title: Pathogenesis and pathology of delayed xenograft rejection in pig-to-rhesus monkey cardiac transplantation.
abstract: It has been recognized that delayed xenograft rejection (DXR) is the major barrier to the acceptance of xenotransplantation after overcoming hyperacute rejection.
  
  
  OBJECTIVE
  This study sought to investigate the pathogenesis and pathology of delayed xenograft rejection following pig-to-rhesus monkey heart xenotransplantation.
  
  
  METHODS
  Heterotopic xenogeneic heart transplants in the abdominal cavity were performed using piglet donors to four monkey recipients. Complete complement depletion was achieved in the recipients with repetitive doses of high-activity cobra venom factor (Y-CVF). The recipients were immunosuppressed with a combination of cyclosporine, cyclophosphamide, and steroids. Sera were analyzed for C3 and C4 levels and complement activity and anti-pig endothelial xenoantibody. The grafts were examined histopathologically and immunohistochemically for C3, C4;C5b-9, IgM, IgG, tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule-1(ICAM-1), CD57(NK cells), CD68 (macrophages), CD4, and CD8.
  
  
  RESULTS
  Xenografts survived 8, 10, 13, and 13 days respectively, all developing DXR. Venous thrombosis was the outstanding feature within DXR xenografts, complicated by interstitial edema, local hemorrhage, myocardial necrosis, and mild to moderate cellular infiltration. The serum C3 levels and complement activity decreased to almost 0 from the day of transplantation due to treatment with Y-CVF. The C4 level began to decrease 2 to 4 days before the cardiac xenografts lost their function. Anti-pig endothelial xenoantibody also decreased after transplantation, slightly increasing during DXR. All rejected xenografts showed C3, C4, C5b-9, IgG, and IgM deposits to various degrees. Large numbers of macrophages (50% of total leukocytes) infiltrated the entire xenograft with a few natural killer cells (8% to 10%), as well as some CD4+ T cells (15%) and CD8+ T cells (25%). Upregulation of ICAM-1 on graft endothelial cells and TNF-alpha in the interstitium were also demonstrated in the rejected heart.
  
  
  CONCLUSIONS
  Both humoral and cell-mediated immunologic reactions may play important roles in the pathogenesis of DXR. Besides C3, C4, C5b-9, IgM, and IgG destroying the xenograft, NK cells, macrophages, and CD4+ and CD8+ T cells may further aggravate the development of DXR.
authors.affiliation: The Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Cao
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.forename: S
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000097:blood; D003165:Complement System Proteins / Q000032:analysis; D016207:Cytokines / Q000097:blood; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology / Q000502:physiology*; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008253:Macaca mulatta; D013552:Swine; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology / Q000502:physiology*; D020246:Venous Thrombosis / Q000209:etiology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D003165:Complement System Proteins