A Transgenic Mouse Model of the Chronic Hepatitis B Surface Antigen Carrier State

Chisari, Francis V.; Pinkert, Carl A.; Milich, David R.; Filippi, P; McLachlan, Alan; Palmiter, Richard D.; Brinster, Ralph L.

doi:10.1126/science.3865369

Cited by 267 publications

(215 citation statements)

References 19 publications

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“…HBsAg transgenic mice C57BL/6J-TgN (AlblHBV) 44Bri (named as HBs-B6 mice in this study) were used, which express HBsAg in serum, liver and kidney tissues to mimic human healthy chronic HBsAg carriers [24,25]. Eight-to 10-week-old male HBs-B6 mice were obtained from VITALRIVER Experiment Animal Company (Beijing) which purchased them from Jackson Lab and bred them for us.…”

Section: Micementioning

confidence: 99%

“…In this study, hepatitis B surface antigen (HBsAg) transgenic mice, which mimic human healthy chronic HBsAg carriers [24,25], were triggered by a synthetic dsRNA analogue Poly(I:C), a ligand of toll-like receptor 3 (TLR3) and also a well-known potent activator for NK cells [13,14,26]. In our previous study, injection of Poly(I:C) could preferentially recruit and activate NK cells in liver and induce mild liver injury in wild mice [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Chen

Sun

Jiang

et al. 2007

Journal of Hepatology

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Background/Aims: The role of natural killer (NK) cells in the development of hepatitis B virus (HBV)-associated liver injury remains obscure. In this study, we elucidated the role of NK cells in liver injury of HBsAg transgenic mice (HBs-B6), a mimic of human healthy chronic HBsAg carriers, triggered by polyinosinic:polycytidylic acid [Poly(I:C)].Methods: HBs-B6 or wild B6 mice were intraperitoneally injected with Poly(I:C) at different doses. Liver injury was evaluated by serum transaminase activity and histopathologic changes.Results: HBs-B6 mice were over-sensitive to Poly(I:C)-induced liver injury, which was absolutely dependent on the presence of NK cells and IFN-c produced by intrahepatic NK cells. Much stronger IFN-c receptor expression was observed on hepatocytes of HBs-B6 mice, which was significantly enhanced by Poly(I:C) injection. Treatment with IFN-c in vitro triggered much higher activation of downstream signals (pSTAT1-IRF-1) in hepatocytes of HBs-B6 mice. Depletion of Kupffer cells and neutralization of endogenous IL-12 did not affect Poly(I:C)-induced over-sensitive liver injury in HBs-B6 mice.Conclusions: NK cells played a critical role in an IFN-c dependent, Kupffer cell-and IL-12-independent manner in oversensitive liver injury triggered by Poly(I:C) in murine chronic HBsAg carriers. Ó

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Section: Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Chen

Sun

Jiang

et al. 2007

Journal of Hepatology

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“…Because HBV does not infect such animals, we decided to produce HBV transgenic mice to achieve this objective. 43 Initially, we showed that mice that express HBV envelope proteins in their hepatocytes develop acute viral hepatitis after adoptive transfer of CD8-positive, MHC class I restricted, envelope (HBsAg)-specific CTL lines and clones. 44,45 Furthermore, we showed that the disease progresses through an orderly series of clearly definable steps.…”

Section: Ctl-induced Liver Disease In Hbv Transgenic Micementioning

confidence: 99%

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

Chisari

2000

The American Journal of Pathology

281

226

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“…[1][2][3][4][5] During the first months of life, the hepatic damage consists of degenerative alterations. 2 Later, an active inflammatory response commences that induces a marked damage-related compensatory proliferative reaction.…”

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confidence: 99%

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

Barone¹,

Maiorano

Ladisa³

et al. 2003

Hepatology

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Hepatitis B virus (HBV) transgenic mice (official designation, Tg [Alb-1 HBV] Bri 44) invariably develop macroscopically evident tumors within the 20th month of life. Sustained proliferative activity seems to play an important role in the development of these lesions. We previously showed that ursodeoxycholate (UDC) stimulates hepatocyte proliferation in various experimental settings. Herein, we tested the assumption that biological factors able to further increase liver cell proliferation, such as UDC, could accelerate tumor development in this animal model. For this study, 22 eight-week-old male transgenic mice were divided into 2 groups; 11 animals received a standard diet, and 11 received a UDC-enriched diet. The 2 groups were further divided into 2 subgroups of 5 and 6 animals each and were sacrificed at 3 and 15 months of age, respectively. These different times were chosen to exclude diet-related toxicity (in 3-month-old mice) and evaluate tumor growth (in 15-month-old mice). In addition, hepatocyte proliferation was assessed in all animals. In 3-month-old mice receiving UDC, cholestatic and cytolytic indices as well as liver histology were comparable to those in controls. At 15 months, all UDC-treated mice showed large multinodular tumors whereas only 33% of controls developed smaller uninodular neoplasms. Hepatocyte proliferation was increased in all animals receiving UDC compared with controls. In conclusion, the increase in serum UDC (undetectable in mice fed a standard diet), in the absence of any toxic effect on the liver, suggests the involvement of this bile salt in the stimulation of hepatocyte proliferation and tumor growth. (HEPATOLOGY 2003;37:880-886.) T ransgenic mice with hepatitis B virus (HBV) sequences encoding for viral proteins pre-S, S, and X (official designation, Tg [Alb-1 HBV] Bri 44) develop progressive hepatocyte damage due to intracellular accumulation of these proteins. 1-5 During the first months of life, the hepatic damage consists of degenerative alterations. 2 Later, an active inflammatory response commences that induces a marked damage-related compensatory proliferative reaction. 3,5 Such a condition should be considered precancerous because it is constantly followed after the 8th to 9th month of life by the development of dysplastic hepatic lesions 3,4 that progress to overt liver cancer after the 12th month of life. 3 The progressive growth of these neoplastic lesions leads to macroscopic nodules that are invariably observed in all transgenic mice within the 20th month of life. 4 Interestingly, these transgenic mice, harboring hepatocellular carcinomas, do not manifest any specific alteration of known oncogenes or tumor suppressor genes at any stage of neoplastic transformation. 6 It has therefore been suggested that the damage-related sustained proliferative activity observed in the liver of these animals could play an important role in tumor development. 5 We have already shown that bile salts can stimulate proliferation in cultured hepatocytes and augment the regene...

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A Transgenic Mouse Model of the Chronic Hepatitis B Surface Antigen Carrier State

Cited by 267 publications

References 19 publications

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

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