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The aim of this project is to develop mathematical models and computer software capable of predicting immune responses to infection and disease. This “artificial immune system” should lead to improved vaccine design and better understanding of what causes the immune system to attack its own body, causing autoimmune disease, or fail to respond, causing immunodeficiency. This enabling science could then lead to improvements in treatment for a range of conditions of clinical importance.
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.
The Role Of The Dendritic Cell Surface Molecule Clec9A In Dendritic Cell Subset Function And Dead Cell Recognition
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Dendritic cells (DC) are sentinels of the immune system. DC monitor the environment and regulate tolerance to self versus immunity to dangerous material. Different types of DC perform different jobs. We have identified a new surface molecule, Clec9A, on some mouse and human DC. We will investigate the function of Clec9A in the immune response. We will also use Clec9A to help unite mouse and human DC biology, since until now there have been few useful marker molecules common to both species.
The activation of T lymphocytes is essential part of our immune system to fend off harmful intruders. Our research aims to understand the process of T cell activation, in particular, the contribution of fats. We found that fats create a highly ordered patch at the T cell activation site. We want to understand how lipids and proteins work together to activate T cells, how this ordered regions function in T cell activation and whether dietary lipids alter these patches and thus T cell activation.
The Role Of T Cell Receptor Avidity In Determining T Cell Repertoires And Responses
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell recepto ....T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell receptor). Each individual has an entire repertoire of T cells with unique T cell receptors which interact with peptides with varying binding strengths. After stimulation of T cells by e.g. viral infection, a subset of the T cell repertoire will become expanded and dominate the anti-viral immune response. This study aims to investigate how, during a viral infection, the strength (or 'avidity') of the interaction between the T cell receptor and the peptide influences (i) whether or not a T cell clone is recruited into the immune response and, if so, its dominance over other clones within that response, and (ii) how efficiently a T cell is activated. It is anticipated that particular virus peptide-specific T cell populations with an overall high avidity will be better able to produce inflammatory mediators and kill infected cells compared to lower avidity T cell populations specific for a different virus peptide. It is also expected that the higher avidity populations will exhibit greater diversity of TCRs. Further, within peptide-specific populations, it is anticipated that the relatively high avidity T cell clones will dominate the specific response. This study will contribute to a greater understanding of factors contributing to T cell recruitment and activation. Armed with this knowledge we will be better able to design vaccines to elicit optimal T cell responses to viral infection.Read moreRead less
Porphyromonas Gingivalis Cysteine Proteinases In Modulation Of Cell-mediated Immune Response In Periodontitis
Funder
National Health and Medical Research Council
Funding Amount
$228,000.00
Summary
Chronic inflammatory diseases of the tissues supporting the teeth comprise some of the most widespread and common diseases to affect mankind. Recent research has indicated the major contributor to the most common form of destructive periodontal disease is the bacterium Porphyromonas gingivalis. This organism produces powerful enzymes which overcome the body's attempts to neutralise them. It is also known that the destructive phase of the disease is characterised by a change in the behaviour of t ....Chronic inflammatory diseases of the tissues supporting the teeth comprise some of the most widespread and common diseases to affect mankind. Recent research has indicated the major contributor to the most common form of destructive periodontal disease is the bacterium Porphyromonas gingivalis. This organism produces powerful enzymes which overcome the body's attempts to neutralise them. It is also known that the destructive phase of the disease is characterised by a change in the behaviour of the immune system cells which accumulate in the diseased tissues. This is manifest as a loss of protective immunity and replacement by ineffective or even tissue damaging responses. Critical in directing the pattern of behaviour of the immune system cells are the potent messenger molecules or cytokines which pass between cells. We have demonstrated that the bacterial proteinases can destroy a critical messenger molecule that instructs the defensive phagocytic cells to attack bacteria. These cells in return normally send a powerful signal back to the controlling T lymphocyte to amplify the protective signals. Associated bacterial molecules stimulate more secretion of messenger molecules which are paradoxically destroyed by the bacterial enzymes. This could cause chaos in the local tissue environment. Further, the bacterial proteinases can also eliminate some important surface molecules of T lymphocyte that are important in the activation process. The effect of this could produce impairment of T lymphocyte at periodontal sites. The planned research will define how the proteinases modulate T lymphocyte immune response. Further, the relation between the capacity of the bacterial enzymes to disrupt the vascular cells and the progression of periodontitis will also be determined.Read moreRead less
A Novel Mechanism For The Regulation Of T Cell Shape And Function.
Funder
National Health and Medical Research Council
Funding Amount
$384,398.00
Summary
T cells are a key component of the immune system, and an understanding of their regulation has already lead to important therapeutic interventions. It is now apparent that the shape of the T cell impacts upon its ability to be activated, to migrate through the body, and to kill target cells. We have identified a novel means by which T cell shape is controlled, involving a group of proteins which orchestrate molecular traffic throughout the cell. This project application is to elucidate the mecha ....T cells are a key component of the immune system, and an understanding of their regulation has already lead to important therapeutic interventions. It is now apparent that the shape of the T cell impacts upon its ability to be activated, to migrate through the body, and to kill target cells. We have identified a novel means by which T cell shape is controlled, involving a group of proteins which orchestrate molecular traffic throughout the cell. This project application is to elucidate the mechanisms by which the group of proteins regulates T cell shape and function. We will test whether the proteins act together to integrate signals throughout the entire T cell, and will test whether the proteins influence T cell function in the test tube and in the mouse.Read moreRead less
Competition For Polarity Influences Lymphocyte Signaling And Function
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
Infectious diseases caused by viruses and bacteria remain a significant health problem. CD46 is a protein on the surface of human cells that is used by a number of viruses and bacteria to enter and infect host cells. Through binding to the CD46 protein, viruses and bacteria can induce changes in immune cells, such as T lymphocytes, that affect the way our immune system responds to infection. For example, immunosuppression induced by infection with measles virus is the primary cause of the mortal ....Infectious diseases caused by viruses and bacteria remain a significant health problem. CD46 is a protein on the surface of human cells that is used by a number of viruses and bacteria to enter and infect host cells. Through binding to the CD46 protein, viruses and bacteria can induce changes in immune cells, such as T lymphocytes, that affect the way our immune system responds to infection. For example, immunosuppression induced by infection with measles virus is the primary cause of the mortality and morbidity associated with the disease, and is a phenomenon that is poorly understood. However, there is evidence to suggest that the interaction between measles-infected cells with CD46 on the immune cells is partly responsible for the immunosuppression observed. Our laboratory has recently found that binding of CD46 (by antibody or measles antigen) on immune cells provides a signal to the cell to change its polarisation state (the way proteins are distributed within the cell) and impairs their ability to recognize and kill target cells, and become activated. These observations indicate a new paradigm by which competition of receptor signals for polarization determines signalling outcomes and provides a possible mechanism for how pathogens that bind CD46, such as measles, subvert normal immune cell communication and induce immunosuppression. This proposal aims to investigate the mechanisms behind the effect of polarising signals on immune cells, and will specifically use CD46 and measles virus as a model. The outcomes of this study will define new paradigms in lymphocyte biology and dissect the key pathways that underpin how CD46 influences immune outcome in response to infection.Read moreRead less
I am an immunologist, working to understand the function of NKT cells, and how these cells can be manipulated as a means of immune therapy for a range of immunologically related diseases.