Role Of Dendritic Cell Subsets In The Generation Of CD4 T Cell Memory
Funder
National Health and Medical Research Council
Funding Amount
$563,554.00
Summary
This project studies the mechanisms responsible for establishing immunologic memory that is generated by vaccination and determines its efficacy. We aim to identify and study previously unacknowledged factors that critically affect the efficacy of vaccination. The results will be significant for both preventative and therapeutic vaccination (cancer, autoimmunity) and will help us to design new vaccines to improve immune function in infection, autoimmunity and cancer.
The Generation Of HSV-1 Specific Effector And Memory CD4+ T Cell Responses.
Funder
National Health and Medical Research Council
Funding Amount
$460,509.00
Summary
This proposal aims to determine the mechanisms underpinning the generation of helper T cell responses following HSV-1 infection. It will determine the factors that allow T cells to access sites of viral replication and the mechanisms by which they provide protection from skin infections.
Generation And Maintenance Of Effective T Cell Memory In Peripheral Organs
Funder
National Health and Medical Research Council
Funding Amount
$336,767.00
Summary
Infectious diseases represent potentially life-threatening events. Immunity against re-infection relies on different types of memory immune cells that constantly patrol through the organism in search for invading agents. Recently, it has emerged that there exists an additional type of memory cells that permanently reside in peripheral tissues where they confer immediate immune protection. This project will examine the requirements for the generation and maintenance of this important cell type.
Effector And Memory CD8+ T Cell Responses To Engineered Influenza A Escape Mutants
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
T cells are a critical component of the immune system after infection with viruses. In particular, virus-specific CD8+ T cells can clear viral infections by killing virally-infected cells and the release of immunomodulators. These are called effector T cells. After the viral infection is cleared, a small proportion of T cells (around 5 to 10%) survives for many years and constitute a memory pool of virus-specific T cells. Memory T cells provide a rapid and effective protection in case of a repea ....T cells are a critical component of the immune system after infection with viruses. In particular, virus-specific CD8+ T cells can clear viral infections by killing virally-infected cells and the release of immunomodulators. These are called effector T cells. After the viral infection is cleared, a small proportion of T cells (around 5 to 10%) survives for many years and constitute a memory pool of virus-specific T cells. Memory T cells provide a rapid and effective protection in case of a repeated infection with the same virus, and hence result in a less severe disease. However, viruses often mutate their genes to escape such efficient T cell responses. In this study, we will investigate T cell responses after infection with mutated strains of influenza viruses. We will engineer a panel of mutant influenza viruses, which alter the nature and characteristics of T cells. We will analyse how efficient are these T cells and whether they can protect against a normal strain of influenza A. Subsequently, we will characterise quantitative and qualitative aspects of memory T cell pools after infection with mutant influenza viruses. Since a number of viruses such as influenza, HIV and HCV rapidly mutate their genes, our study will not only address the question of T cell responses to mutated influenza viruses, but also will provide an excellent model for investigating protective T cell responses to other viral infections.Read moreRead less
Evaluation Of Immune Correlates For Virus-specific CD8+ T Cells Following Prime-boost Vaccination
Funder
National Health and Medical Research Council
Funding Amount
$397,889.00
Summary
This project will use cutting-edge technology to evaluate the quality of virus-specific white blood cells generated following vaccination. Clinically relevant vaccination strategies will be analysed in a well characterised mouse model of infection to produce correlates associated with protective vaccine efficacy, particularly in an immunosupressed setting. This will lead to more focused research and ultimately the development of prophylactic and therapeutic HIV vaccines.
Immune reactions are mediated by the expansion of white blood cells, and the progeny of this expansion is steered down different developmental pathways depending upon the nature of the initial infection or insult. We have recently identified a new means for control of the developmentwhite blood cells, and will here define this mechanism. These studies will open new opportunities for autoimmune therapeutics and vaccine development.
Costimulatory Mechanisms For Enhancing CD8 T Cell Responses During An Acute Respiratory Infection
Funder
National Health and Medical Research Council
Funding Amount
$438,750.00
Summary
Following an infection, a person's immune system responds to fight the pathogen. One of the most important consequences of the immune response to an infectious disease is the establishment of memory to that particular disease so that a person is able to clear the same pathogen faster upon subsequent exposures. This memory is due to specific cells called memory lymphocytes. One subset of these cells are called CD8+ T cells and these are important for controlling and clearing viral infections. New ....Following an infection, a person's immune system responds to fight the pathogen. One of the most important consequences of the immune response to an infectious disease is the establishment of memory to that particular disease so that a person is able to clear the same pathogen faster upon subsequent exposures. This memory is due to specific cells called memory lymphocytes. One subset of these cells are called CD8+ T cells and these are important for controlling and clearing viral infections. New vaccine strategies are aimed at improving CD8 T cell responses so that they are more effective at fighting diseases such as HIV which causes AIDS and Hepatitis C virus. The mechanisms which lead to long lived memory CD8 T cells are not well understood. This research will characterise the function of genes involved in activating CD8 T cells and producing more memory CD8 T cells. The influenza model will be used as it is a well characterised model for studying anti-viral immunity. This project involved studying the mechansims of known genes involved in CD8 T cell responses to influenza. Also the discovery of new genes which are involved in CD8 T cell memory will be identified and characterised using new novel technologies, such as ENU mutagenesis, that only now are able to be utilised since the mouse genome (DNA) has been sequenced. This research will provide a basis for design of new and more effective vaccines.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
NFkB1 Is A Novel Regulator Of CD8+ T Cell Development And Memory Cell Generation
Funder
National Health and Medical Research Council
Funding Amount
$438,039.00
Summary
This project is focused on understanding the role of a regulatory protein- NFkB1 and how it is capable of controlling the development of a class of white blood cells termed T cells. Using a mouse model, we reveal how the absence of NFkB1 is important for producing memory T cells. Studies are proposed to determine whether this is an novel way for generating long lived memory T cells against viral infections and cancer, and potentially a new strategy for vaccine development.
The Role Of IL-18 In Proliferative And Crescentic Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$56,177.00
Summary
Inflammation of the small filters with the kidneys, known as glomerulonephritis, is the commonest cause of kidney failure in Australia. People whose kidneys have failed need either kidney dialysis or a kidney transplant. Our understanding of the immune events that cause glomerulonephritis is patchy. However, it is known that T cells are the directors of immune responses in the body and direct the immune response in glomerulonephritis. Chemical messengers known as cytokines direct the way T cells ....Inflammation of the small filters with the kidneys, known as glomerulonephritis, is the commonest cause of kidney failure in Australia. People whose kidneys have failed need either kidney dialysis or a kidney transplant. Our understanding of the immune events that cause glomerulonephritis is patchy. However, it is known that T cells are the directors of immune responses in the body and direct the immune response in glomerulonephritis. Chemical messengers known as cytokines direct the way T cells behave. One of these cytokines, known as interleukin-18, has been shown to stimulate T cells and other immune cells to induce inflammation that is helpful when the body is fighting infection but is harmful in immune diseases. This project will determine the role of interleukin-18 in glomerulonephritis by studying the way it talks to T cells and the mechanisms by which it incites inflammation in the kidney. Mice with glomerulonephritis will be treated by blocking the actions of interleukin-18 to discover whether interleukin-18 produced by the animal is important in kidney damage induced by glomerulonephritis, to understand the way in which this cytokine works and to assess whether blocking interleukin-18 could be a useful treatment for glomerulonephritis in humans. Current treatments for glomerulonephritis are often ineffective and have unwanted side effects. Knowledge of the way interleukin-18 participates in the immune response in glomerulonephritis may lead directly or indirectly to more effective and more targeted treatments for different forms of glomerulonephritis.Read moreRead less