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