Using Single-cell Genomics To Resolve Functional Diversification By CD4+ T Cells In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$1,048,096.00
Summary
During immune responses, individual CD4+ T cells multiply and produce hundreds of descendants, with close relatives within a family often developing very different skills. How such differences emerge from one ancestor remains unclear. We use new methods to look at individual CD4+ T cells in unprecedented detail, allowing us to see how close relatives begin to grow apart. Using this, we hope to find novel ways of educating CD4+ T cells to prevent infectious and immune-mediated diseases.
Identification Of Mechanisms By Which Mesenchymal Stromal Cells Ameliorate Renal Ischaemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$104,985.00
Summary
Acute kidney injury (AKI) is a common clinical entity which is associated with an increased risk of death and chronic kidney disease. Infusing adult mesenchymal stromal cells (cells which usually reside in the bone marrow but migrate to sites of inflammation or injury) has been shown to be beneficial in animal models of AKI, but it is not known how they have this effect. This project is designed to investigate the mechanism of action of mesenchymal stromal cells in AKI.
The Role Of IL-18 In Proliferative And Crescentic Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$56,177.00
Summary
Inflammation of the small filters with the kidneys, known as glomerulonephritis, is the commonest cause of kidney failure in Australia. People whose kidneys have failed need either kidney dialysis or a kidney transplant. Our understanding of the immune events that cause glomerulonephritis is patchy. However, it is known that T cells are the directors of immune responses in the body and direct the immune response in glomerulonephritis. Chemical messengers known as cytokines direct the way T cells ....Inflammation of the small filters with the kidneys, known as glomerulonephritis, is the commonest cause of kidney failure in Australia. People whose kidneys have failed need either kidney dialysis or a kidney transplant. Our understanding of the immune events that cause glomerulonephritis is patchy. However, it is known that T cells are the directors of immune responses in the body and direct the immune response in glomerulonephritis. Chemical messengers known as cytokines direct the way T cells behave. One of these cytokines, known as interleukin-18, has been shown to stimulate T cells and other immune cells to induce inflammation that is helpful when the body is fighting infection but is harmful in immune diseases. This project will determine the role of interleukin-18 in glomerulonephritis by studying the way it talks to T cells and the mechanisms by which it incites inflammation in the kidney. Mice with glomerulonephritis will be treated by blocking the actions of interleukin-18 to discover whether interleukin-18 produced by the animal is important in kidney damage induced by glomerulonephritis, to understand the way in which this cytokine works and to assess whether blocking interleukin-18 could be a useful treatment for glomerulonephritis in humans. Current treatments for glomerulonephritis are often ineffective and have unwanted side effects. Knowledge of the way interleukin-18 participates in the immune response in glomerulonephritis may lead directly or indirectly to more effective and more targeted treatments for different forms of glomerulonephritis.Read moreRead less
The Study Of T Cell Differentiation And Function Using DNA Microarrays
Funder
National Health and Medical Research Council
Funding Amount
$155,665.00
Summary
The immune system uses specialized cells to combat various infectious agents, such as viruses or large parasites. The immune system remembers such pathogens, and is able to mount an enhanced and more rapid response upon secondary encounter. This property, termed immunological memory, is the basis of vaccination. Sometimes the normal functioning of the immune system goes awry, producing allergic disease (such as asthma) or autoimmune diseases (such as Multiple sclerosis and possibly rheumatoid ar ....The immune system uses specialized cells to combat various infectious agents, such as viruses or large parasites. The immune system remembers such pathogens, and is able to mount an enhanced and more rapid response upon secondary encounter. This property, termed immunological memory, is the basis of vaccination. Sometimes the normal functioning of the immune system goes awry, producing allergic disease (such as asthma) or autoimmune diseases (such as Multiple sclerosis and possibly rheumatoid arthritis). The nature of the cells that mediate immunological memory, or the processes that lead to inflammatory disease are poorly understood. A new approach towards understanding the function and inter-relationships of T cells is to use genomics techniques, that enable tens of thousands of genes to be assessed for their expression in different cells or tissues. An understanding of which genes are inappropriately turned on in different disease states should provide new understanding of disease process, and new targets for pharmaceutical intervention. We will systematically assess gene expression in various subsets of T cells, which have known functions. For instance Th1 cells have been implicated in the pathogenesis of autoimmune disease, and Th2 cells in the pathogenesis of asthma. How these cells regulate gene expression during their differentiation, and use their newly expressed genes for their specific functions is one aim of this study. Another important subdivision of the immune system is between skin homing and gut homing T cells. Gut homing T cells are thought to mediate protection in the gut against gut pathogens, but also to cause diseases such as inflammatory bowel disease (Ulcerative colitis, Crohn's disease). Finally, understanding which cells harbour immunological memory, and how this might be manipulated to improve immune resposes, is of great importance for vaccination programs.Read moreRead less
Glomerulonephritis (Bright's Disease) is the commonest cause of destruction of kidney function that leads to patients requiring artificial kidney treatment (dialysis) and renal transplantation. The glomeruli or filters of the kidney are attacked by inflammation and destroyed. The attack is usually auto-immune, that is the bodys' immune system loses tolerance to kidney tissue and mounts a destructive attack on the glomeruli. In many patients, this attack is mild and resolves with current treatmen ....Glomerulonephritis (Bright's Disease) is the commonest cause of destruction of kidney function that leads to patients requiring artificial kidney treatment (dialysis) and renal transplantation. The glomeruli or filters of the kidney are attacked by inflammation and destroyed. The attack is usually auto-immune, that is the bodys' immune system loses tolerance to kidney tissue and mounts a destructive attack on the glomeruli. In many patients, this attack is mild and resolves with current treatments to dampen the immune response. In others, current treatment is inadequate to dampen the attack and the kidney is destroyed. This research uses experimental models of nephritis to examine how the immune system injures the glomeruli. In particular, how T cells attack and mediate injury. This is a novel concept, as hither to it has been thought antibodies and other factors in the blood (complement) mediate injury. Our group was one of the first to identify T cells mediate injury in forms of glomerulonephritis, previously thought to be solely mediated by antibody and complement. This project will further define which molecules produced by the T cell effect injury of glomeruli. With the potential aim of turning off the T cell attack mechanisms in a more specific way than is achieved by non specific immunosuppressive drugs such as corticosteroids, cytotoxic (anti-cancer) drugs or cyclosporine (an anti-rejection drug). A major part of this project will be to examine the role of cytokines, hormone like molecules that are produced by white cells and mediate injury or regulate other white cells, in effecting injury and in turning off the immune injury.Read moreRead less
Recruitment And Activation Of Alternatively Activated Macrophages By Thioredoxin Peroxidases In Helminth Infections
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
This research will unlock the immunological steps that lead to the development of pathological consequences associated with infectious pathogens and human diseases. The investigation proposed is very timely, as there is a rapid growth in people acquiring infectious diseases in the developing world and inflammatory pathologies in the developed world such as artherosclerosis, asthma, and tumour progression. There is a common denominator between all of these diseases. The body loses its ability to ....This research will unlock the immunological steps that lead to the development of pathological consequences associated with infectious pathogens and human diseases. The investigation proposed is very timely, as there is a rapid growth in people acquiring infectious diseases in the developing world and inflammatory pathologies in the developed world such as artherosclerosis, asthma, and tumour progression. There is a common denominator between all of these diseases. The body loses its ability to regulate a particular type of immune response, termed Th2. This results in the production of a chronic inflammation, which causes lasting damage. We have previously pinpointed the activity of a particular type of white blood cell, the macrophage, as pivotal to the induction of the Th2 immune response. We have also identified a molecule, thioredoxin peroxidase (TPx) that triggers the macrophage to switch on Th2 responses. Once the TPx comes into contact with the surface of the macrophage cell, a series of proteins, called transcription factors become activated in a controlled cascade. This leads to the secretion of substances from the macrophage, which signal the development of Th2. We will identify the mechanism that TPx uses to initiate the process. We propose to investigate this sequence of events by using an in-vitro cell based model to study the enzymatic steps as the macrophage responds to TPx. This goal represents much more than scientific curiosity. A better understanding of the process may reveal how TPx switches on the macrophage. If the trigger for this could be found, it would present a new way to manipulate the macrophage. This will possibly unearth new drug targets and lead to more effective therapeutics against infectious diseases, asthma, artherosclerosis and cancer.Read moreRead less
Immunomodulatory Vaccines In The Treatment Of Peanut Allergy
Funder
National Health and Medical Research Council
Funding Amount
$678,899.00
Summary
Peanut allergy is the most common cause of food-induced anaphylactic reactions in Australia and is a major burden to our healthcare system. Current clinical practice advice dietary avoidance to prevent fatal anaphylactic responses. We propose the use of an immunomodulatory vaccine to re-write the immune response to peanut antigens, from an allergic to a tolerant phenotype. This study will provide novel insights into rational approaches for manipulating immune memory to food allergens.
Development Of Novel Vaccine Strategies To Prevent Genital Tract Chlamydial Infections
Funder
National Health and Medical Research Council
Funding Amount
$33,626.00
Summary
Chlamydia trachomatis is one of the most common sexually transmitted diseases in the developed world. Because an infection can remain undetected it can cause severe long term problems such as infertility. The aim of this project is to develop a successful vaccine using novel immunization regimes that not only protects from infection but also prevents the development of any long term problems.