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Tolerance Induction Protocol For VCA Across Full Mismatch Barriers In MHC-Defined Miniature Swine
Alec R. Andrews, BS1, Philipp Tratnig-Frankl, MD1, Corentin B. Taveau, MD1,2, Michael M. Jonczyk, MD1, Laurent A. Lantieri, MD2, Mark A. Randolph, MAS1, Alexandre G. Lellouch, MD1,2, Gilles Benichou, PhD1, Curtis L. Cetrulo, Jr., MD, FACS1.
1Massachusetts General Hospital, Shriners Hospitals for Children, Boston, MA, USA, 2Service de Chirurgie Plastique, Hôpital Européen Georges Pompidou, Assistance Publique- Hôpitaux de Paris (APHP), Paris, France.

PURPOSE: Vascularized composite allotransplantation (VCA) is a well-established surgical option when autologous surgery is insufficient. However, the clinical application of VCA is limited by the requirement of life long immunosuppression therapy. As demonstrated in renal transplantation, hematopoietic mixed chimerism can enable immunosuppression-free allograft survival. Our group has previously established durable mixed chimerism after combined hind limb and bone marrow transplantation in miniature swine across a class I major histocompatibility complex (MHC) mismatch barrier with the use of CTLA4-Ig. In this study, we applied the same conditioning regimen in an attempt to induce tolerance across a full MHC mismatch disparity.
METHODS: Donor and recipient MHC-defined miniature swine were paired by mismatching both MHC class I and II antigens. Recipient preconditioning included 300cGy whole body and 700cGy thymic irradiation two days before osteomyocutaneous VCA and bone marrow transplantation (POD 0, n=4). Maintenance immunosuppression consisted of tacrolimus (POD 0-45), CTLA4-Ig (20mg/kg, POD 0, 2, 4, 6), and anti-IL-6R (10mg/kg, POD 0, 7, 14, 21, 28). Allograft rejection was evaluated by histology and donor hematopoietic chimerism was assessed weekly by flow cytometry.
RESULTS: All animals developed mixed chimerism in peripheral blood (Figure 1) without signs of acute rejection or graft-versus-host disease during the first 30 days of the protocol. Thrombocytopenia requiring platelet transfusion developed in all animals (n=4). In addition, a high incidence of donor-derived PTLD after POD 21 (n=2) was observed. Removal of CTLA4-Ig from the conditioning regimen led to acute rejection of VCA skin by POD 7 (n=1).
CONCLUSION: Costimulatory blockade is a necessary component of our conditioning regimen to prevent acute rejection of full mismatch VCAs. Despite overcoming acute rejection episodes and achieving donor engraftment, PTLD remains a complication in this model. Future efforts will evaluate differences in hematopoietic recovery that affect PTLD incidence within this cohort.


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