A mouse model for HBV immunotolerance and immunotherapy

Yang, Dan; Liu, Longchao; Zhu, Dongyun; Peng, Hua; Su, Lishan; Fu, Yang–Xin; Zhang, Liguo

doi:10.1038/cmi.2013.43

Cited by 114 publications

(126 citation statements)

References 29 publications

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“…However, low levels of cccDNA have been found in the livers of these animals after crossing them with hepatocyte nuclear factor 1 a-null mice, suggesting that the impairment of cccDNA synthesis in mouse hepatocytes is not absolute (Raney et al 2001). Alternative methods to deliver replication-competent HBV genomes to mouse hepatocytes, such as hydrodynamic injection of naked plasmid DNA and adenovirus-or adeno-associated virus (AAV)-mediated transfer, did not lead to detectable cccDNA formation, confirming the existence of a species restriction on the production of cccDNA (Sprinzl et al 2001;Yang et al 2002Yang et al , 2013Huang et al 2011;Dion et al 2013).…”

Section: Models Of Disease Acute Hepatitismentioning

confidence: 91%

“…On a final note, immuno-competent mouse models based on the use of recombinant AAV carrying replication-competent HBV genomes have been recently reported to display varying levels of hepatic HBV gene expression and replication, which are capable of persisting for many months (Huang et al 2011;Dion et al 2013;Yang et al 2013). In one study, the persistence of hepatic HBVexpression and replication did not cause liver inflammation and liver pathology because of the induction of regulatory T cells or other mechanisms of peripheral tolerance (Dion et al 2013).…”

Section: Chronic Hepatitismentioning

confidence: 99%

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Mouse Models of Hepatitis B Virus Pathogenesis

Iannacone

Guidotti

2015

Cold Spring Harb Perspect Med

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The host range of hepatitis B virus (HBV) is limited to humans and chimpanzees. As discussed in the literature, numerous studies in humans and chimpanzees have generated a great deal of information on the mechanisms that cause viral clearance, viral persistence, and disease pathogenesis during acute or chronic HBV infection. Relevant pathogenetic studies have also been performed in those few species representing natural hosts of hepadnaviruses that are related to HBV, such as the woodchuck hepatitis virus and the duck hepatitis virus. Further insight has been gained from multidisciplinary studies in transgenic or humanized chimeric mouse models expressing and/or replicating HBV to varying degrees. We provide here a concise summary of the available HBV mouse models as well as of the contributions of these models to our understanding of HBV pathogenesis.H BV replicates noncytopathically in the hepatocyte and most of the clinical syndromes associated with HBV infection reflect the immune response, particularly the adaptive immune response (see below). Studies on HBV immunobiology have been hampered by the restricted host range of this virus and by the lack of readily infectable small animal models with a well-defined immune system. Over the last two decades, however, many questions pertaining to the immune-mediated mechanisms responsible for disease pathogenesis and viral clearance have been successfully addressed in mouse models. The various mouse models used and the most significant findings that have emerged from such models are the subject of this review.

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Section: Models Of Disease Acute Hepatitismentioning

confidence: 91%

Section: Chronic Hepatitismentioning

confidence: 99%

Mouse Models of Hepatitis B Virus Pathogenesis

Iannacone

Guidotti

2015

Cold Spring Harb Perspect Med

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“…The liver is an immune tolerant organ with unique predisposition for chronic infections by certain clinically important pathogens (Fahey et al, 2014;Xu et al, 2014;Yang et al, 2014;Zheng et al, 2014). Both pathogenic and protective functions of NK cells in viral infections have been reported (Jost and Altfeld, 2013;Schuch et al, 2014), but it is unclear whether liver trNK cells and cNK cells play similar or distinct roles in anti-viral immune responses.…”

Section: Potential Roles Of Trnk Cells In Liver Diseasesmentioning

confidence: 99%

Tissue-resident natural killer cells in the livers

Peng

Tian

2016

Sci. China Life Sci.

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Nature killer (NK) cells are important lymphocytes of the innate immune system, well known for their pivotal roles in immune surveillance and defense against tumor and virus-infected cells. Current studies have revealed that NK cells are not a homogeneous population, but instead consist of distinct subsets with diverse characteristics. As an organ with predominant innate immunity, the liver is enriched with NK cells, among which two distinct NK cell subsets have recently been identified: conventional NK (cNK) cells and tissue-resident NK (trNK) cells. Liver trNK cells are markedly different from cNK cells in many aspects, representing a new lineage of innate lymphoid cell (ILC) family. Here, we summarize the phenotypic and functional features of liver trNK cells, and review current knowledge regarding developmental pathway of liver trNK cells. We also overview recent advances in human liver trNK cells and discuss the striking shared hallmarks of trNK cells in different tissues.

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“…All mice were housed under controlled temperature and light conditions following the Institutional Animal Care guidelines. The rAAV/HBV infection model was established following the previous protocol [14,16,17]. AAV/HBV viruses were provided by Beijing FivePlus Molecular Medicine Institute (Beijing, China).…”

Section: Mouse Hbv Infection Modelmentioning

confidence: 99%

Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection

Dai

Huang

Sun

et al. 2015

Journal of Leukocyte Biology

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Hepatitis B virus is a major cause of chronic liver inflammation worldwide. Innate and adaptive immune responses work together to restrain or eliminate hepatitis B virus in the liver. Compromised or failed adaptive immune response results in persistent virus replication and spread. How to promote antiviral immunity is a research focus for hepatitis B virus prevention and therapy. In this study, we investigated the role of macrophages in the regulation of antiviral immunity. We found that F4/80 + CD206 + CD80 lo/+ macrophages were a particular hepatic macrophage subset that expressed amphiregulin in our mouse hepatitis B virus infection model. CD206 + macrophage-derived amphiregulin promoted the immunosuppressive activity of intrahepatic regulatory T cells, demonstrated by higher expression of CTLA-4, ICOS, and CD39, as well as stronger inhibition of antiviral function of CD8 + T cells. Amphiregulin-neutralizing antibody diminished the effect of CD206 + macrophages on regulatory T cells. In addition, we found that CD206 + macrophage-derived amphiregulin activated mammalian target of rapamycin signaling in regulatory T cells, and this mammalian target of rapamycin activation was essential for promotion of regulatory T cell activity by CD206 + macrophages. Adoptive transfer of CD206 + macrophages into hepatitis B virusinfected mice increased cytoplasmic hepatitis B virus DNA in hepatocytes and also increased serum hepatitis B surface antigen. The antiviral activity of CD8 + T cells was decreased after macrophage transfer. Therefore, our research indicated that amphiregulin produced by CD206 + macrophages plays an important role in modulating regulatory T cell function and subsequently restrains the antiviral activity of CD8 + T cells. Our study offers new insights into the immunomodulation in hepatitis B virus infection.

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A mouse model for HBV immunotolerance and immunotherapy

Cited by 114 publications

References 29 publications

Mouse Models of Hepatitis B Virus Pathogenesis

Mouse Models of Hepatitis B Virus Pathogenesis

Tissue-resident natural killer cells in the livers

Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection

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