Abstract
BACKGROUND: The establishment of tolerance protocols would avoid the debilitating effects of chronic immunosuppression and render Vascularized Composite Allotransplantation (VCA) a routine procedure. We investigated graft survival and tolerance induction using co-stimulation blockade with either abatacept or the higher-affinity equivalent drug belatacept. METHODS: Fully MHC- and gender mismatched MGH miniature swine underwent heterotopic hind-limb transplantation. Recipient animals received a short course (30 days) of tacrolimus monotherapy, +/- donor BM infusion, and CTLA4Ig (either abatacept or belatacept). Tacrolimus only and untreated animals served as controls. Recipients were assessed for: chimerism (SRY-gene PCR analysis), alloreactivity against donor antigens (in vitro CFSE-MLR assays), and donor-specific antibodies (DSA) production (serum flow cytometry analysis). Robust immune tolerance in vivo was assessed by skin grafting. Tolerance maintenance upon allograft removal was tested by CFSE-MLR. RESULTS: Both regimens using abatacept or belatacept plus donor BM infusion resulted in indefinite graft survival (>200 days). While only transient peripheral chimerism was observed, stable micro-chimerism in various graft and recipient tissues was achieved. An increase in intragraft Tregs was seen in tolerant animals as compared to controls. Tolerant animals displayed unresponsiveness to donor but not to third party allogeneic controls in CFSE-MLRs. Donor-matched skin grafts were accepted while third party grafts where quickly rejected indicating donor-specific tolerance. No signs of chronic rejection or donor-specific antibodies were seen in tolerant recipients in either group (abatacept vs belatacept). Graft removal, however, was associated with loss of donor-unresponsiveness 5 weeks post-graftectomy. CONCLUSIONS: Combined costimulation blockade and donor BM cell infusion induced robust donor-specific immune tolerance in a translational fully MHC-mismatched hind limb transplant model.
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