title: Tolerance to composite tissue allografts across a major histocompatibility barrier in miniature swine.
abstract: BACKGROUND
  Tolerance to composite tissue allografts might allow the widespread clinical use of reconstructive allotransplantation if protocols to achieve this could be rendered sufficiently nontoxic. The authors investigated whether tolerance could be generated in miniature swine to composite tissue allografts across a major histocompatibility (MHC) barrier. A clinically relevant tolerance protocol involving hematopoietic cell transplantation without the need for irradiation or myelosuppressive drugs was tested.
  
  
  METHODS
  Seven recipient animals were transiently T-cell depleted and a short course of cyclosporine was initiated. Twenty-four hours later, a donor hematopoietic cell transplant consisting of cytokine-mobilized peripheral blood mononuclear cells or bone marrow cells and a heterotopic limb transplant were performed. In vitro anti-donor responsiveness was assessed by mixed-lymphocyte reaction and cell-mediated lympholysis assays. Acceptance of the limb allografts was determined by gross and histologic appearance. Chimerism in the peripheral blood and lymphohematopoietic organs was assessed by flow cytometry.
  
  
  RESULTS
  All seven experimental animals accepted the musculoskeletal elements but rejected the skin of the allografts. All but one of the animals displayed donor-specific unresponsiveness in vitro. The animals that received cytokine mobilized-peripheral blood mononuclear cells showed chimerism but had clinical evidence of graft-versus-host disease (GVHD). None of the animals that received bone marrow cells showed stable chimerism and none developed GVHD.
  
  
  CONCLUSIONS
  This protocol can achieve tolerance to the musculoskeletal elements of composite tissue allografts across an MHC barrier in miniature swine. Stable chimerism does not appear to be necessary for tolerance and may not be desirable because of the risk of GVHD.
authors.affiliation: Division of Plastic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. shehan_h@hotmail.com
authors.forename: Shehan
authors.initials: S
authors.lastname: Hettiaratchy
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Melendy
authors.forename: Mark A
authors.initials: MA
authors.lastname: Randolph
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Coburn
authors.forename: David M
authors.initials: DM
authors.lastname: Neville
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.forename: Christene A
authors.initials: CA
authors.lastname: Huang
authors.forename: W P Andrew
authors.initials: WP
authors.lastname: Lee
mesh_terms: D000818:Animals; D001787:Blood Group Incompatibility; D001842:Bone and Bones / Q000503:physiopathology; D006084:Graft Rejection; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000453:epidemiology; D018380:Hematopoietic Stem Cell Transplantation; D006614:Hindlimb / Q000503:physiopathology / Q000637:transplantation*; D015994:Incidence; D012867:Skin / Q000503:physiopathology; D013552:Swine; D013556:Swine, Miniature; D018183:Transplantation Chimera; D023001:Transplantation Tolerance