Local Fk506 Implant Technology In Vca - Successful Bridge To Delayed Mixed Chimerism Protocol
Alexandre G. Lellouch, MD1,2, Corentin B. Taveau, MD1,2, Alec R. Andrews, BS1, Joseph Molde, BS3, Zhi Y. Ng, MD1, Philipp Tratnig-Frankl, MD1, Mark A. Randolph, M.Sc1, Joachim Kohn3, Curtis L. Cetrulo, Jr., MD FACS1.
1Massachusetts General Hospital, Boston, MA, USA, 2Service de Chirurgie Plastique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France, 3New Jersey Center for Biomaterials Rutgers, New Jersey, NJ, USA.
PURPOSE: We have previously reported that topical FK506 does not prevent acute rejection when applied to the skin of vascularized composite allografts (VCAs) in non-human primates (NHPs), likely due to inadequate pharmacokinetics. In this study, we report our experience in optimization of local FK506 delivery in a NHP model of delayed mixed chimerism in VCA.
METHODS: Two full MHC-mismatched NHP pairs underwent partial-face VCA and local FK506 implantation 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). VCA skin biopsies and peripheral blood samples were taken for serial assessment of rejection and mixed chimerism respectively. RESULTS: Both 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. Subsequently, both NHPs had to be terminated from study on POD 77 and 86 due to progressive weight loss from underlying PTLD of recipient-origin.
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 to avoid unnecessary VCA loss. Most importantly, it represents a promising bridge towards the development of future tolerance protocols based on mixed chimerism.
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