IFNgamma expression inhibits LHBs storage disease and ground glass hepatocyte appearance, but exacerbates inflammation and apoptosis in HBV surface protein-accumulating transgenic livers.
OBJECTIVE
Interferon gamma (IFNgamma) controls hepatitis B virus replication. As systemic application may cause severe adverse effects, approaches of liver-directed IFNgamma 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-IFNgamma transgenic animals previously shown to exhibit constitutive hepatic IFNgamma expression, and analyzed the resulting double-transgenic offspring.


RESULTS
We found that IFNgamma coexpression significantly reduced hepatic LHBs expression and thereby inhibited hepatocellular LHBs storage disease and ground glass hepatocyte appearance. The beneficial antiviral IFNgamma effects as observed in Alb1-HBV SAP-IFNgamma double-transgenic livers were associated with significantly elevated serum ALT concentrations, massive mononuclear cell infiltrates, appearance of Councilman bodies, and increased alpha-PARP (poly(ADP-ribose) polymerase cleavage).


CONCLUSIONS
Exacerbation of hepatic necroinflammation and increased hepatocellular apoptosis rate in IFNgamma-expressing Alb1-HBV transgenic livers suggest that special precautions be taken for testing approaches of liver-specific IFNgamma expression in patients with chronic hepatitis B.
Reifenberg
Kurt
K
Central Laboratory Animal Facility, University of Mainz, Mainz, Germany. reifenbe@uni-mainz.de
Hildt
Eberhard
E
Lecher
Bernd
B
Wiese
Elena
E
Nusser
Petra
P
Ott
Sibylle
S
Yamamura
Ken-Ichi
K
Rutter
Gabriel
G
Löhler
Jürgen
J
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D006514:Hepatitis B Surface Antigens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D022781:Hepatocytes / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D006514:Hepatitis B Surface Antigens; D007371:Interferon-gamma