title: Mechanisms of hyperacute rejection in porcine liver transplantation. Antibody-mediated endothelial injury.
abstract: Hyperacute rejection after OLT is an unusual event. We have demonstrated previously that hepatic hyperacute rejection can occur in the presence of high titers of donor-specific cytotoxic antibody. This study addresses the issues of antibody localization within the allograft and the consequences of antibody deposition and complement activation within the transplanted organ. A porcine model of liver transplantation was used and 3 experimental groups were studied. Group I recipients (n = 6) were specifically sensitized to their liver donors with skin grafts from their liver donors before hepatic grafting. Group II recipients (n = 6) underwent third-party skin graft sensitization before liver transplantation. Group III recipients (n = 6) underwent liver grafting without prior sensitization. After liver transplantation, serum complement (CH50) levels declined promptly in all groups; a statistically significant drop as compared with control animals was seen only in group I (P < 0.05). Liver biopsies from donor-specific sensitized recipients showed massive injury by light microscopy within 30 min of revascularization, demonstrating fibrinoid necrosis of vessels and neutrophil influx. On immunofluorescent examination, liver specimens from donor-specific sensitized animals showed intense IgG, IgM, and C3 deposition in the vessels of the portal triads. Antibody deposition was not seen in third-party sensitized animals or control animals. On electron microscopy, control animals and third-party sensitized animals showed minimal ultrastructural alterations. In comparison, livers from donor-specific sensitized animals showed severe microvascular injury with destruction of endothelial cells, edema, hemorrhage, and hepatocyte necrosis. In a passive serum transfer experiment carried out by infusing serum from a skin graft-sensitized pig directly into the portal vein of the skin graft donor, severe liver injury was evident, with identification of antibody deposition by light and electron microscopy and by immunofluorescence. These studies demonstrate that tissue injury in hyperacute hepatic rejection is mediated by antibody deposition within the grafted liver and is associated with systemic activation of the complement cascade.
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor 48109.
authors.forename: L M
authors.initials: LM
authors.lastname: Colletti
authors.forename: K J
authors.initials: KJ
authors.lastname: Johnson
authors.forename: R G
authors.initials: RG
authors.lastname: Kunkel
authors.forename: R M
authors.initials: RM
authors.lastname: Merion
mesh_terms: D000208:Acute Disease; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D003167:Complement Activation / Q000276:immunology; D003176:Complement C3 / Q000032:analysis; D015941:Complement Hemolytic Activity Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D008099:Liver / Q000276:immunology / Q000648:ultrastructure; D016031:Liver Transplantation / Q000276:immunology* / Q000473:pathology; D016038:Skin Transplantation / Q000276:immunology; D013552:Swine
chemical_list: D003176:Complement C3; D007074:Immunoglobulin G; D007075:Immunoglobulin M