title: 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.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Department of Plastic and Reconstructive Surgery Research, University of Manchester, Manchester, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Leonard
authors.forename: J M
authors.initials: JM
authors.lastname: Kurtz
authors.forename: C
authors.initials: C
authors.lastname: Mallard
authors.forename: A
authors.initials: A
authors.lastname: Albritton
authors.forename: R
authors.initials: R
authors.lastname: Duran-Struuck
authors.forename: E A
authors.initials: EA
authors.lastname: Farkash
authors.forename: R
authors.initials: R
authors.lastname: Crepeau
authors.forename: A
authors.initials: A
authors.lastname: Matar
authors.forename: B M
authors.initials: BM
authors.lastname: Horner
authors.forename: M A
authors.initials: MA
authors.lastname: Randolph
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: C A
authors.initials: CA
authors.lastname: Huang
authors.forename: C L
authors.initials: CL
authors.lastname: Cetrulo
mesh_terms: D000818:Animals; D064595:Composite Tissue Allografts / Q000276:immunology* / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex / Q000276:immunology*; D013552:Swine; D013556:Swine, Miniature; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology; D063986:Vascularized Composite Allotransplantation
chemical_list: D007166:Immunosuppressive Agents
keywords: Miniature swine; mixed chimerism; skin transplant tolerance; vascularized composite allograft