title: Severe necroinflammatory reaction caused by natural killer cell-mediated Fas/Fas ligand interaction and dendritic cells in human hepatocyte chimeric mouse.
abstract: The necroinflammatory reaction plays a central role in hepatitis B virus (HBV) elimination. Cluster of differentiation (CD)8-positive cytotoxic T lymphocytes (CTLs) are thought to be a main player in the elimination of infected cells, and a recent report suggests that natural killer (NK) cells also play an important role. Here, we demonstrate the elimination of HBV-infected hepatocytes by NK cells and dendritic cells (DCs) using urokinase-type plasminogen activator/severe combined immunodeficiency mice, in which the livers were highly repopulated with human hepatocytes. After establishing HBV infection, we injected human peripheral blood mononuclear cells (PBMCs) into the mice and analyzed liver pathology and infiltrating human immune cells with flow cytometry. Severe hepatocyte degeneration was observed only in HBV-infected mice transplanted with human PBMCs. We provide the first direct evidence that massive liver cell death can be caused by Fas/Fas ligand (FasL) interaction provided by NK cells activated by DCs. Treatment of mice with anti-Fas antibody completely prevented severe hepatocyte degeneration. Furthermore, severe hepatocyte death can be prevented by depletion of DCs, whereas depletion of CD8-positive CTLs did not disturb the development of massive liver cell apoptosis.
  
  
  CONCLUSIONS
  Our findings provide the first direct evidence that DC-activated NK cells induce massive HBV-infected hepatocyte degeneration through the Fas/FasL system and may indicate new therapeutic implications for acute severe/fulminant hepatitis B.
authors.affiliation: Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Okazaki
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aikata
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.forename: Daiki
authors.initials: D
authors.lastname: Miki
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D017114:Liver Failure, Acute / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D012720:Severity of Illness Index; D018183:Transplantation Chimera; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D019014:fas Receptor