How Deletional And Non-Deletional Tolerance Mechanisms Integrate To Prevent Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$509,944.00
Summary
The body produces millions of immune cells every day to fight infection. Some of these immune cells are defective and dangerous because they can cause autoimmune diseases, like Type I diabetes and multiple sclerosis. To defuse this risk, such immune cells are either caused to die or are inactivated to prevent autoimmunity. We propose to investigate how the processes of immune cell death and inactivation work in health and disease so we may harness these mechanisms to cure autoimmunity.
Understanding The Pathogenesis And Heterogeneity Of Autoimmunity As Failure Of Multiple Steps
Funder
National Health and Medical Research Council
Funding Amount
$504,023.00
Summary
Autoimmune diseases like diabetes, thyroid disease or rheumatoid arthritis affect around 1 in 15 people in Australia. It is clear that defects in a number of different genetic mechanisms can contribute to the development of autoimmunity. But it is currently not clear how these different mechanisms need to interact to prevent the onset of disease. This grant seeks to understand these interactions and how defects in two or more tolerance mechanisms can lead to autoimmunity.
Identifying The Underlying Mechanisms Responsible For The Generation Of Pathogenic B Cells In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$163,755.00
Summary
Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are r ....Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are responsible for most of the damage to the beta cells in T1D. Recent work in this model, however, has demonstrated that another class of immune cell, termed B cells, also play an important role in T1D as NOD mice made deficient in these cells no longer develop disease. In addition to producing antibodies, B cells are one of the few cell types which are able to take up and present protein fragments in a form recognizable to T cells. Normally, this only leads to the activation of T cells recognising foreign insults, like viruses or bacteria, resulting in their destruction. We have shown that a dangerous population of B cells can arise in NOD mice that can specifically take up beta cell proteins and present them to the T cells, which subsequently become armed to recognise and destroy the beta cells. Just like T cells, B cells that recognize the body's own proteins are normally eliminated in healthy mice and human individuals. This research proposal aims to determine the faulty immune mechanisms that give rise to the beta cell specific B cells in NOD mice. We have also set out to identify the diabetes susceptibility genes which control the generation of this dangerous population of B cells in this model. By understanding how these dangerous B cells are generated in NOD mice, we hope to form the basis for new therapies aimed at inhibiting these cells from forming in T1D susceptible humans, thus preventing the disease at an early stage.Read moreRead less
Cancers arise as a result of the impairment of critical cellular processes following the mutation of important regulatory genes. I am a molecular biologist and I study how the proteins of the Bcl-2 family regulate apoptosis, a process of cell death essential to maintain homeostasis in multicellular organisms, with the aim of designing drugs to kill cancer cells selectively. I am also interested in discovering new genes involved in the development of cancer using new genomics technology.
Molecular And Cellular Studies Of The Adaptive Immune Response In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$16,509,154.00
Summary
Immune responses protect us against pathogens such as viruses and bacteria. However inappropriate immune responses can result in autoimmune conditions such as systemic lupus erythmatosus, multiple sclerosis, type I diabetes, asthma as well as immunodeficiencies. The aim of our proposal is to gain a thorough understanding of how all the cells of the immune system function and interact with each other, and what goes wrong when inflammatory diseases develop. We plan to do this using state-of-of-the ....Immune responses protect us against pathogens such as viruses and bacteria. However inappropriate immune responses can result in autoimmune conditions such as systemic lupus erythmatosus, multiple sclerosis, type I diabetes, asthma as well as immunodeficiencies. The aim of our proposal is to gain a thorough understanding of how all the cells of the immune system function and interact with each other, and what goes wrong when inflammatory diseases develop. We plan to do this using state-of-of-the-art technologies, including genetically modified mice, gene microarrays, monoclonal antibodies, and flow cytometry. We have brought together Australia's leading immunologists with complimentary expertise and research interests in specific areas of immunology including cytokines, cell migration, inflammatory diseases, autoimmunity and cell-cell interactions. One aspect of the application is to understand the genetic and molecular basis of immunological diseases. However we also wish to move on from an understanding to treatment of immunological diseases through the development of novel therapeutics. We will form collaborations with biotech and pharmaceutical companies (including our own spin off companies) to advance important new therapeutics for autoimmune and allergic diseases. These conditions represent a significant health burden to Australia.Read moreRead less
The Role Of Self Reactive T Cells In The Normal TCR Repertoire
Funder
National Health and Medical Research Council
Funding Amount
$363,601.00
Summary
The immune system is highly regulated and sophisticated in order to distinguish foreign invaders from our own body. Once control is lost in this system, mistakes can happen, and autoimmunity, attack of ones self may result. Surprisingly potentially dangerous ‘fighter’ T cells can be readily found in healthy individuals whom are free from autoimmunity. The aim of this project is to understand how we can survive with these potentially harmful T cells around and what may activate them.
The Role Of MHC Class I Expression On Pancreatic Ductal Lineage Cells In The Pathogenesis Of Type I Diabetes (TID).
Funder
National Health and Medical Research Council
Funding Amount
$484,300.00
Summary
MHC molecules act as traffic lights to the immune system telling it whether to stop or go, so that only when there is an infection does the immune system receive the signal to destroy target cells. However, the immune system in Type 1 Diabetes patients receives signals to destroy the insulin-producing cells when there is no apparent infection. We aim to determine where the faulty traffic signal occurs and so be in a better position to design intervention strategies to prevent Type 1 Diabetes.
Novel Posttranscriptional Pathways The Control Tfh Cell Numbers
Funder
National Health and Medical Research Council
Funding Amount
$647,539.00
Summary
T follicular helper (Tfh) cells are essential for effective antibody responses against infection. Limiting Tfh cells is crucial for selecting the "fittest" B cells and the success of vaccines. Tfh cell accumulation causes autoimmuity and is associated with inadequate B cell responses in HIV infection. We have recently discovered two novel pathways that control Tfh cells. We speculate they regulate different RNAs that influence Tfh homeostasis and aim to elucidate their mechanism of action.
Germinal Centres, Rogue B Cells And The Genesis Of Immunological Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$753,300.00
Summary
This study will determine how the immune system is normally prevented from producing autoantibodies that target the body's own cells and how this fails in autoimmune diseases such as lupus. Targeted studies of a newly discovered "rogue" white blood cell will also provide new clues on how autoimmune diseases arise. In addition, modeling of human immunological disease in mice via CRISPR/Cas9 mutagenesis will provide valuable new insights into their causes and potential treatments.