The establishment of an immune system that is able to distinguish between self and non-self is of fundamental importance for good health and survival. How this specificity is achieved has been an area of intense investigation for many years because a breakdown of this process leads to the development of autoimmune diseases, such as diabetes, or an inability to fight pathogenic organisms. It has been known for many years that the development T cells, a subset of cells involved in mounting immune ....The establishment of an immune system that is able to distinguish between self and non-self is of fundamental importance for good health and survival. How this specificity is achieved has been an area of intense investigation for many years because a breakdown of this process leads to the development of autoimmune diseases, such as diabetes, or an inability to fight pathogenic organisms. It has been known for many years that the development T cells, a subset of cells involved in mounting immune responses, occurs in the thymus. The thymus produces large numbers of immature T cells (called thymocytes) from which a small number receive the appropriate signals to survive and develop into mature T cells. These tailor-made T cells can then enter the blood and peripheral lymphoid organs where they fight infectious organisms without reacting against host (i.e. self) tissues. The work for this project is aimed at determining how proteins inside thymocytes transmit signals that determine whether thymocytes either survive, and develop into T cells, or are eliminated because they react too strongly with self proteins. We have established that a protein called c-Cbl is central to this process as it regulates the initial strength of the signal that determines the fate of thymocytes. Our aim is to identify the putative key protein regulated by c-Cbl that can sense when a signal is too strong following the binding of a thymocyte to a self protein and directs a cell death signalling response. From this critical point of signal splitting we also aim to identify proteins that relay the death signal to the nucleus where they trigger the production of well-characterised proteins required to mediate cell death. By identifying the proteins in this signalling pathway we will have a greater capacity to control the magnitude of immune responses and therefore be able to lessen tissue damage caused by autoimmune reactions.Read moreRead less
Role Of Plasmacytoid Dendritic Cells And Neutrophils In The Generation Of Antiviral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Work described in this application is important in understanding how two very different types of white blood cells, namely neutrophils and plasmacytoid dendritic cells (PDC), contribute to the generation of an effective immune response and control of virus growth. Both these cell types are activated in the earliest phase of the host response and are likely to play crucial roles in determining the nature of the later components of the response. We have recently shown that animals depleted of Gr-1 ....Work described in this application is important in understanding how two very different types of white blood cells, namely neutrophils and plasmacytoid dendritic cells (PDC), contribute to the generation of an effective immune response and control of virus growth. Both these cell types are activated in the earliest phase of the host response and are likely to play crucial roles in determining the nature of the later components of the response. We have recently shown that animals depleted of Gr-1+ cells, with monoclonal antibody (mAb) RB6-8C5, rapidly succumb to a poxvirus infection (mousepox) with 100% mortality. In contrast, mice treated with a control mAb clear the infection very effectively. Host responses essential for recovery from mousepox, including antiviral cytotoxic T lymphocyte (CTL) response and gamma interferon production, are severely diminished in mice treated with the Gr-1+ cell depleting mAb. Since the mAb can potentially deplete both neutrophils and PDC, this raises the important question of whether one or both of these cell types may be involved in the generation of cytokine and cell-mediated immune responses to viral infection. Although PDC and neutrophils themselves are not thought to present antigen to T cells, the elucidation of how they may control the generation of this major arm of the immune response will be novel and has important implications for vaccine design. Virtually nothing is known about how neutrophils or PDC influence viral antigen presentation by antigen presenting cells. Several murine models of viral infection, that in many ways mimic the diseases in humans, will be used to map the sequence of events initiated by PDC and neutrophils and which end in the clearance of virus from the host. Understanding these pathways and identifying the essential mediators and their interactions is critical in elucidating the role of the two cell types in the host response to virus infection.Read moreRead less
Designing new generation adjuvants for allergy and parasite vaccines. Allergy vaccines have the potential to provide a permanent cure against many allergic diseases, currently affecting 20-30 per cent of people in developed countries. This project will study how allergy vaccines work and how we can improve their effectiveness and safety.
Assessment Of Alpha-galactosylceramide As A Novel Adjuvant For Pandemic Influenza: A Virua Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$220,042.00
Summary
The occurrence of human infections with pathogenic avian H5N1 Influenza A viruses was the first documentation of these viruses demonstrating an ability to directly transmit from birds to humans. The virulent nature of these infections, and the fact that there is no pre-existing immunity to these viruses in the human population has raised the concern that these viruses may emerge to cause the next influenza pandemic. Vaccination is our most effective way of protecting against influenza infection, ....The occurrence of human infections with pathogenic avian H5N1 Influenza A viruses was the first documentation of these viruses demonstrating an ability to directly transmit from birds to humans. The virulent nature of these infections, and the fact that there is no pre-existing immunity to these viruses in the human population has raised the concern that these viruses may emerge to cause the next influenza pandemic. Vaccination is our most effective way of protecting against influenza infection, however there are no commercially available avian influenza vaccines available. Moreover, recent evidence suggests current vaccines strategies may be less than effective. This proposal aims to evaluate the efficacy of a novel vaccine strategy that promotes immune protection against a potential pandemic influenza strain.Read moreRead less
Dissecting the Parameters for the Generation of Cytotoxic T Lymphocyte Immunity. This project aims to identify mechanisms by which antigen-presenting cells, such as dendritic cells, prime CD8+ T cells to generate effector and memory populations at the molecular level. The specific intention is to identify reagents capable of licensing dendritic cells, and examine the down-stream gene products/pathways generated by these signals using microarray analyses. Such knowledge will provide new insight i ....Dissecting the Parameters for the Generation of Cytotoxic T Lymphocyte Immunity. This project aims to identify mechanisms by which antigen-presenting cells, such as dendritic cells, prime CD8+ T cells to generate effector and memory populations at the molecular level. The specific intention is to identify reagents capable of licensing dendritic cells, and examine the down-stream gene products/pathways generated by these signals using microarray analyses. Such knowledge will provide new insight into CTL generation by providing greater understanding of how multicellular systems function both at the cellular and molecular level.Read moreRead less
Imaging of immune responses to pathogens in vivo. This proposal represents an excellent opportunity for Australian science to participate in state-of-the-art research into the immune system and to be internationally competitive with the best researchers in the field. By combining advanced microscopy techniques with well developed biological models used by researchers at the University of Melbourne, this project will greatly improve our understanding of the dynamic interactions that occur betwee ....Imaging of immune responses to pathogens in vivo. This proposal represents an excellent opportunity for Australian science to participate in state-of-the-art research into the immune system and to be internationally competitive with the best researchers in the field. By combining advanced microscopy techniques with well developed biological models used by researchers at the University of Melbourne, this project will greatly improve our understanding of the dynamic interactions that occur between cells of the immune system during infectious diseases. The insight provided by this project will facilitate the design of better vaccines for protection against diseases, including influenza.Read moreRead less
A new approach to reversing and preventing immune-mediated diseases. Chronic inflammatory diseases affect up to 20 per cent of Australians. These diseases reduce wellbeing and life potential and shorten lifespan. This project addresses the urgent need for effective therapies and focuses on developing strategies for disease cure and prevention.