Identification Of Antigen Selection In The Human IgE Response By Analysis Of Somatic Point Mutations
Funder
National Health and Medical Research Council
Funding Amount
$256,973.00
Summary
Allergic disease affects over 25% of the Australian community. It is responsible for significant sickness and death, particularly amongst children, and its incidence is on the increase. The reasons for this, and the underlying causes of allergic disease, remain unclear. Allergic disease results from the actions of molecules called IgE antibodies, which are also associated with parasitic infection. Even in these conditions, where IgE concentrations are raised in the blood, the concentrations are ....Allergic disease affects over 25% of the Australian community. It is responsible for significant sickness and death, particularly amongst children, and its incidence is on the increase. The reasons for this, and the underlying causes of allergic disease, remain unclear. Allergic disease results from the actions of molecules called IgE antibodies, which are also associated with parasitic infection. Even in these conditions, where IgE concentrations are raised in the blood, the concentrations are too low to allow their direct study. We have recently applied molecular biological techniques to study the genes that encode IgE antibodies. Our work suggests that the IgE response can sometimes develop in a different way to that of other antibodies (eg IgG). On the other hand, laboratory (in vitro) studies over many years support the possibility that IgE and IgG develop in parallel. In this study, we wish to identify circumstances in which IgG-like IgE antibodies develop. We therefore wish to study patients with different kinds of allergic disease, and patients with other conditions that are associated with IgE production. We therefore wish to study patients who have infections with parasitic worms. We deduce the processes that give rise to IgE antibodies by analysing patterns of mutations that accumulate in antibody genes during an immune response. Over recent years, we have developed new approaches to the analysis of such mutations, and this project also seeks to further develop our mutation analysis. This more powerful analysis will be applied to the study of mutations in the IgE genes seen in different patient groups, and should allow us to quantify the proportion of IgE antibodies that develop in each way. A better understanding of the relative contributions of the two pathways to IgE, in different conditions, will transform our understanding of the IgE response, and open up new avenues for the investigation of the causes and treatment of allergic disease.Read moreRead less
Tissue Specific T Cells Mediate Drug Hypersensitivity
Funder
National Health and Medical Research Council
Funding Amount
$1,253,980.00
Summary
T cells are immune cells that create dangerous and fatal drug allergies affecting the skin. An individual’s genetic makeup only partially explains predisposition to these reactions, we believe the missing link is contained in immune signatures specific to the skin. We aim to identify drug-specific T cells in the skin and develop a sensitive test to screen for rare, dangerous T cells in the blood. This will enable prediction and prevention of severe drug allergy and development of safer drugs.
Construction And Immunogenic Evaluation Of Recombinant HBsAg-S Virus-like Particles Containing B And T Cell Epitopes Of
Funder
National Health and Medical Research Council
Funding Amount
$170,000.00
Summary
Helicobacter pylori is a significant human pathogen impacting on the health and well being of not only thousands of Australians, but also millions of people world-wide. However, the task of developing a vaccine against H. pylori remains important. Vaccination is the most effective mechanism to prevent disease associated with this infection, particularly gastric cancer, one of the most common causes of cancer death world-wide. However, current attempts to develop an effective vaccine for humans h ....Helicobacter pylori is a significant human pathogen impacting on the health and well being of not only thousands of Australians, but also millions of people world-wide. However, the task of developing a vaccine against H. pylori remains important. Vaccination is the most effective mechanism to prevent disease associated with this infection, particularly gastric cancer, one of the most common causes of cancer death world-wide. However, current attempts to develop an effective vaccine for humans has been limited by the non-availability of an effective and safe adjuvant. The aim is to construct a recombinant Virus-Like Particle which can be used as a safe and effective vaccine against Helicobacter pylori infections. We specifically aim to: · determine the most efficacious singular or combinatorial route-s of delivery of Virus-Like Particles (VLPs) which will induce the desired Th2 and B cell responses in mice · define the Th2 and B cell epitopes of H.pylori Kat A carboxyl terminus that can be used to construct chimeric HBsAg-S-Kat A VLPs · determine if the induction of desired immunological responses in mice are protective against wild type challengeRead moreRead less
Defective Toll-like Receptor 7 Signalling In Plasmacytoid Dendritic Cells Underlies The Inception Of Virus-associated Asthma
Funder
National Health and Medical Research Council
Funding Amount
$552,301.00
Summary
In genetically susceptible individuals, respiratory virus infections are a risk factor for asthma inception and are the most common cause of acute exacerbations. Using a clinically relevant mouse model of disease, this study will investigate whether the altered expression of toll-like receptor 7, a host protein that senses viral invasion, causes the host to mount an inappropriate pro-allergic immune response to the virus.
Shigella Flexneri O Antigen Polysaccharides: Biosynthesis, Function In Virulence, And Interaction With IcsA/VirG
Funder
National Health and Medical Research Council
Funding Amount
$468,055.00
Summary
Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these compo ....Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these components (lipopolysaccharides (LPS) and their polysaccharide chains (O antigens), and IcsA-VirG protein)) are required for initiating actin polymerisation, and mutations affecting synthesis of these components reduce ability to cause disease. In previous studies we have found that O antigen and the synthesis and function of IcsA are interrelated. This project will study how the O antigens are synthesised and their chain length determined by the Wzz protein, and the Wzz structure in relation to its function will also be characterised. The role played by O antigen in intracellular motility will be studied to determine the mechanisms involved. Infection of cells and cell free extracts, antibodies, and an enzyme which specifically degrades the O antigen, will be used to study how O antigen affect the interaction between bacteria with human cell proteins. The relationship between O antigen and IcsA function will be studied using monoclonal antibodies raised to IcsA. The effect of LPS on the outer membrane protease IcsP will be investigated, as will the effect of LPS lipid A mutations on O antigen and virulence. These studies will contribute to a better understanding of the biosynthesis of an ubiquitous bacterial cell surface component (O antigen), its function as a virulence factor in bacterial interactions with host cells. This may lead to novel therapeutic strategies to prevent and control Shigellosis and other bacterial infections.Read moreRead less