%0 Journal Article
%~ PubMed
%A Prakoso, Emilia
%A Jones, Ceridwen
%A Koorey, David James
%A Strasser, Simone Irene
%A Bowen, David
%A McCaughan, Geoffrey William
%A Shackel, Nicholas Adam
%T Terlipressin Therapy for Moderate to Severe Hyponatremia in Patients with Liver Failure.
%B Internal Medicine Journal
%D 2013
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 43
%N 3
%P 240-246
%@ 1445-5994
%X 
%Z FOR Codes: 110307


%0 Journal Article
%~ PubMed
%A Rahman, Wassim
%A Huang, Pauline
%A Belov, Larissa
%A Chrisp, Jeremy S
%A Christopherson, Richard I
%A Stapelberg, Peter M
%A Warner, Fiona J
%A George, Jacob
%A Bowen, David G
%A Strasser, Simone I
%A Koorey, David
%A Sharland, Alexandra F
%A McCaughan, Geoffrey W
%A Shackel, Nicholas A
%T Analysis of human liver disease using a cluster of differentiation (CD) antibody microarray.
%B Liver International
%D 2012
%C United States
%I Wiley-Blackwell Publishing, Inc.
%V 32
%N 10
%P 1527-1534
%@ 1478-3231
%X BACKGROUND: A CD antibody microarray has been previously developed allowing semi-quantitative identification of greater than 80 CD antigens on circulating leucocytes from peripheral blood samples. This assay, which uses a live cell-capture technique, enables an extensive leucocyte immunophenotype determination in a single analysis and to date this has been used successfully to characterise diseases including human leukaemias and HIV infection. AIMS: To determine CD antigen expression profiles for patients with various liver diseases and to look for preserved disease-specific signatures. METHODS: Three liver disease groups including hepatitis C (HCV) (n??=??35), non-alcoholic steatohepatitis (NASH) (n??=??21) and alcohol-related liver disease (n??=??14) were compared with a normal group (n??=??23). Hierarchal Clustering (HCL) and Principal Component Analysis (PCA) of the data revealed distinct binding patterns for patients with and without cirrhosis. RESULTS: Patients with cirrhosis and portal hypertension compared with those without cirrhosis had significantly reduced expression of several markers of T-cell function including CD45, CD8, CD28 and TCR ??/??. Disease prediction algorithms based on the expression data were able to discriminate cirrhotics from non-cirrhotics with 71% overall success, which improved to 77% when only patients with HCV were considered. CONCLUSIONS: These results demonstrate disease-specific consensus patterns of expression of CD antigens for patients with chronic liver disease, suggesting that the CD antibody array is a promising tool in the analysis of human liver disease, and with further refinement may have future research and clinical utility.
%Z FOR Codes: 110704 100402 110307


%0 Journal Article
%~ PubMed
%A Bowen, David G
%T Finding a role for Th17 cells in hepatitis C pathogenesis.
%B Journal of Gastroenterology and Hepatology
%D 2012
%C Australia, Japan, Hong Kong
%I Wiley-Blackwell Publishing Asia
%V 27
%N 2
%P 188-191
%@ 0815-9319
%X 
%Z FOR Codes: 110307 110309


%0 Book Section
%A Bowen, David
%T Immune Responses to HCV: Implications for Therapy
%B Advanced Therapy for Hepatitis C
%D 2012
%C United Kingdom
%I Blackwell Publishing Ltd
%V 
%N 
%P 17-24
%@ 9781405187459
%E McHutchison, John G.
%E Pawlotsky, Jean-Michel
%E McCaughan, Geoffrey
%X 
%Z FOR Codes: 110309


%0 Journal Article
%~ PubMed
%A Holz, Lauren E
%A Benseler, Volker
%A Vo, Michelle
%A McGuffog, Claire
%A Van Rooijen, Nico
%A McCaughan, Geoffrey W
%A Bowen, David G
%A Bertolino, Patrick
%T Naïve CD8 T cells activation by liver bone marrow-derived cells leads to a "neglected" IL-2(low) Bim(high) phenotype, poor CTL function and cell death.
%B Journal of Hepatology
%D 2012
%C Netherlands
%I Elsevier BV
%V 57
%N 4
%P 830-836
%@ 0168-8278
%X BACKGROUND AND AIMS: The occurrence of primary activation of CD8 T cells within the liver, unique among the non-lymphoid organs, is now well accepted. However, the outcome of intrahepatic T cell activation remains controversial. We have previously reported that activation initiated by hepatocytes results in a tolerogenic phenotype characterized by low expression of CD25 and IL-2, poor CTL function and excessive expression of the pro-apoptotic protein Bim. METHODS: To investigate whether this phenotype was due to activation in the absence of costimulation, we generated bone marrow (bm) radiation chimeras in which adoptively transferred na??ve transgenic CD8 T cells were activated in the presence of costimulation by liver bm-derived cells. RESULTS: Despite expressing pro-inflammatory cytokines, high levels of CD25 and CD54, donor T cells activated by liver bm derived cells did not produce detectable IL-2 and displayed poor CTL function, suggesting incomplete acquisition of effector function. Simultaneously these cells expressed high levels of Bim and died by neglect. Transfer of Bim-deficient T cells resulted in increased T cell numbers. CONCLUSIONS: These results imply that expression of CD25 and CD54 is costimulation dependant and distinguishes T cell activated by hepatocytes and liver bm-derived cells. In contrast, low expression of IL-2, poor CTL function and excess Bim production is a more universal phenotype defining T cells undergoing primary activation by both types of hepatic antigen presenting cells. These results have important implications for transplantation in which all liver antigen presenting cells contribute to activation of T cells specific for the allograft.
%Z FOR Codes: 110704 110307


%0 Journal Article
%~ PubMed
%A Alex Bishop, G
%A Bertolino, Patrick D
%A Bowen, David G
%A McCaughan, Geoffrey W
%T Tolerance in liver transplantation.
%B Best Practice & Research. Clinical Gastroenterology
%D 2012
%C United Kingdom
%I Bailliere Tindall
%V 26
%N 1
%P 73-84
%@ 1532-1916
%X Operational tolerance (OT) in liver transplant patients occurs much more frequently than OT of other transplanted organs; however the rate of OT varies considerably with the centre and patient population. Rates of OT range from 15% of the total liver transplant (LTX) patient population down to less than 5%. This review examines the reports of liver OT and compares the factors that could contribute to this variation. Multiple factors were examined, including the time from transplantation when weaning of immunosuppression (IS) was commenced, the rapidity of weaning, the contribution of maintenance and induction IS and the patient population transplanted. The approaches that might be used to increase the likelihood of OT are discussed and the approaches to monitoring OT in LTX patients are reviewed.
%Z FOR Codes: 110307 110708


%0 Journal Article
%~ PubMed
%A Barbier, Louise
%A Tay, Szun Szun
%A McGuffog, Claire
%A Triccas, James A
%A McCaughan, Geoffrey W
%A Bowen, David G
%A Bertolino, Patrick
%T Two lymph nodes draining the mouse liver are the preferential site of DC migration and T cell activation.
%B Journal of Hepatology
%D 2012
%C Netherlands
%I Elsevier BV
%V 57
%N 2
%P 352-358
%@ 0168-8278
%X BACKGROUND & AIMS: Lymph nodes (LNs) play a critical role in host defence against pathogens. In rodents, lymphatic anatomy and drainage have been characterized for many different organs. Surprisingly, the LNs draining the mouse liver have not been clearly identified. This knowledge is of central importance to allow accurate characterization of immune responses to pathogens infecting the liver. It is also important for exploring immune responses in hepatic tumor models, and mechanisms underlying the relative tolerogenic properties of the liver. In this study, we used both anatomical and immunological approaches to identify the LN(s) draining the mouse liver. METHODS: Evans Blue and purified dendritic cells were directly injected into the hepatic parenchyma. RESULTS: Using Evans Blue, we identified three LNs adjacent to the liver that stained with the dye within the first 5 minutes, which we termed portal, celiac, and first mesenteric LNs. We also provide evidence that dendritic cells (DCs) injected under the liver capsule preferentially migrate to the celiac and portal nodes, leading to local activation of antigen-specific naïve CD8 and CD4 T cells, suggesting this is a route of lymphatic drainage from the liver. Consistent with this result, cell-associated antigen injected under the liver capsule was also cross-presented to CD8 T cells in these nodes. CONCLUSIONS: These results suggest for the first time that the celiac and portal nodes are the main LNs draining the liver, and that DCs exiting the liver can elicit primary T cell activation within these lymph nodes; first mesenteric nodes play a secondary role. We propose this nomenclature to be used as common designations for the observed structures.
%Z FOR Codes: 110307 110704 110323


%0 Journal Article
%~ PubMed
%A Wood, Nicole A W
%A Linn, May La
%A Bowen, David G
%T Exhausted or just sleeping: Awakening virus-specific responses in chronic hepatitis C virus infection.
%B Hepatology
%D 2011
%C United States
%I John Wiley & Sons, Inc.
%V 54
%N 5
%P 1879-1882
%@ 1527-3350
%X 
%Z FOR Codes: 110704 110804


%0 Journal Article
%~ PubMed
%A Benseler, Volker
%A Warren, Alessandra
%A Vo, Michelle
%A Holz, Lauren E
%A Tay, Szun S
%A Le Couteur, David G
%A Breen, Eamon
%A Allison, Anthony C
%A van Rooijen, Nico
%A McGuffog, Claire
%A Schlitt, Hans J
%A Bowen, David G
%A McCaughan, Geoffrey W
%A Bertolino, Patrick
%T Hepatocyte entry leads to degradation of autoreactive CD8 T cells.
%B Proceedings of the National Academy of Sciences of the United States of America
%D 2011
%C United States
%I National Academy of Sciences
%V 108
%N 40
%P 16735-40
%@ 0027-8424
%X Although most self-reactive T cells are eliminated in the thymus, mechanisms to inactivate or control T cells specific for extrathymic antigens are required and exist in the periphery. By investigating the site in which autoreactive T cells are tolerized, we identify a unique mechanism of peripheral deletion in which na??ve autoreactive CD8 T cells are rapidly eliminated in the liver after intrahepatic activation. T cells actively invade hepatocytes, enter endosomal/lysosomal compartments, and are degraded. Blockade of this process leads to accumulation of autoreactive CD8 T cells in the liver and breach of tolerance, with the development of autoimmune hepatitis. Cell into cell invasion, or emperipolesis, is a long-observed phenomenon for which a physiological role has not been previously demonstrated. We propose that this "suicidal emperipolesis" is a unique mechanism of autoreactive T-cell deletion, a process critical for the maintenance of tolerance.
%Z FOR Codes: 110704 110703


%0 Journal Article
%~ PubMed
%A McCaughan, Geoffrey W
%A Shackel, Nicholas A
%A Bowen, David G
%T Liver transplantation and hepatitis C: will understanding the interleukin-28B polymorphisms improve outcomes?
%B Liver Transplantation
%D 2011
%C United States
%I John Wiley & Sons, Inc.
%V 17
%N 3
%P 219-221
%@ 1527-6473
%X 
%Z FOR Codes: 110307 110799


%0 Journal Article
%~ PubMed
%A McCaughan, Geoffrey W
%A Bowen, David G
%T Pathogenesis of cholestatic hepatitis C.
%B Journal of hepatology
%D 2011
%C Netherlands, Denmark
%I Elsevier BV
%V 54
%N 2
%P 392-4
%@ 0168-8278
%X 
%Z FOR Codes: 110307 110702 60502


%0 Journal Article
%~ PubMed
%A Benseler, Volker
%A Tay, Szun Szun
%A Bowen, David G
%A Bertolino, Patrick
%T Role of the hepatic parenchyma in liver transplant tolerance: a paradigm revisited.
%B Digestive Diseases
%D 2011
%C Switzerland
%I S. Karger AG
%V 29
%N 4
%P 391-401
%@ 1421-9875
%X Unlike other solid organs, liver transplants are spontaneously accepted in a wide range of animal models. In the clinic, transplanted livers also display privileged immunological properties allowing weaning of immunosuppression therapy in up to 20% of selected patients. To explain this phenomenon, many studies have focused on the role of donor-derived ''passenger'' leukocytes that are thought to induce antigen-specific tolerance by migrating from the graft into recipient secondary lymphoid tissues. Although convincing evidence exists that these cells are able to elicit antiallograft T cell hyporesponsiveness, several studies argue against an exclusive role for this cell population and even question whether it is critical in conferring donor MHC-specific tolerance. Instead, these studies suggest that the hepatic parenchyma plays a more critical role in this phenomenon. In this review we will reinterpret the results of old and more recent literature in light of recent advances in the field of liver immunology to explain the contribution of both passenger leukocytes and liver tissue in the liver tolerance effect.
%Z FOR Codes: 1107


%0 Journal Article
%~ PubMed
%A Wang, Chuanmin
%A Cordoba, Shaun
%A Hu, Min
%A Bertolino, Patrick
%A Bowen, David G
%A Sharland, Alexandra F
%A Allen, Richard D M
%A Alexander, Stephen I
%A McCaughan, Geoffrey W
%A Bishop, G Alex
%T Spontaneous acceptance of mouse kidney allografts is associated with increased Foxp3 expression and differences in the B and T cell compartments.
%B Transplant immunology
%D 2011
%C Netherlands
%I Elsevier BV
%V 24
%N 3
%P 149-56
%@ 1878-5492
%X Spontaneous acceptance of organ allografts can identify novel mechanisms of drug-free transplantation tolerance. Spontaneous acceptance occurs in both mouse kidney transplants and rat liver transplants however the early immune processes of mouse kidney acceptance have not been studied. Acceptance of C57BL/6 strain kidney allografts in fully MHC-incompatible B10.BR recipients was compared with rejection (REJ) of heart allografts in the same strain combination. Graft infiltrate and antibody deposition were examined by immunohistochemical staining. Expression of mRNA was measured by quantitative real-time PCR. Apoptosis was examined by TUNEL staining. The majority of kidney allografts were accepted long-term and induced tolerance (TOL) of donor-strain skin grafts, showing that acceptance was not due to immune ignorance. There was an extensive infiltrate of T cells in the TOL kidney that exceeded the level in REJ hearts but subsequently declined. The main differences were deposition of IgG2a antibody in REJ that was absent in TOL, more B cells infiltrating TOL kidneys and a progressive increase in the ratio of CD8:CD4 cells during rejection. There was also significantly greater Foxp3 mRNA expression in TOL. Kidneys from RAG-/- donors were accepted, showing that donor lymphocytes were not necessary for acceptance. Neutralising antibodies to TGF-?? administered from day 0 to day 6 did not prevent TOL. On the basis of cytokine expression and apoptosis there was no evidence for immune deviation or deletion as mechanisms of acceptance. In accord with the findings of spontaneous acceptance of liver allografts in rats, the main difference between mouse kidney TOL and heart REJ was in the B cell compartment. The major difference to rat liver allograft acceptance was that apoptosis of infiltrate did not appear to play a role. Instead, increased Foxp3 expression in TOL kidneys implies that regulatory T cells might be important.
%Z FOR Codes: 1103 1107


%0 Journal Article
%~ PubMed
%A Holz, Lauren E
%A Warren, Alessandra
%A Le Couteur, David G
%A Bowen, David G
%A Bertolino, Patrick
%T CD8+ T cell tolerance following antigen recognition on hepatocytes.
%B Journal of autoimmunity
%D 2010
%C United Kingdom
%I Academic Press
%V 34
%N 1
%P 15-22
%@ 1095-9157
%X Hepatocytes, the predominant cell type in the liver, are the main cell infected by the hepatitis C virus (HCV) and represent important targets for immune therapy. Although early studies suggested that this parenchymal cell expresses low levels of class I MHC molecules, hepatocytes are emerging as important players in intrahepatic immune responses. Not only do they express high levels of molecules important in antigen presentation, but their expression of these molecules in vivo is also polarized towards the lumen of the sinusoids, thus maximising the efficiency of T cell activation. Electron micrographs indicate that interactions between T cells and hepatocytes occur in vivo via fenestrations in the sinusoidal endothelial layer. In this article, we will review the data showing that hepatocytes function as antigen presenting cells in vivo, and explore the fate of T cells activated by this cell type. We propose that primary activation of na??ve CD8+ T cells by hepatocytes is a critical event occurring during the very early stages of a HCV infection, that contributes to progression to viral persistence via the removal of virus-specific T cells from the T cell repertoire.
%Z FOR Codes: 1107


%0 Journal Article
%~ PubMed
%A Holz, Lauren E
%A Bowen, David G
%A Bertolino, Patrick
%T Mechanisms of T cell death in the liver: to Bim or not to Bim?
%B Digestive Diseases
%D 2010
%C Switzerland
%I S. Karger AG
%V 28
%N 1
%P 14-24
%@ 1421-9875
%X Despite being a non-lymphoid organ, the liver displays immunological properties distinct from other solid organs and is associated with the induction of T cell tolerance. This property has been demonstrated in several clinical settings including transplantation and hepatotropic viral infections, such as those induced by hepatitis B and C viruses. Many models have been proposed to explain the ''liver tolerance effect'', but the molecular and cellular mechanism(s) mediating this phenomenon remain unknown. Using transgenic mouse models, we have previously shown that the liver is the only non-lymphoid organ able to retain and activate na??ve CD8+ T cells independently of lymphoid tissues in an antigen-specific manner. These findings, confirmed by other groups, have opened new possibilities to explain the remarkable capacity of the liver to induce antigen-specific tolerance in transplantation and following infection by hepatotropic viruses, such as the hepatitis C and B viruses. In our models, T cells activated by hepatocytes that proliferate die by neglect in a Bim-dependent manner. This paper will thus review the evidence showing Bim playing a critical role following intrahepatic primary T cell activation.
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Fuller, Michael J
%A Shoukry, Naglaa H
%A Gushima, Toshifumi
%A Bowen, David G
%A Callendret, Benoit
%A Campbell, Katherine J
%A Hasselschwert, Dana L
%A Hughes, Austin L
%A Walker, Christopher M
%T Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection.
%B Hepatology (Baltimore, Md.)
%D 2010
%C United States
%I John Wiley & Sons, Inc.
%V 51
%N 2
%P 378-87
%@ 1527-3350
%X Immune escape driven by selection pressure from virus-specific CD8 T cells has been demonstrated in both chimpanzees and humans infected with the hepatitis C virus (HCV). Although escape mutations have also been characterized in major histocompatibility complex (MHC) class II-restricted HCV epitopes, it is unknown whether selection-driven immune escape by CD4 T cell epitopes is a significant factor in the failure of these responses or contributes to persistent infection. To address this issue, evolution of MHC class I- and class II-restricted HCV epitopes was compared in four chimpanzees persistently infected with the virus for more than 10 years. We identified an amino acid change in a CD4 epitope of the HCV NS3 protein in one of the chimpanzees 3 years after infection. This mutation resulted in diminished activation, cytokine production (interferon-gamma and interleukin-2), and proliferation by an epitope-specific CD4 T cell line. We expanded our analysis to determine if mutations were common in multiple CD4 versus CD8 T cell epitopes in the four chronically infected animals. Whereas we observed mutations in over 75% of CD8 T cell epitopes analyzed in this study, only 18% of CD4 T cell epitopes analyzed showed amino acid changes. The frequency of changes in class II epitopes was not different from flanking regions, so CD4 T cells rarely exert selection pressure against the HCV genome. CONCLUSION: Apparent mutational escape can occur in MHC class II-restricted epitopes, but this is uncommon when compared with class I-restricted epitopes in the same individual. This indicates that other mechanisms for silencing CD4 T cells are dominant in persistent HCV infections.
%Z FOR Codes: 110704 110804


%0 Journal Article
%~ PubMed
%A Shackel, Nicholas A
%A Bowen, David G
%A McCaughan, Geoffrey W
%T Snipping away at hepatitis C.
%B Hepatology
%D 2010
%C United States
%I John Wiley & Sons, Inc.
%V 51
%N 2
%P 703-705
%@ 1527-3350
%X 
%Z FOR Codes: 110307 110804


%0 Journal Article
%~ PubMed
%A Bowen, David G
%T Toward small animal models for the study of human hepatitis viruses.
%B Hepatology (Baltimore, Md.)
%D 2010
%C United States
%I Wiley-Blackwell
%V 52
%N 1
%P 382-4
%@ 1527-3350
%X 
%Z FOR Codes: 110307 60506


%0 Journal Article
%~ PubMed
%A McCaughan, Geoffrey W
%A Shackel, Nicholas A
%A Bertolino, Patrick
%A Bowen, David G
%T Molecular and cellular aspects of hepatitis C virus reinfection after liver transplantation: how the early phase impacts on outcomes.
%B Transplantation
%D 2009
%C United States
%I Lippincott Williams & Wilkins
%V 87
%N 8
%P 1105-1111
%@ 0041-1337
%X Hepatitis C virus (HCV)-related liver disease postliver transplantation is associated with an accelerated course in comparison with that observed in the nonimmunosuppressed individual. Outcomes in transplantation for this indication have, therefore, been a major area of clinical interest in the field of liver transplantation. The factors underlying the rapid progression of HCV-related liver disease posttransplantation are complex and multifactorial. Nevertheless, recent data indicate a range of parameters assessable early posttransplantation that may be useful in the prediction of outcome of transplantation for this condition. This overview, therefore, concentrates on the early events occurring postliver transplantation in the HCV-infected patient, and the implications of these recent observations for the pathogenesis of the various forms of HCV-related allograft injury.
%Z FOR Codes: 110307 110708 60502


%0 Book Section
%A Bowen, David
%A Zekry, Amany
%A Bertolino, Patrick
%A Shackel, Nicholas
%A McCaughan, Geoffrey
%T Pathology and pathogenesis of hepatitis C
%B Hepatitis C: An Expanding Perspective
%D 2009
%C Australia
%I IP Communications
%V 
%N 
%P 43-75
%@ 9780980458657
%E Dore, Gregory
%E Temple-Smith, Meredith
%E Lloyd, Andrew
%X 
%Z FOR Codes: 110804 110399


%0 Journal Article
%~ PubMed
%A Velazquez, Victoria M
%A Bowen, David G
%A Walker, Christopher M
%T Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy.
%B Blood
%D 2009
%C United States
%I American Society of Hematology
%V 113
%N 3
%P 538-545
%@ 0006-4971
%X Recombinant adeno-associated virus (rAAV) vectors are considered promising for human gene replacement because they facilitate stable expression of therapeutic proteins in transduced tissues. Whether the success of gene therapy will be influenced by cellular immune responses targeting transgene-encoded proteins that are potentially immunogenic is unknown. Here we characterized CD8(+) T-cell activity against beta-galactosidase and enhanced green fluorescent protein, model antigens containing major histocompatibility complex (MHC) class I epitopes that are constitutively produced in murine skeletal muscle after rAAV vector transduction. Antigen-specific CD8(+) T cells were detected in the spleen and liver of mice within 7 days of muscle transduction. CD8(+) T-cell frequencies in these organs were stable, and effector functions were intact for months despite ongoing antigen production in muscle. CD8(+) T cells also infiltrated transduced muscle, where frequencies were at least 5-fold higher than in untransduced spleen and liver. Significantly, the majority of antigen-specific CD8(+) T cells in vector-transduced muscle were not functional. Loss of function in the muscle was associated with programmed death of the effector cells. Stable gene expression therefore depended on selective death of CD8(+) T cells at the site of antigen production, an effective mechanism for subverting immunity that is also potentially reversible.
%Z FOR Codes: 110704 100401


%0 Book Section
%A Bertolino, Patrick
%A McCaughan, Geoffrey
%A Bowen, David
%T Immunological Parameters Influencing Adaptive Immune Responses to the Hepatitis C Virus
%B Hepatitis C Virus Disease: Immunobiology and Clinical Applications
%D 2008
%C United States
%I Springer
%V 
%N 
%P 39-70
%@ 9780387713755
%E Jirillo, Emilio
%X 
%Z FOR Codes: 110704 110309


%0 Journal Article
%~ PubMed
%A Holz, Lauren E
%A Benseler, Volker
%A Bowen, David G
%A Bouillet, Philippe
%A Strasser, Andreas
%A O'Reilly, Lorraine
%A d'Avigdor, William
%A Bishop, Alex G
%A McCaughan, Geoffrey W
%A Bertolino, Patrick
%T Intrahepatic Murine CD8 T-Cell Activation Associates With a Distinct Phenotype Leading to Bim-Dependent Death.
%B Gastroenterology
%D 2008
%C INDEPENDENCE SQUARE
%I W B Saunders Co
%V 135
%N 3
%P 989-97
%@ 0016-5085
%X Chronic infections by hepatotropic viruses such as hepatitis B and C are generally associated with an impaired CD8 T-cell immune response that is unable to clear the virus. The liver is increasingly recognized as an alternative site in which primary activation of CD8 T cells takes place, a property that might explain its role in inducing tolerance. However, the molecular mechanism by which intrahepatically activated T cells become tolerant is unknown. Here, we investigated the phenotype and fate of na??ve CD8 T cells activated by hepatocytes in vivo.
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Ramalingam, Ramesh K
%A Meyer-Olson, Dirk
%A Shoukry, Naglaa H
%A Bowen, David G
%A Walker, Christopher M
%A Kalams, Spyros A
%T Kinetic analysis by real-time PCR of hepatitis C virus (HCV)-specific T cells in peripheral blood and liver after challenge with HCV.
%B Journal of Virology
%D 2008
%C United States
%I American Society for Microbiology
%V 82
%N 21
%P 10487-10492
%@ 1098-5514
%X Intrahepatic virus-specific CD8(+) T cells are thought to be important for the control of hepatitis C virus (HCV) infection, yet the precise kinetics for the expansion of epitope-specific T cells over the course of infection are difficult to determine with currently available methods. We used a real-time PCR assay to measure the frequency of clonotypic HCV-specific CD8(+) T cells in peripheral blood and snap-frozen liver biopsy specimens of two chimpanzees (Pan troglodytes) with previously resolved HCV infection who were rechallenged with HCV. In response to rechallenge, the magnitude of each clonotypic response was 10-fold higher in the liver than in the blood, and the peak clonotype frequency was concurrent with the peak viral load. The higher frequency of HCV-specific clonotypes in the liver than in peripheral blood was maintained for at least 3 months after the clearance of viremia. After antibody-mediated CD8(+) T-cell depletion and another viral challenge, the rebound of these clonotypes was seen prior to an appreciable reconstitution of CD8(+) T-cell values and, again, at higher frequencies in the liver than in peripheral blood. These data demonstrate the importance of intrahepatic virus-specific CD8(+) T cells for the clearance of infection and the rapid kinetics of expansion after virus challenge.
%Z FOR Codes: 110704 60506


%0 Journal Article
%~ PubMed
%A Holz, Lauren E
%A McCaughan, Geoffrey W
%A Benseler, Volker
%A Bertolino, Patrick
%A Bowen, David G
%T Liver tolerance and the manipulation of immune outcomes.
%B Inflammation & Allergy Drug Targets
%D 2008
%C Netherlands
%I Bentham Science Publishers Ltd
%V 7
%N 1
%P 6-18
%@ 1871-5281
%X In recent years it has become apparent that the liver holds a distinct immunological position. Previously described as a "graveyard" for T cells activated in the periphery, emerging evidence indicates that this organ may have a more active role in mediating tolerance. Attenuated immune responses in the liver can be beneficial in the transplantation setting, as liver transplants are more readily accepted than other organ allografts even in the absence of immunosuppressive drugs. However, the ability of the liver to induce immunological unresponsiveness could be exploited by some pathogens, such as the hepatitis C virus (HCV), to establish chronic infections with potentially fatal outcomes. Understanding the mechanisms controlling the balance between intrahepatic tolerance and immunity is critical in order to design new strategies to enhance acceptance of solid organ allografts and to promote efficient immune responses against HCV. In this article, we will review current knowledge of the mechanisms regulating intrahepatic immunity and discuss how these mechanisms might potentially be targeted to achieve advantageous clinical outcomes in transplantation and persistent hepatotropic infections.
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Bowen, David G
%T Of mice and molecular mimicry: Modeling autoimmune hepatitis.
%B Hepatology (Baltimore, Md.)
%D 2008
%C United States
%I John Wiley & Sons Inc.
%V 48
%N 3
%P 1013-5
%@ 0270-9139
%X 
%Z FOR Codes: 110703


%0 Journal Article
%~ PubMed
%A Bowen, David G
%A Shoukry, Naglaa H
%A Grakoui, Arash
%A Fuller, Michael J
%A Cawthon, Andrew G
%A Dong, Christine
%A Hasselschwert, Dana L
%A Brasky, Kathleen M
%A Freeman, Gordon J
%A Seth, Nilufer P
%A Wucherpfennig, Kai W
%A Houghton, Michael
%A Walker, Christopher M
%T Variable patterns of programmed death-1 expression on fully functional memory T cells after spontaneous resolution of hepatitis C virus infection.
%B Journal of Virology
%D 2008
%C United States
%I American Society for Microbiology
%V 82
%N 10
%P 5109-5114
%@ 0022-538X
%X The inhibitory receptor programmed death-1 (PD-1) is present on CD8(+) T cells in chronic hepatitis C virus (HCV), but expression patterns in spontaneously resolving infections are incompletely characterized. Here we report that PD-1 was usually absent on memory CD8(+) T cells from chimpanzees with resolved infections, but sustained low-level expression was sometimes observed in the absence of apparent virus replication. PD-1-positive memory T cells expanded and displayed antiviral activity upon reinfection with HCV, indicating conserved function. This animal model should facilitate studies of whether PD-1 differentially influences effector and memory T-cell function in resolved versus persistent human infections.
%Z FOR Codes: 110309


%0 Journal Article
%~ PubMed
%A Bertolino, Patrick
%A Bowen, David G
%A Benseler, Volker
%T T cells in the liver: there is life beyond the graveyard.
%B Hepatology (Baltimore, Md.)
%D 2007
%C United States
%I John Wiley & Sons Inc.
%V 45
%N 6
%P 1580-1582
%@ 0270-9139
%X Influenza A virus infection of C57BL/6 mice is a well-characterized model for studying CD8+ T cell-mediated immunity. Analysis of primary and secondary responses showed that the liver is highly enriched for CD8+ T cells specific for the immunodominant H2D(b)NP(366-374) (D(b)NP(366)) epitope. Functional analysis established that these liver-derived virus-specific CD8+ T cells are fully competent cytotoxic effectors and IFN-gamma secretors. In addition, flow cytometric analysis of early apoptotic cells showed that these influenza-specific CD8+ T cells from liver are as viable as those in the spleen, bronchoalveolar lavage, mediastinal lymph nodes, or lung. Moreover, cytokine profiles of the influenza-specific CD8+ T cells recovered from different sites were consistent with the bronchoalveolar lavage, rather than liver population, being the most susceptible to activation-induced cell death. Importantly, adoptively transferred influenza virus-specific CD8+ T cells from the liver survived and were readily recalled after virus challenge. Together, these results show clearly that the liver is not a "graveyard" for influenza virus-specific CD8+ T cells.
%Z FOR Codes: 110307


%0 Journal Article
%~ PubMed
%A Benseler, Volker
%A McCaughan, Geoffrey W
%A Schlitt, Hans J
%A Bishop, G Alex
%A Bowen, David G
%A Bertolino, Patrick
%T The liver: a special case in transplantation tolerance.
%B Seminars in liver disease
%D 2007
%C United States
%I Thieme Medical Publishers
%V 27
%N 2
%P 194-213
%@ 0272-8087
%X Liver transplants are not often rejected in patients weaned from immunosuppression and are spontaneously accepted in some animal models. We review past and recent findings of liver transplantation and propose a unified model in which several mechanisms act in concert to induce and maintain tolerance in both naïve and effector T cell compartments. First, passenger leukocytes migrate to lymphoid tissues and induce apoptosis of alloreactive naïve T cells. Second, antigen-specific activation and subsequent deletion of naïve and effector cells within the liver itself purge the repertoire of alloreactive T cells. Other mechanisms such as microchimerism and migration of donor dendritic cells to the thymus may play a predominant role in maintaining tolerance, and soluble major histocompatibility complex molecules, donor peptides, and regulatory T cells may participate in the induction and maintenance phases. Thus, the major challenge in liver transplantation will be to favor these tolerogenic processes while developing strategies that specifically inhibit alloreactive memory T cells.
%Z FOR Codes: 110703