Vascularized Composite Allograft Tolerance Across MHC Barriers in a Large Animal Model

Abstract

Vascularized composite allograft (VCA) transplantation can restore form and function following severe craniofacial injuries, extremity amputations or massive tissue loss. The induction of transplant tolerance would eliminate the need for long-term immunosuppression, realigning the risk–benefit ratio for these life-enhancing procedures. Skin, a critical component of VCA, has consistently presented the most stringent challenge to transplant tolerance. Here, we demonstrate, in a clinically relevant miniature swine model, induction of immunologic tolerance of VCAs across MHC barriers by induction of stable hematopoietic mixed chimerism. Recipient conditioning consisted of T cell depletion with CD3-immunotoxin, and 100 cGy total body irradiation prior to hematopoietic cell transplantation (HCT) and a 45-day course of cyclosporine A. VCA transplantation was performed either simultaneously to induction of mixed chimerism or into established mixed chimeras 85–150 days later. Following withdrawal of immunosuppression both VCAs transplanted into stable chimeras (n =4), and those transplanted at the time of HCT (n =2) accepted all components, including skin, without evidence of rejection to the experimental end point 115–504 days posttransplant. These data demonstrate that tolerance across MHC mismatches can be induced in a clinically relevant VCA model, providing proof of concept for long-term immunosuppression-free survival.

Longitudinal immunological characterization of the first presensitized recipient of a face transplant

“…Despite our successful medium-term outcome in this case, we would advise caution in performing a transplant in a patient with a positive crossmatch at time of transplant. Strategies to reduce the rejection events after face transplantation are warranted, which may include tolerance protocols or the use of agents to promote immune regulation, such as low-dose IL-2 (37)(38)(39). A limitation of the present study is that our findings are derived from a single patient.…”

Reviewing immunosuppressive regimens in animal models for vascularized composite allotransplantation

“…No immunosuppression [66] Swine Mismatched donor to recipient MGH miniature swine Heterotopic Fasciocutaneous flap TBI 100 cGy and CD3-IT conditioning prior to 3 doses of HCT 15 × 10 9 cells/kg with CSA (target trough 400-800 ng/mL) for 45 days [67] Canine Beagles autotransplant Transferred to groin region…”

Systematic pathological component scores for skin-containing vascularized composite allografts

“…6 Animals were housed at the Transplantation Biology Research Center in accordance with the Guide for the Care and Use of Laboratory Animals. All experiments were conducted with the approval of the Institutional Animal Care and Use Committee of the MGH.…”

“…6 The treatment protocol for Group A animals included CD3-Immunotoxin 50ug/kg twice daily day -4 to -1, 100cGy TBI day -2, haematopoietic cell transplant (HCT) day 0-2 at 15 £ 10 9 cells/kg, followed by VCA on day 3. HCT was with cytokine mobilized pBMC collected from donors by leukapheresis after mobilization with pIL3 and pSCF injected IM at dose of 100ug/ kg to 30kg body weight, then 50ug/kg for each additional kg.…”