7, 8 CTLs can kill target cells using two distinct lytic pathways: the degranulation pathway, in which perforin is used to puncture the membranes of infected cells, and the Fas-based pathway, in which the interaction between Fas ligand (FasL) expressed on cytolytic lymphocytes and Fas on target cells triggers apoptosis and target cell death.9 However, the role of innate immune cells, especially natural killer (NK) cells, in fulminant hepatitis remains obscure. NK cells have recently been reported to contribute to the pathogenesis of human hepatitis and animal models of liver

injury.10, 11 Replication of HBV is host cell dependent, and the study of cellular immune response in hepatitis B has long been hampered by the lack of TGF-beta inhibitor a small animal model that supports the replication of HBV and elimination of infected cells by immune response. Before the advent of human hepatocyte chimeric mice,12, 13 only chimpanzees had been used as a model for HBV infection and inflammation, although fulminant hepatitis B (FHB) had never been reported, and severe liver inflammation is rare in chimpanzees.14 We previously established an HBV-infection animal model using learn more chimeric mice, in which the livers were extensively repopulated

with human hepatocytes.15-17 In this study, we attempted to establish an animal model of HBV-infected human hepatocytes with human immunity by transplanting human peripheral mononuclear cells (PBMCs) to HBV-infected human hepatocyte chimeric mice. APC, allophycocyanin; asialo GM1, ganglio-N-tetraosylceramide; click here CD, cluster of differentiation; CHB, chronic hepatitis B; CTLs, cytotoxic T lymphocytes; DC, dendritic cell; FasL, Fas ligand; FHB, fulminant hepatitis B; HBcAg, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HLA, human leukocyte antigen; HSA, human serum albumin; IFN, interferon; IP, intraperitoneally; ISG, interferon-stimulated gene; mAb, monoclonal antibody; mDC, myeloid DC; mRNA, messenger RNA; NK, natural killer; PBMCs, peripheral blood mononuclear cells; PCR, polymerase chain reaction; pDC, plasmacytoid

DC; SCID, severe combined immunodeficiency; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; uPA, urokinase-type plasminogen activator. Generation of the urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficiency (SCID)+/+ mice and transplantation of human hepatocytes with human leukocyte antigen (HLA)-A0201 were performed as described previously.15, 16 All mice were transplanted with frozen human hepatocytes obtained from the same donor. Infection, extraction of serum samples, and euthanasia were performed under ether anesthesia. Concentration of human albumin, which is correlated with the repopulation index,15 was measured in mice as described previously.