Local delivery of FK506 to prevent VCA early acute rejection in a delayed mixed chimerism protocol
Alexandre G. Lellouch1,2,3, Corentin B. Taveau1,2,3, Alec R. Andrews1,2, Marion P. Goutard1,2,3, Philipp Tratnig-Frankl1,2, Elise L. Lupon1,2,4, Joseph Molde5, Zhi Y. Ng1,2, Mark A. Randolph1,2, Joachim Kohn5, Curtis L. Cetrulo Jr.1,2.
1Division of Plastic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; 2Division of Plastic Surgery, Shriners Hospitals for Chidren, Boston, MA, United States; 3Service de Chirurgie Plastique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France; 4Service de Chirurgie Plastique, Rangueil Hospital, University Toulouse III Paul Sabatier, Toulouse, France; 5New Jersey Center for Biomaterials Rutgers, New Jersey, NJ, United States
Purpose: Skin is the most immunogenic component of vascularized composite allograft (VCA). We previously reported that topical gel application of FK506 does not prevent acute rejection in non-human primates (NHPs), likely due to inadequate pharmacokinetics. In this study, we report our experience in optimization of local FK506 delivery in an NHP model of delayed mixed chimerism in VCA.
Materials and Methods: Three full MHC-mismatched NHP pairs underwent partial-face VCA and local FK506 subcutaneous discs implantation. Between twenty and thirty discs were placed along the suture line between donor and recipient skin. Post-operatively, recipients were maintained on standard immunosuppression (steroids, MMF, FK506) for 2 months before undergoing tolerance induction with donor bone marrow transplantation (DBMT) after conditioning. VCA skin biopsies and peripheral blood samples were taken for serial assessment of rejection and mixed chimerism respectively.
Results and Discussion: All subjects remained rejection-free clinically and on histology for 2 months. Following conditioning, one generated mixed chimerism (96-97% granulocytes and 7-11% lymphocytes of donor-origin) at 2-3 weeks post-DBMT. Three NHPs had to be terminated from study on POD 64, 77 and 86 due to progressive weight loss from underlying post-transplant lymphoproliferative disease (PTLD) of recipient-origin. One out of 3 animals developed a mixed chimerism. Our hypothesis is that vascularized bone marrow transplant in a VCA model might be held accountable for occurrence of PTLD in the NHP model.
Conclusion: In both clinical patients and experimental NHP, acute rejection of VCA is nearly inevitable in the early post-transplantation period despite current immunosuppression regimens. The enhanced local drug delivery from FK506 implants in this study has shown promise in preventing acute rejection which would negate successful tolerance induction due to sensitization (as has been observed in previous delayed tolerance induction models in solid organ transplantation). This adjunct may allow reduction of overall immunosuppression load and improve patient compliance. Although, it is not clear why PTLD was a recurring limitation in our study. Most importantly, it represents a promising bridge towards the development of future tolerance protocols based on mixed chimerism.
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