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I am an immunologist-cell biologist investigating the regulation of human immune responses in health and disease. The overall goal of this work is to improve immunity in individuals with immunodeficiencies, or during vaccination, or to attenuate immune re
Cytokines In Milk Modulate The Development Of Immune Responses In The Infant
Funder
National Health and Medical Research Council
Funding Amount
$188,912.00
Summary
There is substantial epidemiological evidence that formula fed infants are more susceptible than breast fed infants to auto-immune diseases later in life. However direct evidence is lacking and the mechanism is not understood. We aim to provide direct experimental evidence to test the hypothesis that maternal milk regulates infant immune responses by providing the factors that modulates antigen presentation and priming in the neonatal gut. The significance of the study lies in the absence of the ....There is substantial epidemiological evidence that formula fed infants are more susceptible than breast fed infants to auto-immune diseases later in life. However direct evidence is lacking and the mechanism is not understood. We aim to provide direct experimental evidence to test the hypothesis that maternal milk regulates infant immune responses by providing the factors that modulates antigen presentation and priming in the neonatal gut. The significance of the study lies in the absence of these regulatory factors in infant formula. The results will allow more fully informed decisions regarding breast feeding, and may lead to the development of infant formula that modulate immune responses in a manner analogous to natural maternal milk.Read moreRead less
Crystallographic Studies Of Non-canonical Peptides Binding To MHC Class I Molecules.
Funder
National Health and Medical Research Council
Funding Amount
$489,750.00
Summary
Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called T-cell lymphocytes. This recognition process is the key step in the immune response and some fundamental questions in immunology are centred on the nature of this process. At the molecular level, the recognition is mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called t ....Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called T-cell lymphocytes. This recognition process is the key step in the immune response and some fundamental questions in immunology are centred on the nature of this process. At the molecular level, the recognition is mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called the MHC on the surface of the target cell. The target cell can be a cancer cell, or an infected antigen presenting cell (specialised cells in the body which present protein fragments (peptides) on their surface via MHC). The structure of a TCR and TCR-MHC have been solved in terms of the shape of the molecules at atomic resolution, bringing detailed information on how these two proteins interact with each other. In this proposal the structural basis of antigen presentation and recognition in cell-mediated immunity will be determined by three-dimensional structures of different peptides on MHC by x-ray crystallography. Cell surface antigen presentation by MHC molecules is crucial for initiating the cellular immune response against invading pathogens and cancer. This proposal encompasses a combined biochemical, immunological, and biophysical approach to understand the range of ligands which can bind to MHC which are subsequently recognised by the TCR. To understand the antigenic properties of modified peptides at the structure level, the x-ray structure of MHC with modified bound synthetic peptides will be determined.Read moreRead less
The Role Of Non-classical MHC Class I Molecules In Adaptive Immunity
Funder
National Health and Medical Research Council
Funding Amount
$443,834.00
Summary
Specialised proteins called MHC class Ia molecules (MHC-Ia) stimulate killer T cells to lyse virus infected cells. In contrast, the function of the closely related MHC-Ib is uncertain. Recent findings have demonstrated that MHC-Ib can also be recognised by T cells and this interaction is important in the control of viral infections. However, despite the similarity to MHC-Ia, it is unclear how this interaction occurs. This project aims to investigate how killer T cells recognise MHC-Ib molecules.
Pathogenic Role Of MicroParticles In Cerebral Malaria
Funder
National Health and Medical Research Council
Funding Amount
$250,000.00
Summary
Cerebral malaria (CM) is a life-threatening complication of infection caused by parasites. The mechanisms leading to coma, convulsions and death in CM remain unknown. CM in children is associated with high levels of endothelial microparticles (MP). However, not only the levels but also the phenotypes of MP can be altered in CM as well as their related functional properties. The project aims to develop a better definition of the MP released during CM and to study MP phenotypes in relation to clin ....Cerebral malaria (CM) is a life-threatening complication of infection caused by parasites. The mechanisms leading to coma, convulsions and death in CM remain unknown. CM in children is associated with high levels of endothelial microparticles (MP). However, not only the levels but also the phenotypes of MP can be altered in CM as well as their related functional properties. The project aims to develop a better definition of the MP released during CM and to study MP phenotypes in relation to clinical syndrome, disease severity and disease outcome.Read moreRead less
Immunity And Pathogenesis In Tropical And Infectious Diseases: Implications For Vaccines And
Funder
National Health and Medical Research Council
Funding Amount
$15,794,553.00
Summary
Malaria, streptococcal diseases, helminthiases and scabies are diseases of indigenous people on a massive scale, which lack vaccines. We aim to understand the pathogenesis of these diseases and develop vaccines and other treatments to combat them. Team includes senior experts on infectious diseases with long collaborative histories and younger members with impressive credentials. The work proposed also concerns inventive new ways of making such vaccines by novel chemical methods and aspects of d ....Malaria, streptococcal diseases, helminthiases and scabies are diseases of indigenous people on a massive scale, which lack vaccines. We aim to understand the pathogenesis of these diseases and develop vaccines and other treatments to combat them. Team includes senior experts on infectious diseases with long collaborative histories and younger members with impressive credentials. The work proposed also concerns inventive new ways of making such vaccines by novel chemical methods and aspects of delivery.Read moreRead less
Investigation Of Early Cell Surface Rearrangements Mediating Adequate TCR-pMHC Engagement
Funder
National Health and Medical Research Council
Funding Amount
$303,708.00
Summary
This project aims to use advanced cell imaging techniques to view precise interactions that occur between cells as our immune system attacks and destroys infected cells. The techniques to be employed are highly advanced and involve cutting edge science. Essentially these techniques allow the production of movies of the body's immune system in action. Determining these interactions in such detail is important for understanding the body’s ability to fight infection.
Characterisation Of Susceptibility To Abacavir Hypersensitivity Carried On The HLA-B-5701, -DRB*07 And -DQ3 Haplotype
Funder
National Health and Medical Research Council
Funding Amount
$545,250.00
Summary
Drug hypersensitivity reactions (HSR) are a significant iatrogenic cause of morbidity, and even of mortality. Unfortunately the underlying mechanisms are poorly understood, making it difficult to predict which individuals may be at risk of these reactions. Research indicates that the interaction between specific drugs and the host immune system in HSR is similar to that observed in transplantation and that the major histocompatibility complex (MHC) region of the human genome assumes importance i ....Drug hypersensitivity reactions (HSR) are a significant iatrogenic cause of morbidity, and even of mortality. Unfortunately the underlying mechanisms are poorly understood, making it difficult to predict which individuals may be at risk of these reactions. Research indicates that the interaction between specific drugs and the host immune system in HSR is similar to that observed in transplantation and that the major histocompatibility complex (MHC) region of the human genome assumes importance in this setting, as it does in determining if a transplanted organ is 'rejected' or 'accepted'. We have identified a striking association between MHC genetic markers (HLA-B*5701, -DRB1*0701, and -DQ3) and HSR to the HIV drug abacavir. Carriage of these markers was found in 72% (13-18) of individuals with this reaction, and 0% (0-185) of those who tolerated abacavir (odds ratio 822), thus predicting HSR in 100% of cases, and abacavir tolerance in 97%. This represents one of the most powerful MHC gene associations with a clinical syndrome yet described. As abacavir HSR affects ~5% of abacavir users, knowledge of these genetic factors would be predicted to significantly reduce the risk of susceptible individuals developing HSR, without inappropriately denying access to abacavir. This association between the MHC and abacavir HSR in the clinical setting provides a unique opportunity to characterise mechanisms that underlie this HSR, which may give insights into drug HSR generally. Continued support of this research in the public domain, rather than in the commercial sector, will ensure that commercial considerations do not restrict the dissemination of these findings. Given the high predictive value of this readily performed genetic test in identifying at-risk individuals, there is also a clinical imperative to rapidly identify the gene(s) involved, to provide the most targeted risk assessment possible.Read moreRead less