title: The Effect of MHC Antigen Matching Between Donors and Recipients on Skin Tolerance of Vascularized Composite Allografts.
abstract: The emergence of skin-containing vascularized composite allografts (VCAs) has provided impetus to understand factors affecting rejection and tolerance of skin. VCA tolerance can be established in miniature swine across haploidentical MHC barriers using mixed chimerism. Because the deceased donor pool for VCAs does not permit MHC antigen matching, clinical VCAs are transplanted across varying MHC disparities. We investigated whether sharing of MHC class I or II antigens between donors and recipients influences VCA skin tolerance. Miniature swine were conditioned nonmyeloablatively and received hematopoietic stem cell transplants and VCAs across MHC class I (n = 3) or class II (n = 3) barriers. In vitro immune responsiveness was assessed, and VCA skin-resident leukocytes were characterized by flow cytometry. Stable mixed chimerism was established in all animals. MHC class II-mismatched chimeras were tolerant of VCAs. MHC class I-mismatched animals, however, rejected VCA skin, characterized by infiltration of recipient-type CD8+lymphocytes. Systemic donor-specific nonresponsiveness was maintained, including after VCA rejection. This study shows that MHC antigen matching influences VCA skin rejection and suggests that local regulation of immune tolerance is critical in long-term acceptance of all VCA components. These results help elucidate novel mechanisms underlying skin tolerance and identify clinically relevant VCA tolerance strategies.
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.|Department of Plastic Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: K
authors.initials: K
authors.lastname: Shanmugarajah
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: H
authors.initials: H
authors.lastname: Powell
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.|Department of Plastic Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: D A
authors.initials: DA
authors.lastname: Leonard
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: C
authors.initials: C
authors.lastname: Mallard
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: A
authors.initials: A
authors.lastname: Albritton
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: E
authors.initials: E
authors.lastname: Harrington
authors.affiliation: Department of Plastic Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: M A
authors.initials: MA
authors.lastname: Randolph
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: E
authors.initials: E
authors.lastname: Farkash
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.|Department of Biology, Emmanuel College, Boston, MA.
authors.forename: J M
authors.initials: JM
authors.lastname: Kurtz
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.|Department of Plastic Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: C L
authors.initials: CL
authors.lastname: Cetrulo
mesh_terms: D000818:Animals; D064595:Composite Tissue Allografts / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D007518:Isoantibodies / Q000097:blood / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D016038:Skin Transplantation / Q000009:adverse effects*; D013552:Swine; D013556:Swine, Miniature; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D063986:Vascularized Composite Allotransplantation / Q000009:adverse effects*
chemical_list: D007518:Isoantibodies
keywords: animal models: porcine; basic (laboratory) research/science; histocompatibility; immunosuppression/immune modulation; immunosuppressive regimens; minimization/withdrawal; tolerance: chimerism; tolerance: experimental; translational research/science; vascularized composite and reconstructive transplantation