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Article: The Current Role and Future Applications of Machine Perfusion in Liver Transplantation.

Staubli, Sebastian M / Ceresa, Carlo D L / Pollok, Joerg M

2023 Volume 10, Issue 5

Abstract: The relative paucity of donor livers suitable for transplantation has sparked innovations to preserve and recondition organs to expand the pool of transplantable organs. Currently, machine perfusion techniques have led to the improvement of the quality ... ...

Abstract	The relative paucity of donor livers suitable for transplantation has sparked innovations to preserve and recondition organs to expand the pool of transplantable organs. Currently, machine perfusion techniques have led to the improvement of the quality of marginal livers and to prolonged cold ischemia time and have allowed for the prediction of graft function through the analysis of the organ during perfusion, improving the rate of organ use. In the future, the implementation of organ modulation might expand the scope of machine perfusion beyond its current usage. The aim of this review was to provide an overview of the current clinical use of machine perfusion devices in liver transplantation and to provide a perspective for future clinical use, including therapeutic interventions in perfused donor liver grafts.
Language	English
Publishing date	2023-05-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2746191-9
ISSN	2306-5354
ISSN	2306-5354
DOI	10.3390/bioengineering10050593
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Article ; Online: Enhanced recovery for liver transplantation: recommendations from the 2022 International Liver Transplantation Society consensus conference.

Pollok, Joerg M / Tinguely, Pascale / Berenguer, Marina / Niemann, Claus U / Raptis, Dimitri A / Spiro, Michael

The lancet. Gastroenterology & hepatology

2022 Volume 8, Issue 1, Page(s) 81–94

Abstract: There is much controversy regarding enhanced recovery for recipients of liver transplants from deceased and living donors. The objectives of this Review were to summarise current knowledge on individual enhanced recovery elements on short-term outcomes, ... ...

Abstract	There is much controversy regarding enhanced recovery for recipients of liver transplants from deceased and living donors. The objectives of this Review were to summarise current knowledge on individual enhanced recovery elements on short-term outcomes, identify key components for comprehensive pathways, and create internationally accepted guidelines on enhanced recovery for liver-transplant recipients. The ERAS4OLT.org collaborative partnered by the International Liver Transplantation Society performed systematic literature reviews on the effect of 32 relevant enhanced perioperative recovery elements on short-term outcomes, and global specialists prepared expert statements on deceased and living donor liver transplantation. The Grading Recommendations, Assessment, Development and Evaluations approach was used for rating of quality of evidence and grading of recommendations. A virtual international consensus conference was held in January, 2022, in which results were presented, voted on by the audience, and discussed by an independent international jury of eight members, applying the Danish model of consensus. 273 liver transplantation specialists from 30 countries prepared expert statements on elements of enhanced recovery for liver transplantation based on the systematic literature reviews. The consensus conference yielded 80 final recommendations, covering aspects of enhanced recovery for preoperative assessment and optimisation, intraoperative surgical and anaesthetic conduct, and postoperative management for the recipients of liver transplants from both deceased and living donors, and for the living donor. The recommendations represent a comprehensive overview of the relevant elements and areas of enhanced recovery for liver transplantation. These internationally established guidelines could direct the development of enhanced recovery programmes worldwide, allowing adjustments according to local resources and practices.
MeSH term(s)	Humans ; Liver Transplantation/methods ; Living Donors ; Consensus
Language	English
Publishing date	2022-12-09
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ISSN	2468-1253
ISSN (online)	2468-1253
DOI	10.1016/S2468-1253(22)00268-0
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Article ; Online: Enhanced recovery after surgery programs improve short-term outcomes after liver transplantation-A systematic review and meta-analysis.

Tinguely, Pascale / Morare, Nolitha / Ramirez-Del Val, Alejandro / Berenguer, Marina / Niemann, Claus U / Pollok, Joerg M / Raptis, Dimitri A / Spiro, Michael

Clinical transplantation

2021 Volume 35, Issue 11, Page(s) e14453

Abstract: This systematic review aimed to investigate the available quality of evidence (QOE) of enhanced recovery after surgery (ERAS) for liver transplantation (LT) on short-term outcomes, grade recommendations, and identify relevant components for ERAS ... ...

Abstract	This systematic review aimed to investigate the available quality of evidence (QOE) of enhanced recovery after surgery (ERAS) for liver transplantation (LT) on short-term outcomes, grade recommendations, and identify relevant components for ERAS protocols. A systematic review and meta-analysis were conducted on short-term outcomes after LT when applying comprehensive ERAS protocols (> 1 ERAS component) versus control groups (CRD42021210374), following the GRADE approach for grading QOE and strength of recommendations. Endpoints were morbidity, mortality, length of stay, and readmission rates after ERAS for LT. Of 858 screened articles, two randomized controlled trials, two prospective, and one retrospective cohort studies were included (2002-2020). Frequent ERAS components were early extubation and postoperative antibiotic, fluid, and nutrition management. Overall complications were reduced in ERAS versus control cohorts (OR .4 (CI .2, .7), with no significant differences in mortality and hospital readmission rates. Intensive care unit and hospital length of stay were shorter in ERAS groups (percentage decrease, 55% and 29%, respectively). QOE for individual outcomes was rated moderate to low. ERAS protocols in LT are related to improved short-term outcomes after LT (QOE; Moderate to low \| Grade of Recommendation; Strong), but currently lack standardization.
MeSH term(s)	Enhanced Recovery After Surgery ; Humans ; Length of Stay ; Liver Transplantation ; Postoperative Complications ; Prospective Studies ; Retrospective Studies
Language	English
Publishing date	2021-09-16
Publishing country	Denmark
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	639001-8
ISSN	1399-0012 ; 0902-0063
ISSN (online)	1399-0012
ISSN	0902-0063
DOI	10.1111/ctr.14453
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Zs.A 2204: Show issues

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Article ; Online: Role of colectomy in preventing recurrent primary sclerosing cholangitis in liver transplant recipients.

Buchholz, Bettina M / Lykoudis, Panagis M / Ravikumar, Reena / Pollok, Joerg M / Fusai, Giuseppe K

World journal of gastroenterology

2018 Volume 24, Issue 28, Page(s) 3171–3180

Abstract: Aim: To study the published evidence on the impact of colectomy in preventing recurrent primary sclerosing cholangitis (rPSC).: Methods: An unrestricted systematic literature search in PubMed, EMBASE, Medline OvidSP, ISI Web of Science, Lista (EBSCO) ...

Abstract	Aim: To study the published evidence on the impact of colectomy in preventing recurrent primary sclerosing cholangitis (rPSC). Methods: An unrestricted systematic literature search in PubMed, EMBASE, Medline OvidSP, ISI Web of Science, Lista (EBSCO) and the Cochrane library was performed on clinical studies investigating colectomy in liver transplantation (LT) recipients with and without rPSC in the liver allograft. Study quality was evaluated according to a modification of the methodological index for non-randomized studies (MINORS) criteria. Primary endpoints were the impact of presence, timing and type of colectomy on rPSC. Overall presence of inflammatory bowel disease (IBD), time of IBD diagnosis, posttransplant IBD and immunosuppressive regimen were investigated as secondary outcome. Results: The literature search yielded a total of 180 publications. No randomized controlled trial was identified. Six retrospective studies met the inclusion criteria of which 5 studies were graded as high quality articles. Reporting of IBD was heterogenous but in four publications, either inflammatory bowel disease, ulcerative colitis or in particular active colitis post-LT significantly increased the risk of rPSC. The presence of an intact ( Conclusion: The data favours a protective role of pre-/peri-LT colectomy in rPSC but the current evidence is not strong enough to recommend routine colectomy for rPSC prevention.
MeSH term(s)	Cholangitis, Sclerosing/etiology ; Cholangitis, Sclerosing/pathology ; Cholangitis, Sclerosing/prevention & control ; Colectomy ; Colon/microbiology ; Cyclosporine/therapeutic use ; Dysbiosis/complications ; Dysbiosis/epidemiology ; Dysbiosis/microbiology ; Dysbiosis/surgery ; Gastrointestinal Microbiome ; Humans ; Immunosuppressive Agents/therapeutic use ; Inflammatory Bowel Diseases/complications ; Inflammatory Bowel Diseases/epidemiology ; Inflammatory Bowel Diseases/microbiology ; Inflammatory Bowel Diseases/surgery ; Liver Transplantation/adverse effects ; Perioperative Care/methods ; Risk Assessment ; Risk Factors ; Secondary Prevention/methods ; Tacrolimus/therapeutic use ; Treatment Outcome
Chemical Substances	Immunosuppressive Agents ; Cyclosporine (83HN0GTJ6D) ; Tacrolimus (WM0HAQ4WNM)
Language	English
Publishing date	2018-07-31
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2185929-2
ISSN	2219-2840 ; 1007-9327
ISSN (online)	2219-2840
ISSN	1007-9327
DOI	10.3748/wjg.v24.i28.3171
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Article ; Online: Pregnancy in Budd-Chiari Syndrome: Case Report and Proposed Risk Score.

Merz, Waltraut M / Rüland, Anna M / Hippe, Valeria / Poetzsch, Bernd / Meyer, Carsten / Pollok, Joerg M / Gembruch, Ulrich / Trebicka, Jonel

Medicine

2016 Volume 95, Issue 22, Page(s) e3817

Abstract: Due to its rarity, experience with pregnancy in Budd-Chiari syndrome (BCS) is limited. With the advent of new treatment modalities, transjugular intrahepatic portosystemic shunt in particular, numbers of affected women seeking pregnancy with BCS are ... ...

Abstract	Due to its rarity, experience with pregnancy in Budd-Chiari syndrome (BCS) is limited. With the advent of new treatment modalities, transjugular intrahepatic portosystemic shunt in particular, numbers of affected women seeking pregnancy with BCS are expected to rise. Here, we use a case that ended lethal within 2 years after delivery to discuss the effect of pregnancy on BCS and vice versa, and to highlight the necessity of a multidisciplinary teamwork. Additionally, a risk classification is proposed which may serve as a framework for preconception counseling and assist in the establishment and evaluation of treatment algorithms; its criteria need to be defined and assessed for their applicability in further studies.
MeSH term(s)	Adult ; Budd-Chiari Syndrome/physiopathology ; Budd-Chiari Syndrome/surgery ; Female ; Heparin, Low-Molecular-Weight/administration & dosage ; Humans ; Patient Care Team/organization & administration ; Portasystemic Shunt, Transjugular Intrahepatic/methods ; Pregnancy ; Risk Assessment ; Risk Factors
Chemical Substances	Heparin, Low-Molecular-Weight
Language	English
Publishing date	2016-06-03
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	80184-7
ISSN	1536-5964 ; 0025-7974
ISSN (online)	1536-5964
ISSN	0025-7974
DOI	10.1097/MD.0000000000003817
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Article ; Online: Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology.

Ceresa, Carlo D L / Nasralla, David / Watson, Christopher J E / Butler, Andrew J / Coussios, Constantin C / Crick, Keziah / Hodson, Leanne / Imber, Charles / Jassem, Wayel / Knight, Simon R / Mergental, Hynek / Ploeg, Rutger J / Pollok, Joerg M / Quaglia, Alberto / Shapiro, A M James / Weissenbacher, Annemarie / Friend, Peter J

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society

2019 Volume 25, Issue 10, Page(s) 1503–1513

Abstract: Clinical adoption of normothermic machine perfusion (NMP) may be facilitated by simplifying logistics and reducing costs. This can be achieved by cold storage of livers for transportation to recipient centers before commencing NMP. The purpose of this ... ...

Abstract	Clinical adoption of normothermic machine perfusion (NMP) may be facilitated by simplifying logistics and reducing costs. This can be achieved by cold storage of livers for transportation to recipient centers before commencing NMP. The purpose of this study was to assess the safety and feasibility of post-static cold storage normothermic machine perfusion (pSCS-NMP) in liver transplantation. In this multicenter prospective study, 31 livers were transplanted. The primary endpoint was 30-day graft survival. Secondary endpoints included the following: peak posttransplant aspartate aminotransferase (AST), early allograft dysfunction (EAD), postreperfusion syndrome (PRS), adverse events, critical care and hospital stay, biliary complications, and 12-month graft survival. The 30-day graft survival rate was 94%. Livers were preserved for a total of 14 hours 10 minutes ± 4 hours 46 minutes, which included 6 hours 1 minute ± 1 hour 19 minutes of static cold storage before 8 hours 24 minutes ± 4 hours 4 minutes of NMP. Median peak serum AST in the first 7 days postoperatively was 457 U/L (92-8669 U/L), and 4 (13%) patients developed EAD. PRS was observed in 3 (10%) livers. The median duration of initial critical care stay was 3 days (1-20 days), and median hospital stay was 13 days (7-31 days). There were 7 (23%) patients who developed complications of grade 3b severity or above, and 2 (6%) patients developed biliary complications: 1 bile leak and 1 anastomotic stricture with no cases of ischemic cholangiopathy. The 12-month overall graft survival rate (including death with a functioning graft) was 84%. In conclusion, this study demonstrates that pSCS-NMP was feasible and safe, which may facilitate clinical adoption.
MeSH term(s)	Adolescent ; Adult ; Aged ; Allografts/blood supply ; Cold Temperature ; End Stage Liver Disease/diagnosis ; End Stage Liver Disease/surgery ; Feasibility Studies ; Female ; Follow-Up Studies ; Graft Survival ; Humans ; Intensive Care Units/statistics & numerical data ; Length of Stay/statistics & numerical data ; Liver/blood supply ; Liver Transplantation/adverse effects ; Liver Transplantation/methods ; Male ; Middle Aged ; Organ Preservation/adverse effects ; Organ Preservation/methods ; Perfusion/adverse effects ; Perfusion/methods ; Postoperative Complications/epidemiology ; Postoperative Complications/etiology ; Prospective Studies ; Severity of Illness Index ; Time Factors ; Warm Ischemia/adverse effects ; Young Adult
Language	English
Publishing date	2019-07-18
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2006866-9
ISSN	1527-6473 ; 1527-6465
ISSN (online)	1527-6473
ISSN	1527-6465
DOI	10.1002/lt.25584
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Zs.A 4702: Show issues

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Article ; Online: Four-year allograft survival in a highly sensitized combined liver-kidney transplant patient despite unsuccessful anti-HLA antibody reduction with rituximab, splenectomy, and bortezomib.

Koch, Martina / Gräser, Christian / Lehnhardt, Anja / Pollok, Jörg M / Kröger, Nikolaus / Verboom, Murielle / Thaiss, Friedrich / Eiermann, Thomas / Nashan, Björn

Transplant international : official journal of the European Society for Organ Transplantation

2013 Volume 26, Issue 8, Page(s) e64–8

Abstract: Although donor-specific lymphocytotoxic antibodies are regarded as a contraindication for kidney transplantation (KTx), the data available for liver or combined liver or kidney transplantation (cLKTx) are scarce. Here, we report a case of a highly ... ...

Abstract	Although donor-specific lymphocytotoxic antibodies are regarded as a contraindication for kidney transplantation (KTx), the data available for liver or combined liver or kidney transplantation (cLKTx) are scarce. Here, we report a case of a highly sensitized young man receiving his sixth liver and second kidney graft. Multiple anti-HLA antibodies were present at the time of transplantation. As a result of suspected antibody-mediated graft damage, the patient was treated with rituximab, plasmapheresis, intravenous immunoglobulins, splenectomy, and bortezomib to decrease the antibody production. So far, patient and allograft survival has reached 4 years despite failure to achieve a permanent reduction of anti-HLA antibodies, and particularly nondonor directed antibodies.
MeSH term(s)	Adult ; Antibodies, Monoclonal, Murine-Derived/therapeutic use ; Boronic Acids/therapeutic use ; Bortezomib ; Graft Rejection/immunology ; Graft Survival ; HLA Antigens/immunology ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Kidney Transplantation/adverse effects ; Liver Transplantation/adverse effects ; Male ; Plasmapheresis ; Pyrazines/therapeutic use ; Rituximab ; Splenectomy
Chemical Substances	Antibodies, Monoclonal, Murine-Derived ; Boronic Acids ; HLA Antigens ; Immunoglobulins, Intravenous ; Pyrazines ; Rituximab (4F4X42SYQ6) ; Bortezomib (69G8BD63PP)
Language	English
Publishing date	2013-08
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	639435-8
ISSN	1432-2277 ; 0934-0874
ISSN (online)	1432-2277
ISSN	0934-0874
DOI	10.1111/tri.12120
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Zs.A 2358: Show issues

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Article ; Online: Strong antiviral activity of the new l-hydroxycytidine derivative, l-Hyd4FC, in HBV-infected human chimeric uPA/SCID mice.

Volz, Tassilo / Lütgehetmann, Marc / Allweiss, Lena / Warlich, Michael / Bierwolf, Jeanette / Pollok, Joerg M / Petersen, Joerg / Matthes, Eckart / Dandri, Maura

Antiviral therapy

2012 Volume 17, Issue 4, Page(s) 623–631

Abstract: Background: Suppression of viral replication with nucleoside/nucleotide inhibitors has been shown to greatly improve the outcome of chronic HBV infection. β-l-nucleoside analogues, especially β-l-deoxycytidine derivatives represent one of the most ... ...

Abstract	Background: Suppression of viral replication with nucleoside/nucleotide inhibitors has been shown to greatly improve the outcome of chronic HBV infection. β-l-nucleoside analogues, especially β-l-deoxycytidine derivatives represent one of the most efficient groups of antiretroviral compounds. We recently described that hydroxylation of the amino group of these β-l-deoxycytidine derivatives preserved their strong HBV inhibitory activity in vitro, but strongly reduced their cytotoxicity. From this new group of compounds we selected β-l-2',3'-didehydro-2',3'-dideoxy-N(4)-hydroxy-5-fluorocytidine (l-Hyd4FC) for a first in vivo investigation. The aim of this study was to determine the antiviral activity of l-Hyd4FC in HBV-infected human liver chimeric urokinase plasminogen activator (uPA)/SCID mice. Methods: Stably infected animals (median 6×10(7) HBV DNA/ml) were injected daily with either l-Hyd4FC (50 mg/kg) or saline as controls. Mice treated with lamivudine served to compare the in vivo antiviral potency of l-Hyd4FC. Virological changes were determined by quantitative PCR. Results: Treatment with l-Hyd4FC for 4 weeks induced a 2-log reduction of viraemia, while a median 1.5-log decline was achieved with lamivudine. Intrahepatically, l-Hyd4FC induced a median eightfold decline of viral activity (relaxed circular DNA/covalently closed circular DNA), and threefold reduction of pregenomic RNA/GAPDH levels. No significant decline of subgenomic HBV transcripts, as well as of circulating hepatitis B e antigen and hepatitis B surface antigen was detected. Maintenance of human serum albumin concentrations throughout the study, negative TUNEL staining and occurrence of viral rebound after drug withdrawal indicated that l-Hyd4FC was not toxic in human hepatocytes. Conclusions: Administration of l-Hyd4FC in uPA/SCID mice harbouring HBV-infected human hepatocytes demonstrated the high antiviral potency of this drug in vivo. Such characteristics make l-Hyd4FC a good candidate for further investigations a as potential HBV therapeutic agent.
MeSH term(s)	Animals ; Antiviral Agents/therapeutic use ; Chimera ; Cytidine/analogs & derivatives ; Cytidine/chemistry ; DNA, Viral ; Hepatitis B/drug therapy ; Humans ; Lamivudine/therapeutic use ; Mice ; Mice, SCID ; Molecular Structure ; Urokinase-Type Plasminogen Activator/genetics ; Viremia ; Zalcitabine/analogs & derivatives ; Zalcitabine/chemistry
Chemical Substances	2',3'-didehydro-2',3'-dideoxy-N4 -hydroxy-5-fluorocytidine ; Antiviral Agents ; DNA, Viral ; Lamivudine (2T8Q726O95) ; Cytidine (5CSZ8459RP) ; Zalcitabine (6L3XT8CB3I) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)
Language	English
Publishing date	2012
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1339842-8
ISSN	2040-2058 ; 1359-6535
ISSN (online)	2040-2058
ISSN	1359-6535
DOI	10.3851/IMP2075
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Zs.A 4877: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection.

Giersch, Katja / Allweiss, Lena / Volz, Tassilo / Helbig, Martina / Bierwolf, Jeanette / Lohse, Ansgar W / Pollok, Joerg M / Petersen, Joerg / Dandri, Maura / Lütgehetmann, Marc

Journal of hepatology

2015 Volume 63, Issue 2, Page(s) 346–353

Abstract: Background & aims: The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in ... ...

Abstract	Background & aims: The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in the setting of co-infection with hepatitis B virus (HBV) compared to HBV mono-infection using human liver chimeric mice. Methods: Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence. Results: Upon HBV/HDV inoculation, all mice developed viremia, which was accompanied by a significant induction of hISGs (i.e. hISG15, hSTATs, hHLA-E) compared to uninfected mice, while HBV mono-infection led to weaker hISG elevations. In the setting of chronic infection enhancement of innate defense mechanisms was significantly more prominent in HBV/HDV infected mice. Also the induction of human-specific cytokines (hIP10, hTGF-ß, hIFN-ß and hIFN-λ) was detected in HBV/HDV co-infected animals, while levels remained lower or below detection in uninfected and HBV mono-infected mice. Moreover, despite the average increase of hSTAT levels determined in HBV/HDV infected livers, we observed a weaker hSTAT accumulation in nuclei of hepatocytes displaying very high HDAg levels, suggesting that HDAg may in part limit hSTAT signaling. Conclusions: Establishment of HDV infection provoked a clear enhancement of the antiviral state of the human hepatocytes in chimeric mice. Elevated pre-treatment ISG and interferon levels may directly contribute to inflammation and liver damage, providing a rationale for the more severe course of HDV-associated liver disease. Such antiviral state induction might also contribute to the lower levels of HBV activity frequently found in co-infected hepatocytes.
MeSH term(s)	Animals ; Coinfection/immunology ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/complications ; Hepatitis B, Chronic/immunology ; Hepatitis B, Chronic/virology ; Hepatitis D, Chronic/complications ; Hepatitis D, Chronic/immunology ; Hepatitis D, Chronic/virology ; Hepatitis Delta Virus/genetics ; Hepatocytes/pathology ; Hepatocytes/virology ; Humans ; Immunity, Innate ; Mice ; Mice, SCID ; Real-Time Polymerase Chain Reaction ; Receptors, Cytokine/metabolism ; Viral Load
Chemical Substances	IP10-Mig receptor ; Receptors, Cytokine
Language	English
Publishing date	2015-08
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2015.03.011
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Zs.A 2027: Show issues

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Article ; Online: Hepatitis B virus limits response of human hepatocytes to interferon-α in chimeric mice.

Lütgehetmann, Marc / Bornscheuer, Till / Volz, Tassilo / Allweiss, Lena / Bockmann, Jan-Hendrick / Pollok, Joerg M / Lohse, Ansgar W / Petersen, Joerg / Dandri, Maura

Gastroenterology

2011 Volume 140, Issue 7, Page(s) 2074–83, 2083.e1–2

Abstract: Background & aims: Interferon (IFN)-α therapy is not effective for most patients with chronic hepatitis B virus (HBV) infection for reasons that are not clear. We investigated whether HBV infection reduced IFN-α-mediated induction of antiviral defense ... ...

Abstract	Background & aims: Interferon (IFN)-α therapy is not effective for most patients with chronic hepatitis B virus (HBV) infection for reasons that are not clear. We investigated whether HBV infection reduced IFN-α-mediated induction of antiviral defense mechanisms in human hepatocytes. Methods: Human hepatocytes were injected into severe combined immune-deficient mice (SCID/beige) that expressed transgenic urokinase plasminogen activator under control of the albumin promoter. Some mice were infected with HBV; infected and uninfected mice were given injections of human IFN-α. Changes in viral DNA and expression of human interferon-stimulated genes (ISGs) were measured by real-time polymerase chain reaction, using human-specific primers, and by immunohistochemistry. Results: Median HBV viremia (0.8log) and intrahepatic loads of HBV RNA decreased 3-fold by 8 or 12 hours after each injection of IFN-α, but increased within 24 hours. IFN-α activated expression of human ISGs and nuclear translocation of signal transducers and activators of transcription-1 (STAT1) in human hepatocytes that repopulated the livers of uninfected mice. Although baseline levels of human ISGs were slightly increased in HBV-infected mice, compared with uninfected mice, IFN-α failed to increase expression of the ISGs OAS-1, MxA, MyD88, and TAP-1 (which regulates antigen presentation) in HBV-infected mice. IFN-α did not induce nuclear translocation of STAT1 in HBV-infected human hepatocytes. Administration of the nucleoside analogue entecavir (for 20 days) suppressed HBV replication but did not restore responsiveness to IFN-α. Conclusions: HBV prevents induction of IFN-α signaling by inhibiting nuclear translocation of STAT1; this can interfere with transcription of ISGs in human hepatocytes. These effects of HBV might contribute to the limited effectiveness of endogenous and therapeutic IFN-α in patients and promote viral persistence.
MeSH term(s)	Active Transport, Cell Nucleus ; Albumins/genetics ; Animals ; Antiviral Agents/administration & dosage ; DNA, Viral/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Guanine/administration & dosage ; Guanine/analogs & derivatives ; Hepatitis B/diagnosis ; Hepatitis B/drug therapy ; Hepatitis B/genetics ; Hepatitis B virus/drug effects ; Hepatitis B virus/genetics ; Hepatitis B virus/growth & development ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Hepatocytes/transplantation ; Humans ; Immunohistochemistry ; Interferon-alpha/administration & dosage ; Liver/drug effects ; Liver/metabolism ; Liver/virology ; Mice ; Mice, SCID ; Mice, Transgenic ; Promoter Regions, Genetic ; RNA, Viral/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism ; Time Factors ; Transplantation Chimera ; Urokinase-Type Plasminogen Activator/genetics
Chemical Substances	Albumins ; Antiviral Agents ; DNA, Viral ; Interferon-alpha ; RNA, Viral ; STAT1 Transcription Factor ; STAT1 protein, human ; entecavir (5968Y6H45M) ; Guanine (5Z93L87A1R) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)
Language	English
Publishing date	2011-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2011.02.057
Database	MEDical Literature Analysis and Retrieval System OnLINE

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