Immunopathogenesis And Manipulation Of The HIV Reservoir
Funder
National Health and Medical Research Council
Funding Amount
$494,732.00
Summary
Kelleher is a Clinical immunologist with a globally recognised, sustained track record of translational research which has impacted both on our understanding of HIV immunopathogenesis and on the way HIV infection is treated. He will conduct a series of studies that encompass basic scientific techniques through to pivotal pre-clinical and clinical studies that will provide a pathway towards control of HIV-infection without daily therapy.
The NF-kB Transcription Factors C-Rel And RelA Control Multiple Steps In Natural CD4 Regulatory T Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$566,592.00
Summary
An unfortunate consequence of immune function is that occasionally rogue immune cells are produced that attack the host and lead to the development of so-called autoimmune diseases such as arthritis. Normally a white blood cell called a regulatory T cell suppresses these self-reactive immune cells. We have identified factors that govern the generation of regulatory T cells. Understanding how these factors work should permit the development of new strategies to combat autoimmune diseases. ?
HIV infection continues to be a global problem, an effective vaccine is critical to halting its spread. For those infected there is no cure. They require life-long, expensive therapy. The proposed research looks to provide insights that will contribute to the development of an effective vaccine and to clearing the virus from infected patients by using cutting edge laboratory techniques to study patients in populations that are pathogenically informative.
The Molecular Identification Of FoxP3 +ve Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$483,273.00
Summary
The immune system has a series of checks and balances in place to distinguish foreign bodies from normal, or self-antigens. In healthy individuals this prevents the immune system from attacking the cells and tissues of the body, food proteins, and the beneficial bacteria of the gut. However in autoimmune disease the system becomes imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes, asthma and rheumatoid arthritis. One of the key players in the maintenance of a h ....The immune system has a series of checks and balances in place to distinguish foreign bodies from normal, or self-antigens. In healthy individuals this prevents the immune system from attacking the cells and tissues of the body, food proteins, and the beneficial bacteria of the gut. However in autoimmune disease the system becomes imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes, asthma and rheumatoid arthritis. One of the key players in the maintenance of a healthy immune system is a specialized set of T cells known as T Regulatory cells. These cells are rare, at 1-4% of all T cells, yet are potent modulators of other T cells, and can prevent the activation of a T cell if it is reacting to a self-antigen. If they can control the cause of autoimmune disease, and patient Treg cells can be manipulated, it may be possible to use them therapeutically. Recently the switch that is required to generate regulatory cells was identified from patients with a rare autoimmune disease called Immunodysregulation, polyendocrynopathy, enteropathy, X-linked syndrome or IPEX. A mouse disease, Scurfy, with similar symptoms, is caused by the same mutations. The mutated gene encodes a protein, FoxP3, and this protein is able to bind to other genes in T cells and regulate their function. Without this protein, there are no T regulatory cells, resulting in autoimmune disorders. At this time there is very little known about how the FoxP3 gene is able to make a T cell become a regulatory T cell, and nothing is known about the genes that are turned off and on to facilitate this. If we can understand better the role of this protein, FoxP3, in the generation and maintenance of T cells with regulatory function, we may better be able to diagnose and treat autoimmune diseases, and this knowledge will have broad application to many autoimmune disorders.Read moreRead less
The Role Of C-Cbl In The Regulation Of T Cell Signalling And Development
Funder
National Health and Medical Research Council
Funding Amount
$527,250.00
Summary
c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) ....c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) mice show that Cbl proteins are important in regulating the development of, and signalling by, cells of the immune system called T cells. c-Cbl knockout mice show greatly enhanced PTK-signalling responses and deregulated activity of a PTK called ZAP-70. The mechanism of this is not known, but analysis of a c-Cbl mutant mouse shows that this is not dependent on the tyrosine kinase binding (TKB) domain of c-Cbl. Therefore other functional domains of Cbl must be responsible for the increased signalling response in the c-Cbl knockout mouse. One candidate is the highly conserved RING finger domain which can modify Cbl-associated PTKs by addition of ubiquitin molecules. Ubiquitination of a protein often, but not always, leads to its degradation, and this could be how Cbl controls the strength and duration of signalling in T cells. However there may be other functions of the conserved RING finger yet to be identified. c-Cbl itself is prominently and very rapidly modified by tyrosine phosphorylation on tyrosine 737 by the Fyn PTK following T cell activation, but the role of this modification is not known and could also be essential for c-Cbl s function in T cells. We plan to investigate the roles of the RING finger domain and Fyn-mediated tyrosine phosphorylation in c-Cbl regulation of T cell signalling by analyzing knock-in mice that carry specific mutations disrupting the RING finger or tyrosine 737 in the c-Cbl gene.Read moreRead less
Systematically Exploring The Contribution Of Immunoproteasome To Immunodominance And T Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$499,860.00
Summary
Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes a ....Vaccine will help us to fight both infectious diseases and malignancy. However, there are few successful vaccines for infectious agents and there is simply no vaccine to cure any tumor at the moment. So, it is essential for us to learn the basics related to vaccine development. Killer T cells eliminate tumour cells or virally infected host cells by recognising fragments (epitopes) derived from tumour- or virus-derived proteins displayed on a host molecule called MHC. Normally multiple epitopes are generated as part of the protein recycling program referred as proteine degradation which is mainly conducted by bundled enzyme complex, called proteasome. Two major forms of proteasomes are expressed by most cells. One called house-keeping proteasome and the other, which replaces the house-keeping one during viral infections is called immunoproteasome. The role that the immunoproteasome plays during anti-viral and anti-tumoral immune responses is not fully understood. In addition, the immunoproteasome is also expressed by a few cell types that do not suppose to need it if its function is entirely to generate better epitopes for MHC to display. In this project, we will sytematically explore the contribution of the immunoproteasome to overall anti-viral and anti-tumoral immune responses in three mouse model systems. The shared feature of these systems is that multiple killer T cell epitopes have been defined, which could potentially provide us with very sensitive assessments. The three systems are anti-influenza, anti-vaccinia virus and anti-tumor antigen (NY-ESO-1) mouse models.Read moreRead less
MAIT cells are a recently discovered type of lymphocyte that plays a unique and important role in the immune system. However, these cells vary widely in number between healthy individuals, for reasons that are unclear. This project is designed to understand the factors that control the development of MAIT cells as a step toward regulating their numbers and activity.
Role Of The CD8-Heparan Sulfate Interaction In CD8+ T Cell Development And Function
Funder
National Health and Medical Research Council
Funding Amount
$649,135.00
Summary
The immune system can recognise a large array of foreign pathogens without reacting to self-components. For this to occur T cells, the main mediators of immunity, must be made to tolerate self-molecules as they develop in the thymus. We have identified a novel interaction between a molecule called CD8 on T cells and a complex carbohydrate called heparan-sulfate, which helps auto-reactive T cells to be eliminates in the thymus. The aim of this project is to further investigate this phenomenon.