Novel Approaches To The Pathogenesis Of Chronic Hepatitis C Virus Associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated ....The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated. Our preliminary experiments indicated that one particular set of genes related to cell death is upregulated in HCV cirrhosis more than in other kinds of cirrhosis. We propose to pursue the diagnostic-prognostic potential of one of these molecules. Primarily this project will ask what kinds of genes are activated by HCV infection and at various stages of disease progression through to fibrosis and cirrhosis and following liver transplantation to better understand these processes. We believe that this research is likely to lead to a new understanding of hepatitis C associated liver disease that may lead to novel approaches to therapy.Read moreRead less
Understanding Rapid T-cell Clearance By The Liver: A Critical Step Towards Improved Liver Transplantation.
Funder
National Health and Medical Research Council
Funding Amount
$412,134.00
Summary
The liver has paradoxical properties: it is the site of effective immune responses to pathogens, but under some circumstances, it is known to induce harmless immune responses. Poor responses can be beneficial in a transplantation setting because, in the absence of immunosuppressive drugs, liver transplants are more readily accepted than other organ allografts. Not only are liver transplants well accepted, they can induce secondary acceptance of kidney or heart grafts from the same donor that wou ....The liver has paradoxical properties: it is the site of effective immune responses to pathogens, but under some circumstances, it is known to induce harmless immune responses. Poor responses can be beneficial in a transplantation setting because, in the absence of immunosuppressive drugs, liver transplants are more readily accepted than other organ allografts. Not only are liver transplants well accepted, they can induce secondary acceptance of kidney or heart grafts from the same donor that would otherwise be rejected. However, this ability of the liver to induce unresponsiveness may allow some viruses to persist, particularly , Hepatitis B and C. Four in every five patients infected with hepatitis C develop a chronic disease due to the inability of the immune system to clear the virus. Although it is known that white blood cells enter the liver and become unresponsive, little is known about the mechanisms that prevent an effective response. The CIA s work has been at the forefront of liver immunology and transplantation by demonstrating that the architecture and vasculature of the liver, and therefore the type of unique cellular interactions taking place within it, are essential to gain an understanding of its unique immunological properties. Using the CIB s unique protocols for solid-organ transplantation in rodents, we will provide evidence for a new mechanism that occurs at very early stages after antigen encounter in the liver. We propose to unravel this mechanism using well characterised transgenic mouse models and advanced analytical technology. We will determine the role of this mechanism in liver transplantation. Our preliminary data point to a very high chance of success. This project will have important implications for transplantation studies and for the development and treatment of food allergies and chronic hepatitis C and other of immune-mediated liver diseases.Read moreRead less
Role Of Hepatocytes In Inducing Primary CD8+ T Cell Activation And Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$159,662.00
Summary
It is well known that tolerance to liver allografts is more readily achieved than to other organ grafts, even across a major histocompatibility (MHC) barrier. According to some experiments, preferential tolerance to liver grafts may be due to development of chimerism involving the very large number of passenger leukocytes of donor hematopoietic origin present in an organ of this size. However, such a concept does not explain all the available data, particularly those relevant to CD8+ T cells, th ....It is well known that tolerance to liver allografts is more readily achieved than to other organ grafts, even across a major histocompatibility (MHC) barrier. According to some experiments, preferential tolerance to liver grafts may be due to development of chimerism involving the very large number of passenger leukocytes of donor hematopoietic origin present in an organ of this size. However, such a concept does not explain all the available data, particularly those relevant to CD8+ T cells, the primary effectors of graft rejection. Moreover, it does not take into account the fact that the liver possesses a unique fenestrated endothelium which is permeable to naive as well as activated T cells, nor the tolerogenic properties of hepatocytes themselves. Our recent experiments suggest that the liver is a site of primary activation for CD8 T cells and that a normal liver contains a significant number of self-reactive CD8+ T cells. The aim of this project is to determine whether activation of CD8+ T cells by hepatocytes contributes to the striking ability of liver grafts to be accepted and to induce tolerance in the CD8 T cell compartment. This would indicate that the liver plays an important role in peripheral tolerance of CD8+ T cells, providing the basis for novel therapies in transplantation and the treatment of autoimmune diseases. Moreover, this project also aims to generate a unique animal model of chronic liver inflammation in the absence of viral infection. Such a model is needed to study cirrhosis and hepatocarcinoma in the absence of potential oncogenes carried by viruses such as hepatitis B.Read moreRead less
Transgenic Mice : A Unique Model To Reassess Specific T Cell Suppression
Funder
National Health and Medical Research Council
Funding Amount
$272,545.00
Summary
Acceptance of transplanted organs is currently achieved by treating the recipient with immunosuppressive drugs that block T cell responses. However, because these drugs are non-specific, they will block all T cell responses, including those directed to undesirable viral or bacterial infections. So, whilst this strategy is the best available at the moment, it is far from ideal. The best treatment would be to induce specific graft acceptance without immunosuppression. In the 1970 s several studies ....Acceptance of transplanted organs is currently achieved by treating the recipient with immunosuppressive drugs that block T cell responses. However, because these drugs are non-specific, they will block all T cell responses, including those directed to undesirable viral or bacterial infections. So, whilst this strategy is the best available at the moment, it is far from ideal. The best treatment would be to induce specific graft acceptance without immunosuppression. In the 1970 s several studies have described treatment of recipients achieving specific suppression mediated by a subset of T lymphocytes. Although the phenomenon can be observed, no consensus has been reached to explain the mechanisms involved in the different models. One reason was the unability to track a population of suppressive T cells. We have now the technology and more knowledge to reassess these studies and understand how specific suppression can be achieved. Our lab has developed transgenic mice to study these phenomenon. One of our transgenic models mimicks the T cell response following liver transplantation. Acceptance of liver transplants is more readily achieved than to other organ grafts, even across a major histocompatibility (MHC) barrier and without immunosuppressive drugs. Not only are liver transplants well accepted, but they may induce secondary acceptance of kidney or heart grafts from the same donor, which would otherwise be rejected. Although this property has been made use of by surgeons, the amazing capacity of the liver to be accepted and to induce acceptance of other organs is still not understood. Previous studies and our own model suggests that specific suppression is involved. Our model which enable us to track the relevant cells provides therefore a unique tool to understand how specific suppression can be achieved. Understanding these mechanisms would help us to design strategies to induce tolerance to any organ without immunosuppressing the patient.Read moreRead less
MOLECULAR AND CELLULAR PATHOGENESIS OF HUMAN LIVER DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$4,928,323.00
Summary
n humans, chronic liver diseases cause cirrhosis of the liver in some but not all individuals. This leads to protracted ill-health, complications (fluid retention in the abdomen, confusion, bloodstream infections, kidney failure, liver cancer) resulting in hospitalisation, liver transplantation and premature death. In Australia, cirrhosis is an important cause of death and of years of potential life lost, while liver cancer has recently doubled and is predicted to treble by 2020. The common caus ....n humans, chronic liver diseases cause cirrhosis of the liver in some but not all individuals. This leads to protracted ill-health, complications (fluid retention in the abdomen, confusion, bloodstream infections, kidney failure, liver cancer) resulting in hospitalisation, liver transplantation and premature death. In Australia, cirrhosis is an important cause of death and of years of potential life lost, while liver cancer has recently doubled and is predicted to treble by 2020. The common causes are hepatitis C, fatty liver disorders, alcohol and hepatitis B; when 2 of these are present together, there is a higher risk of cirrhosis. This program aims to unravel the pathological processes which cause cirrhosis at the molecular and cellular levels, in order to understand why some people are at higher risk. These processes could result from genetic predisposition, other constitutional factors (age, gender) or from lifestyle factors (overnutrition, inactivity, alcohol). The 3 chief investigators from Westmead s Millennium Institute and the Centenary Institute of Royal Prince Alfred Hospital are international experts in hepatitis C, non-alcoholic steatohepatitis (NASH) and other fatty liver disorders, autoimmune hepatitis, liver transplantation, and scarring processes that lead to cirrhosis of the liver. The new knowledge that will result from these studies will be used to help prevent people developing severe forms of chronic liver disease, and for treating cirrhosis if it has already occurred.Read moreRead less
Implementing And Enhancing Evidence-based Research And Practice In Hepatology
Funder
National Health and Medical Research Council
Funding Amount
$569,219.00
Summary
The overall aim of this proposal is to tackle unmet challenges in liver disease research. This will be achieved through (a) Population level programs to deliver new treatments for patients with hepatitis C; (b) Developing integrated care models to treat hepatitis B; (c) Developing population-level programs for liver cancer control; and (d) Identification of patients at risk of severe liver disease through understanding the genetic basis of disease progression.
I am infectious disease physician undertaking research on natural history and therapeutic strategies in viral hepatitis, including acute hepatitis C, chronic hepatitis C and chronic hepatitis B. The hepatitis C therapeutic research has a particular focus
Host Determinants Of Hepatitis C-associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$610,376.00
Summary
Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat ....Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat (steatosis) in the liver. This results in the production of biochemical products that lead to tissue damage and to eventual destruction of the liver. Further evidence has recently emerged to suggest that the susceptibility to, and outcome of HCV infection may be influenced by genetic variation in the infected population. The chief investigators on this project have established the best characterised clinical cohort of HCV infected persons worldwide. Further, they have developed considerable expertise in the field of genetics, i.e. the analysis of genes that influence the host's response to an illness. Using this information and expertise, we propose in the present study to analyse in detail the host genetic factors that contribute to variations in the response to HCV, and its correlation with HCV-associated liver damage. This data could allow the development of better patient care strategies and the design of novel therapeutics.Read moreRead less
The Role Of CXCR3 Chemokines In Hepatitis C And Other Forms Of Viral Hepatitis
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 10-20 years. This liver disease is primarily a result of the host immune response to liver cells (hepatocytes) infected with HCV. As part of this immune response there in an increase in the number of immune cells that infiltrate the liver. To date we do not fully understand the mechanims that attract these cells to the liver but a class of molecules called chemokines is the ....The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 10-20 years. This liver disease is primarily a result of the host immune response to liver cells (hepatocytes) infected with HCV. As part of this immune response there in an increase in the number of immune cells that infiltrate the liver. To date we do not fully understand the mechanims that attract these cells to the liver but a class of molecules called chemokines is the most likely candidate. Thus a greater understanding of the chemokines expressed in the liver, their modulation and role in attracting immune cells to the liver in HCV-related liver disease will help us understand the basic mechanisms of liver disease with the possibility of development of novel therapeutic strategies. In pilot studies we have shown that the chemokine interferon-inducible T cell alpha chemoattractant (I-TAC) is significantly increased in the liver of persons infected with HCV. I-TAC is a member of the CXCR3 ligand chemokine family that attracts lymphocytes to sites of inflammation and as such may play an important role in hepatitis C. We have also shown that hepatocytes express I-TAC and that HCV can upregulate expression of I-TAC in a laboratory model of HCV replication. This proposal plans to determine the molecular mechanisms of I-TAC expression in response to HCV replication and to investigate if I-TAC expression is unique for hepatits C or a general feature of viral infections of the liver. We also plan to determine the the role of I-TAC and other CXCR3 ligand family members in a mouse model of viral hepatitis through the use of CXCR3 ligand antagonists. These experiments will enhance or knowledge of the role of the CXCR3 ligands in hepatitis C and viral hepatitis in general.Read moreRead less