-dose) CNI does not prevent graft rejection. The use of transient high-dose tacrolimus +/- CTLA4-Ig allows long-term graft survival.
Conclusions: A conditioning regimen consisting of peritransplant high-dose tacrolimus without myeloablative conditioning leads to tolerance of VCA containing vascularized bone marrow. These encouraging findings hint to the potential use of an induction regimen to eliminate the need for long-term immunosuppression and its complications in reconstructive transplantation.
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