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
Polarized Epithelia And The Natural History Of Hepatitis Viruses
Funder
National Health and Medical Research Council
Funding Amount
$358,770.00
Summary
The viruses causing hepatitis in man must cross specialised cell layers in the body to reach the liver, and must again cross these cell layers and liver cells in order to be transmitted to subsequent hosts. This research will examine how each of the hepatitis viruses (HAV to HEV) are able to enter and exit the body, and the role that these mechanisms may play in the development of acute disease and of chronic infections with hepatitis B and C viruses. The findings will contribute to development ....The viruses causing hepatitis in man must cross specialised cell layers in the body to reach the liver, and must again cross these cell layers and liver cells in order to be transmitted to subsequent hosts. This research will examine how each of the hepatitis viruses (HAV to HEV) are able to enter and exit the body, and the role that these mechanisms may play in the development of acute disease and of chronic infections with hepatitis B and C viruses. The findings will contribute to development of improved methods for the prevention and control of viral hepatitis.Read moreRead less
I am an infectious diseases physician and basic scientist interested in the immunopathogenesis of HIV and hepatitis B virus. My work focuses on HIV viral reservoirs and immune reconstitution and the adaptive immune response to hepatitis B virus.
Hepatitis B is a leading cause of cirrhosis and liver cancer. Treatments for hepatitis B control the virus, but do not cure it, so people stay on treatment for many years. We have identified an exciting new treatment approach by targeting a gene that controls liver metabolism, called TM6SF2. We will target this gene to develop a cure for hepatitis B.
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
Protein Topogenesis And The Assembly/disassembly Of The Enveloped Hepatitis B Virus.
Funder
National Health and Medical Research Council
Funding Amount
$197,884.00
Summary
An estimated 350 million people worldwide, and 250,000 in Australia, are chronically infected with the hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current treatments are inadequate. A major obstacle to the study of this virus is the lack of a cell culture infection system. We have used the duck hepatitis B virus (DHBV) model to study the events leading up to assembly of the virus in ....An estimated 350 million people worldwide, and 250,000 in Australia, are chronically infected with the hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current treatments are inadequate. A major obstacle to the study of this virus is the lack of a cell culture infection system. We have used the duck hepatitis B virus (DHBV) model to study the events leading up to assembly of the virus in a way which prepares the viral envelope or outer coat for its foray into a new host cell. The project will examine the specific interactions of two proteins, the large and the small envelope protein, in addition to a third envelope protein we have recently discovered, which together make up the viral envelope. This will reveal which envelope components are required to make up the specific structures known to be essential for the disruption of the host cell membrane and subsequent entry of the virus to a new cell. An understanding of the changes that occur to the viral envelope upon entry will enable development of strategies for the inhibition or blocking of this change, thus identifying targets for the development of new antiviral agents. Because HBV is just one of many viruses which have an envelope, all of which must enter the cell in some way, our studies of HBV will also provide new clues with respect to the replication of other viruses such as measles, influenza and HIV. A related part of the study will examine the orientation of the large envelope protein within the virus particle and how it changes its orientation to assume its many important functional roles, in the late stages of particle assembly. Expanding on our finding that the small protein is essential to the orientation of the large protein, this study will reveal the mechanism of a unique method of protein transport which may have wider implications in cell biology.Read moreRead less
A New Insight Into Hepatitis B Infection:the HBV Fusion Peptide
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Three hundred and fifty million people worldwide and 250,000 in Australia are chronically infected with hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current therapies are inadequate. New antiviral treatments requiring the identification of new antiviral targets are needed to combat the disease but a major obstacle to the study of HBV is the lack of a cell culture system. As a result n ....Three hundred and fifty million people worldwide and 250,000 in Australia are chronically infected with hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through cirrhosis, liver failure and liver cancer, but current therapies are inadequate. New antiviral treatments requiring the identification of new antiviral targets are needed to combat the disease but a major obstacle to the study of HBV is the lack of a cell culture system. As a result nothing is known about how HBV enter and fuses with the host liver cell but we have made significant progress with the identification of the entry and fusion events of the related duck hepatitis B virus, using the duck infection model. This knowledge is now ready for application to the medically important HBV by use of primary human liver cells and the techniques developed in the duck hepatitis B virus model.Read moreRead less