The Molecular Basis To The Development And Function Of The Thymic Microenvironment.
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The ability of the body to defend itself against infection is dependent on white cells in the blood called T lymphocytes, so-named because they are produced in the thymus gland. In the absence of these T cells, there is severe immunodeficiency. On other hand if the T cells are hyperactive, they can confuse their role and destroy normal tissues (autoimmunity). Imbalances in the types of T cells can also predispose patients to allergies and failures in responses to tumours. This project seeks to i ....The ability of the body to defend itself against infection is dependent on white cells in the blood called T lymphocytes, so-named because they are produced in the thymus gland. In the absence of these T cells, there is severe immunodeficiency. On other hand if the T cells are hyperactive, they can confuse their role and destroy normal tissues (autoimmunity). Imbalances in the types of T cells can also predispose patients to allergies and failures in responses to tumours. This project seeks to identify the genes required to create T cells in the thymus. Specifically it addresses the structural cells of the thymus which provide the unique environment for converting bone marrow precursors exclusively into T lymphocytes. Understanding the genetic and thus molecular basis to this will be very important biologically but may also provide more sophisticated stratgies for treating diseases on T cell origin.Read moreRead less
Tapasin And Major Histocompatibility Complex Class I Antigen Presentation
Funder
National Health and Medical Research Council
Funding Amount
$226,650.00
Summary
An effective T cell response (cellular immune response) to infections is vital to a functional immune system. Normally, proteins are cleaved into small molecules called peptides and these peptides are in turn presented by Major Histocompatibility Complex molecules to T cells. However, we have only partial understanding of what determines the choice of peptides that are finally presented to T cells. Recent research suggests that a molecule called tapasin may also influence the choice of peptides. ....An effective T cell response (cellular immune response) to infections is vital to a functional immune system. Normally, proteins are cleaved into small molecules called peptides and these peptides are in turn presented by Major Histocompatibility Complex molecules to T cells. However, we have only partial understanding of what determines the choice of peptides that are finally presented to T cells. Recent research suggests that a molecule called tapasin may also influence the choice of peptides. This research proposal aims to examine the role of tapasin in this regard. A thorough understanding of the basic principles of peptide presentation to T cells is crucial to the design of effective vaccines. Furthermore it will also broaden our understanding of immunological responses to cancer, autoimmune diseases and infections.Read moreRead less
The Role Of Fc RIIa In Antibody Dependent Tissue Destruction In Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$538,206.00
Summary
These studies will attempt to identify the cause autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus we are using a unique strain of mice carrying a unique human protein called Fc receptor that triggers inflammatory cells. We will identify the processes that start inflammation, and those that continue throughout chronic autoimmune disease. These studies will be applied to the development of new treatments for autoimmune disease.
How IL-4 Suppresses TNF And IL-1 Production By Activated Human Monocytes And Macrophages
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Chronic inflammatory diseases are an enormous and growing health problem. There is a continuing search for improved and more targeted treatments. We have been studying a cytokine called interleukin-4 which can suppress the production by blood cells of many of the inflammatory mediators that initiate and maintain inflammation. With the recognition that interleukin-4 has this anti-inflammatory activity on blood cells, there was considerable optimism that this molecule may not only be a natural reg ....Chronic inflammatory diseases are an enormous and growing health problem. There is a continuing search for improved and more targeted treatments. We have been studying a cytokine called interleukin-4 which can suppress the production by blood cells of many of the inflammatory mediators that initiate and maintain inflammation. With the recognition that interleukin-4 has this anti-inflammatory activity on blood cells, there was considerable optimism that this molecule may not only be a natural regulator of inflammation but also used in immunotherapy. However we do not know how this molecule downregulates inflammatory blood cells. It will be necessary to know this if it is to be used in human gene therapy for treatment of inflammatory diseases. Cells must be activated before a molecule which is anti-inflammatory can be effective. Different cell types from different inflammatory sites will be studied to better characterise different activation pathways. How interleukin-4 regulates these pathways will be studied. Once identified, treatments based on the properties of interleukin-4 may be designed-optimised.Read moreRead less
Pathophysiological Significance Of Reverse Signaling Through Membrane TNF
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surfac ....Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surface of the cell and then it is 'clipped off' and released as a smaller, soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We believe that binding of tumour necrosis factor receptors to the cytokine while it is in its membrane form can also send a message backwards, into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell. In this project we will investigate this phenomenon in detail. The results will be extremely relevant to new methods of treatment of diseases, that rely either on 'masking' tumour necrosis factor by administering soluble forms of its receptor or on blocking the release of the soluble form of the molecule from the surface of the cell. Our work will enable us to understand the consequences of these approaches more fully. We will also be looking at the role of the membrane form of tumour necrosis factor in a model of infectious disease. Influenza virus is responsible for a great deal of morbidity and mortality around the world. We, and others, have shown, in a mouse model, that some cells in the lungs make tumour necrosis factor during the course of viral pneumonia. Here we will determine whether the membrane form of this cytokine plays a role in clearing virus or causing some of the complications of this disease. This also may have relevance to other inflammatory and infectious disease.Read moreRead less
T cells are a central component of the immune system and without T cells the body is very vulnerable to infections. One subgroup of T cells is the killer T cells that are important for identifying and killing cells infected by viruses and bacteria. The immune system works to maintain T cell numbers at a fairly constant level and part of this process includes sending signals to the killer T cells from other cells via cell surface protein interactions and soluble mediators, such as cytokines. We h ....T cells are a central component of the immune system and without T cells the body is very vulnerable to infections. One subgroup of T cells is the killer T cells that are important for identifying and killing cells infected by viruses and bacteria. The immune system works to maintain T cell numbers at a fairly constant level and part of this process includes sending signals to the killer T cells from other cells via cell surface protein interactions and soluble mediators, such as cytokines. We have been studying killer T cells, which are missing a protein SOCS1. SOCS1 is important for switching off the signals generated by a group of cytokines. As a consequence of being unable to correctly regulate cytokine signals these killer T cells multiply inappropriately and contribute to disease development. Our current work is aimed at achieving a better understanding of the particular interactions between killer T cells and other immune system cells and the soluble factors that deliver important signals for maintaining killer T cells in the immune system. The ability to better understand the factors controlling the maintenance of killer T cells will enable us to more intelligently target the immune system ,which is important for improving vaccine strategies and cancer immunotherapy as well as for controlling T cells that are activated inappropriately, such as in autoimmune disease.Read moreRead less
Regulation Of Natural Killer Cell Homeostasis By Multiple Components Of The Immune System
Funder
National Health and Medical Research Council
Funding Amount
$327,151.00
Summary
Differentiation and homeostasis of immune cell populations such as CD4 and CD8 T cells and dendritic cells has been key to understanding their function during inflammation. In contrast, late stage natural killer (NK) cell differentiation has largely been ignored. Given the key role of NK cells in providing innate effector immunity and shaping adaptive responses, a better understanding of the cues that regulate their differentiation is clearly warranted.
Receptors And Ligands Regulating Human NK Cell Proliferation
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
A white blood cell called a Natural Killer (NK) cell is critical in the early control of viral infections and cancer. NK cells kill the diseased cells and secrete immunological hormones (cytokines) that alter how cells of the blood and immune systems respond. These functions of NK cells are markedly increased when NK cells are stimulated to divide. This project seeks to understand how NK cell proliferation is controlled. Receptors that recognise 'self' inhibit NK cell function and cell division ....A white blood cell called a Natural Killer (NK) cell is critical in the early control of viral infections and cancer. NK cells kill the diseased cells and secrete immunological hormones (cytokines) that alter how cells of the blood and immune systems respond. These functions of NK cells are markedly increased when NK cells are stimulated to divide. This project seeks to understand how NK cell proliferation is controlled. Receptors that recognise 'self' inhibit NK cell function and cell division thereby preserving self and destroying diseased cells. Yet many NK cells express both an inhibitory and activating receptor for this same 'self' protein. We will investigate what determines the outcome of this competing information. Many NK cell receptors remain to be identified and we will use a gene expression approach and monoclonal antibodies to identify these and determine how they affect NK cell proliferation. We will use molecular engineering to construct multimeric arrays of new NK cell receptors to search for the ligand molecules that they interact with on other cells. Identifying NK cell receptors and their ligands regulating NK cell proliferation and function will enable us to understand the role of these cells in health and in inflammatory diseases and cancer.Read moreRead less
Identification Of Novel Regulators Of Flt3 Receptor-dependent Dendritic Cell Development And Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$605,043.00
Summary
Dendritic cells are specialized immune cells that play a key role in regulating the immune system. In the resting animal, their differentiation is largely regulated by signalling though the Flt3 pathway - the pathway most frequently dysregulated in leukemias. This project will generate a a detailed map of the important signals that instruct dendritic cell development along the Flt3 pathway and provide improved understanding of the cellular and molecular controls of this pathway.
Control Of The Antigen-specific Cytotoxic T Cell Memory Response
Funder
National Health and Medical Research Council
Funding Amount
$95,044.00
Summary
Individuals who survive infections by a given pathogenic micro-organism are usually protected from subsequent infections by these same agents. This is the basis of adaptive immunity, which defines the body's ability to maintain a memory of prior infection or vaccination and in so doing, mount a far more effective response to subsequent infection by these agents. This proposal deals with the mechanisms by which this memory is maintained. It specifically focuses on cytotoxic T lymphocytes (CTL) wh ....Individuals who survive infections by a given pathogenic micro-organism are usually protected from subsequent infections by these same agents. This is the basis of adaptive immunity, which defines the body's ability to maintain a memory of prior infection or vaccination and in so doing, mount a far more effective response to subsequent infection by these agents. This proposal deals with the mechanisms by which this memory is maintained. It specifically focuses on cytotoxic T lymphocytes (CTL) which are leucocytes or white blood cells that kill virus infected cells. Using new technology which permits visualisation of CTL directed against specific viruses we are going to define what determines the survival and replacement of these memory cells over time. We will also identify the agents that alter the memory CTL's ability to deal with infections within localised sites in the body. In so doing, this work will provide valuable insight into approaches that can be used to better vaccinate individuals against infections by pathogenic viruses.Read moreRead less