Delineating Aberrant Adaptive Immune Responses Due To Germline Mutations In The PI3K Signalling Pathway
Funder
National Health and Medical Research Council
Funding Amount
$975,476.00
Summary
Activation of immune cells is required to generate appropriate immune responses that protect is from disease caused by pathogens. The inability to receive the correct type of signals causes immunodeficiency. The PI3 kinase pathway is central to immune cell activation – and genetic errors in this pathwat compromise the functioning of immune cells. We will investigate the nature of these defects and pursue avenues of overcoming them using pharmacological inhibitors of the PI3K pathway.
HMGB1: A Novel Player In The Pathogenesis Of Inflammatory Myositis?
Funder
National Health and Medical Research Council
Funding Amount
$84,800.00
Summary
The project aims to determine whether HMGB1, a pro-inflammatory molecule, plays a key role in the cause of inflammatory myositis, an extremely disabling muscle condition characterised by progressive weakness.
Genetic And Biochemical Mechanisms Dysregulating CD4 T Cell Tolerance In Organ-specific Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$456,000.00
Summary
This project will analyse mechanisms that regulate CD4 T cells and normally prevent the immune system from attacking parts of our own body. Unknown errors in the control of T cells result in autoimmune diseases such as Type 1 diabetes, multiple sclerosis, and thyroid disease, where T cells damage or destroy vital organs. In order to develop rational, specific methods for treating and preventing these diseases, it is necessary to identify and understand the genetic and biochemical mechanisms that ....This project will analyse mechanisms that regulate CD4 T cells and normally prevent the immune system from attacking parts of our own body. Unknown errors in the control of T cells result in autoimmune diseases such as Type 1 diabetes, multiple sclerosis, and thyroid disease, where T cells damage or destroy vital organs. In order to develop rational, specific methods for treating and preventing these diseases, it is necessary to identify and understand the genetic and biochemical mechanisms that normally control T cell cell responses to self components, and how inherited defects lead these mechanisms to break down. The project focuses on defining how CD4 T cell regulation breaks down in two well established examples of inherited susceptibility to autoimmune disease. The direct action of autoimmune susceptibility genes will be determined at the level of the specific T cells responsible for autoimmune attack and in terms of the biochemical pathways within T cells that are dysregulated. By identifying the mechanisms and biochemical pathways that are dysregulated in autoimmune disorders, the results of this project will reveal targets for understanding and diagnosing autoimmune diseases and for developing new drugs or or vaccines to prevent T cells damaging vital organs and cure these diseases.Read moreRead less
Monoclonal Antibodies Targeting Plasma Cells As Novel Therapeutic Agents And Diagnostic Tools
Funder
National Health and Medical Research Council
Funding Amount
$199,275.00
Summary
We have a new tool to identify a very rare immune cell type. This cell makes antibodies, powerful and exquisitely specific proteins that fight infection. In health, antibody-producing cells are beneficial, but in disease (rheumatoid arthritis, lupus and myeloma), these cells cause disease or death. Antibody-producing cells are long-lived. We have no means to specifically deplete them. We are developing reagents to identify and deplete antibody-producing cells to use as novel therapeutic agents.
An Exploration Of The Balance Between West Nile Virus Pathogenesis And Immune System Mediated Control
Funder
National Health and Medical Research Council
Funding Amount
$325,442.00
Summary
West Nile Virus (WNV) is a mosquito transmitted infectious disease that is emerging globally. Infection can lead to the development of fatal encephalitis and currently there is no vaccine available for human use. Killer T cells, a component of the immune system, are essential for viral clearance from the brain. This project aims to further explore WNV pathogenesis and whether killer T cells can be utilized to keep the infection localised and prevent the spread of the virus to the brain.
DEVELOPMENT OF CLINICALLY APPLICABLE STRATEGIES TO INDUCE AND MONITOR LONG TERM ACCEPTANCE OF LIVER ALLOGRAFTS
Funder
National Health and Medical Research Council
Funding Amount
$287,036.00
Summary
Liver transplantation is the only therapy for end-stage liver disease and thousands of Australian lives have been saved with this treatment. The major complication of liver transplantation is rejection which leads to loss of about half of the transplanted livers by ten years. Liver transplants in many animal models are not rejected and function normally for the life of the animal. Using one such animal model we have shown that white cells from the donor are responsible for the absence of rejecti ....Liver transplantation is the only therapy for end-stage liver disease and thousands of Australian lives have been saved with this treatment. The major complication of liver transplantation is rejection which leads to loss of about half of the transplanted livers by ten years. Liver transplants in many animal models are not rejected and function normally for the life of the animal. Using one such animal model we have shown that white cells from the donor are responsible for the absence of rejection. Of interest, these cells appear to stimulate a rapid and extreme immune response, which closely resembles rejection. The main difference is that it is quicker and more marked than rejection and then exhausts itself. This observation is unexpected and suggests possibilities for new treatments. Furthermore it questions the effectiveness of our present treatment for rejection of transplanted livers. We have already shown that some kinds of drugs given to prevent rejection in humans actually have the opposite effect in the animal model and prevent long-term acceptance of liver transplants. The aim of this work is to develop in our animal model a better way of treating human liver transplant patients. This will incorporate injection of donor white cells and treatment with drugs which promote the beneficial effects of these cells. We will also develop ways of testing the blood or the liver of the human liver transplant patients early after transplantation to find out whether the patient is accepting the liver or not. This means that we should be able to try this new treatment method in liver transplant patients once it has been optimised in the animal model.Read moreRead less
Chronic infectious diseases have a devastating effect on global health. HIV and Plasmodium falciparum both cause chronic disease and have evaded effective vaccine design. Vaccines rely on immune memory – the ability to clear an infection rapidly to a previously encountered pathogen. This proposal investigates the formation and dysfunction of immune memory in chronic infectious diseases, which will be vital for creating new and effective vaccines.
Identifying The Molecular Basis Of Memory B Cell Function And Human Immunoglobulin E Memory Via Hyper Immunoglobulin E Syndromes
Funder
National Health and Medical Research Council
Funding Amount
$96,009.00
Summary
Memory B cells generate rapid and potent antibody responses to known threats. The molecular basis for this is unknown, but defects increase the risk of infection, autoimmunity, and allergy. Autoimmunity and allergy are often mediated by a poorly understood antibody subclass, immunoglobulin E (IgE). My project will use emerging single-cell technologies to reveal the molecular mechanisms of antibody memory and IgE regulation, enabling the design of superior vaccines and immunomodulatory therapy.