title: Critical role of effector macrophages in mediating CD4-dependent alloimmune injury of transplanted liver parenchymal cells.
abstract: Despite the recognition that humoral rejection is an important cause of allograft injury, the mechanism of Ab-mediated injury to allograft parenchyma is not well understood. We used a well-characterized murine hepatocellular allograft model to determine the mechanism of Ab-mediated destruction of transplanted liver parenchymal cells. In this model, allogeneic hepatocytes are transplanted into CD8-deficient hosts to focus on CD4-dependent, alloantibody-mediated rejection. Host serum alloantibody levels correlated with in vivo allospecific cytotoxic activity in CD8 knockout hepatocyte rejector mice. Host macrophage depletion, but not CD4(+) T cell, NK cell, neutrophil, or complement depletion, inhibited in vivo allocytotoxicity. Recipient macrophage deficiency delayed CD4-dependent hepatocyte rejection and inhibited in vivo allocytotoxicity without influencing alloantibody production. Furthermore, hepatocyte coincubation with alloantibody and macrophages resulted in Ab-dependent hepatocellular cytotoxicity in vitro. These studies are consistent with a paradigm of acute humoral rejection in which CD4(+) T cell-dependent alloantibody production results in the targeting of transplanted allogeneic parenchymal cells for macrophage-mediated cytotoxic immune damage. Consequently, strategies to eliminate recipient macrophages during CD4-dependent rejection pathway may prolong allograft survival.
authors.affiliation: Department of Surgery, Comprehensive Transplant Center, Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Phillip H
authors.initials: PH
authors.lastname: Horne
authors.forename: Jason M
authors.initials: JM
authors.lastname: Zimmerer
authors.forename: Mason G
authors.initials: MG
authors.lastname: Fisher
authors.forename: Keri E
authors.initials: KE
authors.lastname: Lunsford
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Nadasdy
authors.forename: Tibor
authors.initials: T
authors.lastname: Nadasdy
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Ginny L
authors.initials: GL
authors.lastname: Bumgardner
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007518:Isoantibodies / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D014184:Transplantation, Homologous
chemical_list: D007518:Isoantibodies