Plastic Surgery Research Council

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Tolerance Induction of Vascularized Composite Allografts Across a Class I Barrier in Swine
Alexandre G. Lellouch, MD1,2, Gaelle Saviane, MSc1, Laura C. Burlage, MD3,4, Ilse M. Schol, BS1, Laurent A. Lantieri, MD2, Mark A. Randolph, Msc1, Gilles Benichou, PhD1, Curtis L. Cetrulo, Jr., MD, FACS5.
1MGH / Harvard Medical School, Boston, MA, USA, 2European Georges Pompidou Hospital, Paris, France, 3MGH / Harvard Medical SchoolMGH, Boston, MA, USA, 4Medical Center Groningen, Groningen, Netherlands, 5MGH, Boston, MA, USA.

PURPOSE: Vascularized composite allografts (VCAs) are an established option for restoration of complex soft tissue defects. The limiting factors for VCA include the risks of immunosuppression and the specter of chronic rejection. Therefore, the development of tolerance protocols remains a priority. We sought to optimize our mixed hematopoietic chimerism VCA tolerance protocol with the addition of co-stimulatory blockade, Tregulatory cell augmentation, inflammatory cytokine inhibition and augmentation of hematopoietic cell engraftment.METHODS: Prior to VCA, MGH swine received non-myeloablative conditioning with 300 cGy total body and 700 cGy thymic irradiation on day -2. Osteomyocutaneous hind limb VCAs were transplanted into MHC class I-mismatched recipients (n=8). Tacrolimus was administrated for 45 days (target level 10-15 ng/mL). CTLA4-Ig (20 mg/kg) was administered on POD 0 and on days 2, 4, 6. Anti-IL6R (10mg/kg) was given on POD 0, 7, 14, 21, 28. VCA skin and muscle biopsies were performed on POD 30, 50 and 100. Systemic immune function and chimerism status were assayed. Split thickness skin grafts were placed at POD 150 from self, donor, and third-party donor to assess acceptance/rejection of the original donor skin.
RESULTS: Three animals out of eight completed the protocol: swine 23645 became tolerant of the VCA, including the skin, and was terminated at 251 days, corresponding to the endpoint of the study. For other animals, we elected to extend the endpoint to 400 days. 24087 and 24356 has been tolerant up to POD 400. One episode of acute epidermal rejection occurred at POD 252 (after 207 days off immunosuppression) but resolved spontaneously without needing additional immunosuppression. All animals showed mixed hematopoietic chimerism in the blood. Split thickness skin grafts placed at POD 150 showed acceptance of self and donor skin grafts, whereas the third-party graft was rejected in the normal 8-12-day time frame. We observed an increase of anti-inflammatory cytokines in the blood stream.CONCLUSION: We demonstrate tolerance in a Class I mismatch swine model of all components of the allograft, including epidermis.This VCA tolerance induction protocol is notable for the use of donor bone marrow as a hematopoietic cell source as well as clinically-approved induction agents. This protocol is being tested in full MHC mismatch swine in anticipation of clinical translation.


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