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
I am interested in determining the molecular basis of immune recognition of foreign and self-antigens in the context of viral, tumor and auto-immunity as well as transplantation. In addition to fundamental observations this knowledge is also applied in va
Regulation Of Leukocyte Trafficking By Macrophage Migration Inhibitory Factor (MIF).
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
The entry of white blood cells in to tissues is a primary event which drives tissue and organ damage in a number of inflammatory and immune mediated conditions. Diseases as diverse as rheumatoid arthritis, lupus or shock due to bacterial infection (septic shock) have many different triggers and manifestations. However almost all autoimmune and inflammatory diseases have one common feature: white blood cells must leave the blood and enter tissue in order to cause tissue inflammation and ultimatel ....The entry of white blood cells in to tissues is a primary event which drives tissue and organ damage in a number of inflammatory and immune mediated conditions. Diseases as diverse as rheumatoid arthritis, lupus or shock due to bacterial infection (septic shock) have many different triggers and manifestations. However almost all autoimmune and inflammatory diseases have one common feature: white blood cells must leave the blood and enter tissue in order to cause tissue inflammation and ultimately tissue damage and loss of function. The mechanism whereby white blood cells leave the blood stream and cross blood vessel walls to get into tissues is a multi-step process often referred to as white blood cell trafficking. Most of the current treatments for immune and inflammatory conditions have the primary aim of keeping white blood cells out of tissue in order to prevent damage. Some of these treatments, like steroids (cortisone), are very effective but cannot be used for prolonged periods because of the risk of problems like bone thinning (osteoporosis), high blood pressure or diabetes. Other treatments and immunosuppressive agents can also be effective but are themselves associated with toxicity and risk of organ damage. Although substantial progress has been made in the management of immune and inflammatory conditions in the last 50 years, the current treatment options are far from ideal. Macrophage migration inhibitory factor (MIF) is an inflammatory substance released by cells which comprise the blood vessel wall as well as by white blood cells themselves. It is known to contribute to the build up of white blood cells in inflamed tissue. The effect of MIF on white blood cell trafficking has never been examined. Understanding how MIF promotes white cell entry in to tissues could be crucial in our understanding of this important process and blocking MIF may prove to be a useful and effective way to prevent it.Read moreRead less
The Role Of Interferon Gamma And Nitric Oxide As Downregulating Molecules In Central Nervous System Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$526,644.00
Summary
Cytokines are soluble factors which participate in inflammatory responses. Interferon gamma is a cytokine which in the context of central nervous system inflammation has been considered a Obad? molecule, as has the gas nitric oxide which is induced by interferon gamma. We now have direct evidence that indicate quite the contrary, ie interferon gamma and nitric oxide can a do act as down regulators of inflammation. The present work is designed to determine if this down regulating function is rest ....Cytokines are soluble factors which participate in inflammatory responses. Interferon gamma is a cytokine which in the context of central nervous system inflammation has been considered a Obad? molecule, as has the gas nitric oxide which is induced by interferon gamma. We now have direct evidence that indicate quite the contrary, ie interferon gamma and nitric oxide can a do act as down regulators of inflammation. The present work is designed to determine if this down regulating function is restricted only to a single model of CNS inflammation or is a general phenomenon within the CNS. The project will also involve a number of experiments designed to elucidate the mechanism(s) by which down regulation occurs. This project is highly significant in that a single uncontrolled clinical trial of interferon gamma for the therapy of MS has been carried out and reported as indicating that interferon gamma made the disease worse. The design of that trial however was such that the validity of that claim is questionable. If our experiments confirm the general nature of interferon gamma as a down regulator in inflammation in a number of different models of MS then a case for revisiting the use of interferon, or a downstream product of interferon, in the therapy of MS might be made.Read moreRead less
Role Of Tetraspanins In Integrin Function And Leukocyte Migration
Funder
National Health and Medical Research Council
Funding Amount
$419,223.00
Summary
Cell migration is a very important component of the immune system. White blood cells, migrate from tissues to lymph nodes to initiate immune responses, and can migrate from blood to sites of inflammation to fight infection. This grant studies a type of protein called a tetraspanin that we believe controls white blood cell migration. Understanding the precise role of tetraspanins in this process will further our understanding of inflammation in disease processes.
Regulating Tolerogenic Signals By Inhibitory Co-receptors
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
Immunoreceptors play an important role in balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease and to provoke immunological memory to vaccination. We have discovered that Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a new immunoreceptor, that belongs to a very important family of proteins, the Ig-ITIM superfamily which is a subset of the immunoglobulin superfamily. We w ....Immunoreceptors play an important role in balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease and to provoke immunological memory to vaccination. We have discovered that Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a new immunoreceptor, that belongs to a very important family of proteins, the Ig-ITIM superfamily which is a subset of the immunoglobulin superfamily. We wish to determine if PECAM-1 functions as an inhibitory receptor in the lymphoid microenvironment using genetically engineered mice which lack the protein. As some of the functional features may display modest features, we plan to cross the PECAM-1 deficient mice with hen egg lysozyme transgenic mice to test the importance of PECAM-1 in peripheral tolerance. We will also define its importance in T cell function. We will test if the PECAM-1 deficient mice are more susceptible to the onset of inducible autoimmunde diseases including mouse models of collagen-induced arthritis and diabetes. Finally, we will produce transgenic mice expressing normal and disabled signaling motifs of PECAM-1 to test their requirement in autoimmunity.Read moreRead less
The Role Of PAC-1 In Leukocyte Activation And Inflammatory Responses
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
The MAP kinase pathway is fundamental for signalling a variety of cellular responses. This pathway is particularly important for immune responses ie. cytokine signalling, chemotaxis, and proliferation. PAC-1, a MAP kinase phosphatase, is an important regulator of this pathway. Extensive gene profiling of various immune cells using Affymetrix GeneChips identified PAC-1 as a highly regulated molecule in activated mast cells. Mast cells are important inflammatory cells, particularly for rheumatoid ....The MAP kinase pathway is fundamental for signalling a variety of cellular responses. This pathway is particularly important for immune responses ie. cytokine signalling, chemotaxis, and proliferation. PAC-1, a MAP kinase phosphatase, is an important regulator of this pathway. Extensive gene profiling of various immune cells using Affymetrix GeneChips identified PAC-1 as a highly regulated molecule in activated mast cells. Mast cells are important inflammatory cells, particularly for rheumatoid arthritis and asthma. We have shown that PAC-1 deficient mice are highly protected from inflammation and disease in a mouse model of rheumatoid arthritis. This grant aims to extend these exciting initial findings to other inflammatory diseases, particularly asthma and type 1 Diabetes, and to establish the basis for PAC-1 inhibition of disease. This research should establish PAC-1 as a new and important target for inflammatory disease, provide understanding on inflammatory processes, and possibly lead to improved therapies for diseases such as rheumatoid arthritis.Read moreRead less