Purpose: The achievement of tolerance in Vascularized composite allografts (VCA) could avoid the risks of immunosuppression in this setting. We investigated strategies for tolerance induction in a large animal model and assessed whether current VCA recipients could be weaned off of immunosuppression while maintaining an intact graft using only a co-stimulation blockade agent.

Methods: 19 MGH miniature swine underwent heterotopic osteomyocutaneous hind limb transplantat across full MHC mismatch. All animals received non-myeloablative conditioning with 50cGy total body and 350cGy thymic irradiation for induction and differed as follows. Group I: high-dose tacrolimus (15-20ng/ml) maintenance therapy. Group II: low-dose tacrolimus (4-6ng/ml). Group III: low-dose tacrolimus and 20 mg/kg of CTLA4-Ig administered on POD2,7,14,30,60,90 and 120. Group IV: transient high-dose tacrolimus until POD60. Group V: transient high-dose tacrolimus until POD60 and then CTLA4-Ig 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. In group III, 2/5 animals demonstrated rejection prior to POD150, while 3/5 animals achieved long-term graft survival beyond POD300. 3/3 animals in group IV and 4/5 animals in group V achieved indefinite graft survival despite weaning of all immunosuppression. The 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 MLR. The addition of CTLA4-Ig to subtherapeutic (low-dose) CNI did not prevent graft rejection. The use of transient high-dose tacrolimus +/- CTLA4-Ig allowed 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.

CITATION INFORMATION: Leto Barone A, Wang H, Swanson E, Kolegraff K, Lopez J, Furtmüller G, Oh B, Alfadil S, Mermulla S, Sacks J, Bonawitz S, Raimondi G, Shores J, Cooney D, Lee W, Brandacher G. Transient High Dose Tacrolimus Allows Tolerance of a Vascularized Composite Allograft Tolerance Across a Full MHC Mismatch. Am J Transplant. 2017;17 (suppl 3).

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