Abstract: Background/Aims: Interferon γ (IFNγ) controls hepatitis B virus replication. As systemic application may cause severe adverse effects, approaches of liver-directed IFNγ gene therapy may represent an attractive alternative for treatment of chronic viral hepatitis B and thus needs testing in vivo in suitable animal models.
Methods: We therefore crossbred Alb-1HBV transgenic mice overexpressing the large HBV surface protein (LHBs) in their livers and developing LHBs storage disease and ground glass hepatocyte appearance with SAP-IFNγ transgenic animals previously shown to exhibit constitutive hepatic IFNγ expression, and analyzed the resulting double-transgenic offspring.
Results: We found that IFNγ coexpression significantly reduced hepatic LHBs expression and thereby inhibited hepatocellular LHBs storage disease and ground glass hepatocyte appearance. The beneficial antiviral IFNγ effects as observed in Alb1-HBV SAP-IFNγ double-transgenic livers were associated with significantly elevated serum ALT concentrations, massive mononuclear cell infiltrates, appearance of Councilman bodies, and increased α-PARP (poly(ADP-ribose) polymerase cleavage).
Conclusions: Exacerbation of hepatic necroinflammation and increased hepatocellular apoptosis rate in IFNγ-expressing Alb1-HBV transgenic livers suggest that special precautions be taken for testing approaches of liver-specific IFNγ expression in patients with chronic hepatitis B.