Regulation Of Macrophage Function And Gene Expression By The Th2-Promoting Stimulus, ES-62
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
White blood cells are responsible for co-ordinating the immune response against foreign micro-organisms. Macrophages are a particular type of white blood cell that attempt to destroy microbes during the initial stages of an infection, but also release toxic substances that are responsible for pathology and side effects during many immune responses. This project aims to address how macrophages are involved in a particular type of immune response that develops when individuals are susceptible to c ....White blood cells are responsible for co-ordinating the immune response against foreign micro-organisms. Macrophages are a particular type of white blood cell that attempt to destroy microbes during the initial stages of an infection, but also release toxic substances that are responsible for pathology and side effects during many immune responses. This project aims to address how macrophages are involved in a particular type of immune response that develops when individuals are susceptible to certain diseases including asthma and diseases associated with intracellular infections. We are identifying genes expressed in macrophages during these immune responses that are likely to be involved in susceptibility to such diseases.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
Immunity To Colonising Bacteria Of The Respiratory Tract In Atopic And Non-atopic Children
Funder
National Health and Medical Research Council
Funding Amount
$246,478.00
Summary
Evidence that seemingly harmless and common bacterial infections have a role, in the development of allergic disease has been uncovered. The development of immune responses to these microbes will be studied in children with and without allergy to inhalant allergens.
Studies On The Effects Of RSV Infection During Infancy On Aeroallergen-specific T-cell Immunity And Lung Function
Funder
National Health and Medical Research Council
Funding Amount
$130,475.00
Summary
Many infants who develop transient severe wheezing in association with respiratory infections, go on to develop asthma which can persist throughout childhood and some times into adult life. It is not known whether the respiratory infections are a direct cause of later asthma, or whether they simply function as flag which identifies children who have a genetic predisposition to wheeze e.g. because they have abnormally narrow airways. This project will compare the effects of respiratory infection ....Many infants who develop transient severe wheezing in association with respiratory infections, go on to develop asthma which can persist throughout childhood and some times into adult life. It is not known whether the respiratory infections are a direct cause of later asthma, or whether they simply function as flag which identifies children who have a genetic predisposition to wheeze e.g. because they have abnormally narrow airways. This project will compare the effects of respiratory infection in infants with the RSV virus, who contract the disease at different ages, and who have varying levels of genetic risk for respiratory allergies. In particular, it will examine the possibility that in certain cases, infection of genetically susceptible individuals during early infancy will boost the development of allergies to airborne environmental allergens (such as house dust mite) which are known to trigger asthma attacks in older children and adults.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
Modulation Of Asthmatic Airway Inflammation By Activation Of Epithelial Proteinase Activated Receptors
Funder
National Health and Medical Research Council
Funding Amount
$188,912.00
Summary
Children and adults feel the symptoms of asthma because their airways close up too easily. We have discovered a new mechanism that the healthy lung uses to keep airways open. The epithelial cells which line the airway release an enzyme that cuts of a small part of another protein, called a PAR receptor, that sits on the same cell. When this happens the epithelial cell releases relaxing substances from their lower surface. The relaxing substances keep the airways open. This grant application is d ....Children and adults feel the symptoms of asthma because their airways close up too easily. We have discovered a new mechanism that the healthy lung uses to keep airways open. The epithelial cells which line the airway release an enzyme that cuts of a small part of another protein, called a PAR receptor, that sits on the same cell. When this happens the epithelial cell releases relaxing substances from their lower surface. The relaxing substances keep the airways open. This grant application is designed to test whether the relaxing system also stops the airways from developing inflammation. If the relaxing system does this we will be able to use the knowlege we have that lets us activate the PAR receptors artificially to design new types of drugs. These drugs would be better than existing asthma drugs because they would prevent inflammation and relax the airways at the same time. These drugs could also be useful in other lung diseases such as chronic bronchitis.Read moreRead less
Cellular And Molecular Pathways Regulating Airway Mucosal Dendritic Cells During Onset Of Allergic Airways Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$491,065.00
Summary
Allergic airways inflammation (AAI), which leads to debilitating disease such as allergic asthma, is a condition medaited by the abnormal activity of the immune system towards essentially harmless inhlaed allergens. Two special cell types of the immmune system that are important in controlloing the onset and persistence of AAI are known as dendritic cells (DC) and T helper type 2 cells (Th2 cells). DC are located in all parts of the respiratory tract and are important in providing control signal ....Allergic airways inflammation (AAI), which leads to debilitating disease such as allergic asthma, is a condition medaited by the abnormal activity of the immune system towards essentially harmless inhlaed allergens. Two special cell types of the immmune system that are important in controlloing the onset and persistence of AAI are known as dendritic cells (DC) and T helper type 2 cells (Th2 cells). DC are located in all parts of the respiratory tract and are important in providing control signals to Th2 cells to become switched on and start to react to an inhaled allergen. Th2 cells then generate a variety of signals that initiate an cascade of immune responses towards the allergen that ultimately can lead to AAI and asthma if left unchecked, however this process remians relatively poorly understood. This project aims to examine how DC and Th2 interact, and at what level DC activity can be regulated so that unchecked Th2 immunity to harmless inhaled allergens can be controlled. The hope is to be able to identify new cellular and molecular pathways that can eventually become the target for new generations of preventative and therapeutic drugs.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
Regulation Of Perforin And Granzyme Expression In The Primary Cytolytic T Lymphocyte Response
Funder
National Health and Medical Research Council
Funding Amount
$756,000.00
Summary
The white blood cells known as cytolytic T lymphocytes (CTL) play important roles in elimination of some viruses, bacteria and tumours. Many vaccines and new therapies to prevent or control infections and cancer therefore seek to improve the production and activities of CTL. CTL kill infected cells and tumours by releasing packets of toxic molecules, including the pore-forming protein perforin and enzymes known as granzymes. However, while the roles of perforin and one granzyme, granzyme B, in c ....The white blood cells known as cytolytic T lymphocytes (CTL) play important roles in elimination of some viruses, bacteria and tumours. Many vaccines and new therapies to prevent or control infections and cancer therefore seek to improve the production and activities of CTL. CTL kill infected cells and tumours by releasing packets of toxic molecules, including the pore-forming protein perforin and enzymes known as granzymes. However, while the roles of perforin and one granzyme, granzyme B, in cell killing are now quite well understood, little is known about the other granzymes and how they contribute to immune protection. We have recently discovered that production of perforin and the three most prominent granzymes (A, B and C) can be separately controlled and that they are produced in different levels in different types of immune response. This suggests that they may each serve a different purpose and are therefore required in different amounts depending on the nature of the immune challenge. We have also found that an important hormone of the immune system, interleukin 4, has a profound effect on CTL, preventing their production of perforin and granzymes B and C and hence limiting their ability to kill target cells. In this project we plan a comprehensive analysis of perforin and granzyme production by CTL in response to different signals under controlled conditions in cell culture, and in response to different types of immune challenge in mice. We will also explore how interleukin 4 inhibits perforin and granzyme production and whether this has an impact on the effectiveness of the immune response. Mice in which one or more of the genes coding for perforin and granzymes has been damaged will be used to investigate how the absence of these molecules affects the immune response. We anticipate that these studies will suggest new strategies to improve therapeutic CTL induction by regulating perforin and granzyme production.Read moreRead less