Role Of The Novel G Protein-coupled Receptor EBI2 In B And T Cell Responses
Funder
National Health and Medical Research Council
Funding Amount
$304,815.00
Summary
The ability of the immune system to fight infections relies on the capacity of immune cells to traffic within immune organs in order to encounter invading pathogens and to interact with each other. Cells are guided in their migration by “homing receptors”, which recognize localization signals. This study aims at understanding the role of a novel member of this class of receptors, Epstein-Barr virus-induced gene 2 (EBI2), in the immune system and in protection against infectious microorganisms.
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
A Congenic Approach To Analysing The Genomic Control Of Innate Immunity In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$240,156.00
Summary
In addition to the lymphocytes, which are specialised white cells that can learn to defeat the infections that the body has been previously exposed, the body has a number of other defences. These non-learning systems have been honed by evolution and usually form an effective first-line of defence. This proposal deals with three: complement, and two highly specialised types of white blood cell, the Natural Killer cells and the NKT cells. The project will study mice especially bred to carry differ ....In addition to the lymphocytes, which are specialised white cells that can learn to defeat the infections that the body has been previously exposed, the body has a number of other defences. These non-learning systems have been honed by evolution and usually form an effective first-line of defence. This proposal deals with three: complement, and two highly specialised types of white blood cell, the Natural Killer cells and the NKT cells. The project will study mice especially bred to carry different versions of the genes which control these defences. Particular attention will be paid to their involvement in the autoimmune diseases, type 1 diabetes and lupus.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
Antigens, Allergens And Immune Responses In Normal And Crusted Scabies
Funder
National Health and Medical Research Council
Funding Amount
$302,036.00
Summary
Scabies (itch mite), a parasitic skin infestation of the mite Sarcoptes scabiei, is a major problem among most children in many Aboriginal communities in Australia, often accompanied by streptococcal infections which cause serious diseases. Our world-first molecular studies utilised variable microsatellite markers to demonstrate that scabies mites on people are genetically distinct from those on dogs. This has important implications in control programs in Aboriginal communities. In our current N ....Scabies (itch mite), a parasitic skin infestation of the mite Sarcoptes scabiei, is a major problem among most children in many Aboriginal communities in Australia, often accompanied by streptococcal infections which cause serious diseases. Our world-first molecular studies utilised variable microsatellite markers to demonstrate that scabies mites on people are genetically distinct from those on dogs. This has important implications in control programs in Aboriginal communities. In our current NHMRC program we have cloned scabies antigens, with the aim of understanding more about immunity, which normally limits infestation from developing to the extreme levels seen in the debilitating disease crusted scabies. Our hypothesis is that crusted scabies is the consequence of an immune deficit in these patients. The first such cloned antigen is the equivalent of a known asthma-inducing allergen from a closely related housedust mite. We seek support to continue this successful program and to extend it to search for candidate vaccine antigens.The development of a vaccine would be a step of major importance in prevention. Recent reports estimate up to 300 million scabies cases worldwide, commonly associated with overcrowding and poverty. We are the first laboratory worldwide to have successfully initiated molecular studies on scabies. We have formed close collaborations with the only laboratory with an animal model (Arlian, USA), and the best group working on epidemiology and control of human scabies (Taplin, USA) and co-published with these groups. It is imperative that our NHMRC support be continued and increased to a level compatible with the importance, potential and achievements so far of this unique program.Read moreRead less