BACKGROUND: Vascular Composite Allografts (VCA), such as extremity and face transplants, contain vascularized bone marrow (BM) and a BM niche representing a constant source of donor-derived stem cells, which can favour chimerism induction, and thus make tolerance protocols particularly appealing. This study investigates the immunological effects of vascularized BM within VCA under co-stimulation blockade-based regimen and its impact on allograft survival and tolerance induction.
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 (60x107cells/kg), and CTLA4Ig. Short course tacrolimus only and untreated animals served as controls. Chimerism was assessed by SRY-gene PCR analysis. Tissue biopsies were performed for histology. Alloreactivity against donor antigens was assessed in vitro using Carboxyfluorescein succinimidyl ester-based mixed lymphocyte reaction (CFSE-MLR) assays. Challenge with secondary skin grafts demonstrated robust immune tolerance in vivo.
RESULTS: The co-stimulation blockade based immunomodulatory protocol resulted in indefinite graft survival (>150 days) in 3 out of 5 animals whereas control and tacrolimus only groups rejected allografts at days 7 (sd=+/-1) and 29 (sd=+/-1) respectively. Combined costimulation blockade with augmented donor BM infusion resulted in indefinite graft survival in 2 out of 3 animals (150 days). Long-term survivors demonstrated only transient peripheral but stable micro-chimerism in various graft and recipient tissues. CFSE-MLR data showed unresponsiveness to donor but not to third party allogeneic controls. Secondary skin grafting demonstrated advanced rejection of third party grafts (day 7) while donor-matched grafts were accepted indicating donor-specific tolerance.
CONCLUSION: Combined costimulation blockade and donor BM cell infusion induced robust immune tolerance in a fully MHC mismatched hind limb transplant model. Such targeted immunomodulatory protocols might eliminate the need for long-term multi-drug immunosuppression after reconstructive transplantation.
To cite this abstract in AMA style:Barone ALeto, Ibrahim Z, Wu L, Furtmueller G, Sarhane K, Alrakan M, Pang J, Zhu S, Christensen J, Wimmers E, Schneeberger S, Cooney D, Shores J, Bonawitz S, Sacks J, Lee W, Brandacher G. Immune Tolerance across a Full MHC Barrier in a Swine Hind Limb Transplantation Model Using a Combined Co-Stimulatory Blockade and Donor Bone Marrow Cells Approach [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/immune-tolerance-across-a-full-mhc-barrier-in-a-swine-hind-limb-transplantation-model-using-a-combined-co-stimulatory-blockade-and-donor-bone-marrow-cells-approach/. Accessed May 5, 2021.
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