title: Patterns of immune responses evoked by allogeneic hepatocytes: evidence for independent co-dominant roles for CD4+ and CD8+ T-cell responses in acute rejection.
abstract: BACKGROUND
  This is the first in a series of reports that characterizes immune responses evoked by allogeneic hepatocytes using a functional model of hepatocyte transplantation in mice.
  
  
  METHODS
  "Donor" hepatocytes expressing the transgene human alpha-1-antitrypsin (hA1AT-FVB/N, H2q) were transplanted into C57BL/6 (H2b) or MHC II knockout (H2b) hosts treated with anti-CD4, anti-CD8, or a combination of anti-CD4 and anti-CD8 monoclonal antibodies (mAbs). Hepatocyte rejection was determined as a loss of circulating ELISA-detectable transgene product (hA1AT). In addition, some C57BL/6 mice underwent transplantation with FVB/N heterotopic cardiac allografts and were treated with anti-CD4 mAb. Cardiac allograft rejection was determined by palpation. Graft recipients were tested for donor-reactive alloantibodies and donor-reactive delayed-type hypersensitivity (DTH) responses.
  
  
  RESULTS
  The median survival time (MST) of allogeneic hepatocytes in normal C57BL/6 mice was 10 days (no treatment), 10 days (anti-CD4 mAb), 14 days (anti-CD8 mAb), and 35 days (anti-CD4 and anti-CD8 mAbs). The MST of hepatocytes in B6 MHC class II knockout mice was 10 days (no treatment) and 21 days (anti-CD8 mAb). The MST of cardiac allografts was 11 days (no treatment) and >100 days (anti-CD4 mAb). Donor-reactive DTH responses were readily detected in both untreated and mAb-treated recipients. Donor-reactive alloantibody was barely detectable in untreated hosts.
  
  
  CONCLUSIONS
  These studies demonstrate that allogeneic hepatocytes are highly immunogenic and stimulate strong cell-mediated immune responses by both CD4+ and CD8+ T cells, even when treated with agents that can cause acceptance of cardiac allografts. Indeed, CD4+ or CD8+ T cells seem to independently cause hepatocellular allograft rejection. Allogeneic hepatocytes evoked strong donor-reactive DTH responses but were poor stimuli for donor-reactive antibody production. This is an unusual pattern of immune reactivity in allograft recipients.
authors.affiliation: Department of Surgery, The Ohio State University and Medical Center, Columbus 43210, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Bumgardner
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: J D
authors.initials: JD
authors.lastname: Prologo
authors.forename: M
authors.initials: M
authors.lastname: Heininger
authors.forename: C G
authors.initials: CG
authors.lastname: Orosz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000961:Antilymphocyte Serum / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000096:biosynthesis; D008099:Liver / Q000166:cytology* / Q000276:immunology*; D016031:Liver Transplantation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D008954:Models, Biological; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D007518:Isoantibodies