An Autoantibody In Type 1 Diabetes That Mediates Autonomic Complications
Funder
National Health and Medical Research Council
Funding Amount
$254,591.00
Summary
Type 1 diabetes is a chronic autoimmune disease characterised by destruction of insulin producing cells in the pancreas. One of the most common and serious complications of type 1 diabetes is disruption of the autoimmune nervous system, and once symptoms appear the 5-year mortalityrate is approximately 50%. Symptoms of autonomic dysfunction can be extensive, and involve the stomach, intestine, bladder, heart and reproductive organs. Currently, the management of autonomic dysfunction remains prim ....Type 1 diabetes is a chronic autoimmune disease characterised by destruction of insulin producing cells in the pancreas. One of the most common and serious complications of type 1 diabetes is disruption of the autoimmune nervous system, and once symptoms appear the 5-year mortalityrate is approximately 50%. Symptoms of autonomic dysfunction can be extensive, and involve the stomach, intestine, bladder, heart and reproductive organs. Currently, the management of autonomic dysfunction remains primative due to our poor understanding of the mechanisms underlaying the disease. Recent work from our group has identified an excitatory autoantibody (an antibody against the self) to calcium channels in patients with type 1 diabetes. The anti-calcium channel autoantibody profoundly disrupts gut and bladder function by interfering with autonomic regulation of smooth muscle within these organs. The anti-calcium channel autoantibody is the first functional autoantibody to be detected in type 1 diabetes, and represents a conceptual advance in our understanding of immune mechanisms in this disease. Using animal models and a panel of novel, functional assays of colon, stomach and bladder we will investigate how the anti-calcium channel autoantibodies contribute to autonomic dysfunction in type 1 diabetes. Understanding the mechanisms by which this autoantibody effects autonomic regulation of organ function will enable the development of new therapeutic strategies for better management of patients.Read moreRead less
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
Investigations In Multiple Sclerosis Patients With Coexistent Autoimmune Thyroid Disease
Funder
National Health and Medical Research Council
Funding Amount
$557,100.00
Summary
Multiple sclerosis (MS) is a common chronic neurological disease affecting over one million people around the world. MS is generally thought to be an autoimmune disease, in which a person's own immune cells start to attack components of the brain and spinal cord. However, it is thought that the same components are not attacked in all patients, and that the pathway that leads to MS varies from one person to another. Therefore, in order to develop successful treatment strategies for MS, it will be ....Multiple sclerosis (MS) is a common chronic neurological disease affecting over one million people around the world. MS is generally thought to be an autoimmune disease, in which a person's own immune cells start to attack components of the brain and spinal cord. However, it is thought that the same components are not attacked in all patients, and that the pathway that leads to MS varies from one person to another. Therefore, in order to develop successful treatment strategies for MS, it will be necessary to look for patterns in the clinical symptoms and signs and other features of a person's MS that may give clues as to which particular pathway is leading to disease in that person. Some people who develop MS also develop other autoimmune diseases, or have these other diseases before they develop MS, or have other family members who have other autoimmune diseases. We have recently found that people who have the same combination of coexistent MS and autoimmune thyroid disease (AITD) show similar clinical signs of MS, and tend to have damage (lesions) to the same areas of their nervous system. This suggests that these people may have the same underlying pathways leading to the development of MS, and that they may be a very informative group in which to look for immune or genetic abnormalities that might explain why they develop MS. This project will investigate people who have both MS and AITD and other members of their families to see if we can work out what the links are between having the same combination of autoimmune diseases and developing lesions in particular parts of the nervous system. It will provide information on the pathways that lead to the development of MS, and information obtained from this study may eventually be of use in developing more specific therapeutic agents, by tailoring therapies to specific people with MS, depending on the clinical and immunological profile of that person.Read moreRead less
This project introduces a new biomarker in systemic lupus erythematosus termed an apotope. The aims are to study the diagnostic potential of an apotope of Ro60, a key target in lupus, together with its ability to initiate the disease and cause organ damage. The interaction of the Ro60 apotope with a novel protective factor called beta2-glycoprotein I will also be studied. These discoveries are likely to lead to new diagnostic tests and preventions for lupus and neonatal lupus.
Dendritic Cells And CCAAT/enhancer Binding Protein-delta (CEBP?) In Neuroinflammation And Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$576,538.00
Summary
This projects aims to develop new treatments by finding the cells and chemicals that naturally stop inflammation in the central nervous system in diseases like MS. It also aims to test new treatments by delivering them to where this inflammation takes place. This targeted delivery should mean fewer side effects because the rest of the body is not exposed to the treatment. Hopefully this will reduce the impact of these diseases on the community, and reduce side effects for the patient.
A Functional Autoantibody In Human Narcolepsy: Direct Evidence For The Autoimmune Hypothesis
Funder
National Health and Medical Research Council
Funding Amount
$444,928.00
Summary
Narcolepsy is a chronic disabling sleep disorder causing irresistible sleepiness and, in most cases, brief attacks of weakness on emotional arousal (cataplexy). Other symptoms include a transient paralysis at the beginning or end of sleep and vivid hallucinations at the start of sleep. Symptoms usually appear during adolescence or early adulthood. It affects between one in 1,000 and one in 2,000 people, yet the diagnosis is often delayed for several years because of the lack of a simple diagnost ....Narcolepsy is a chronic disabling sleep disorder causing irresistible sleepiness and, in most cases, brief attacks of weakness on emotional arousal (cataplexy). Other symptoms include a transient paralysis at the beginning or end of sleep and vivid hallucinations at the start of sleep. Symptoms usually appear during adolescence or early adulthood. It affects between one in 1,000 and one in 2,000 people, yet the diagnosis is often delayed for several years because of the lack of a simple diagnostic marker. It has been suspected for some time that narcolepsy is caused by a malfunctioning immune system, but direct evidence for the so-called autoimmune hypothesis has been lacking. We have recently discovered the smoking gun in the form of an autoantibody that circulates in the bloodstream and produces some of the features of narcolepsy on transfer to experimental animals. The identification of the autoantibody, which we term a functional autoantibody because it directly alters the function of nerves thought to be involved in narcolepsy and cataplexy, opens a new chapter in narcolepsy research that has important diagnostic and therapeutic implications. Testing for the autoantibody in subjects recruited from national and international centres for sleep research will determine its value in the diagnosis of narcolepsy and may help distinguish narcolepsy from other sleep disorders. Preliminary findings are encouraging and suggest that the autoantibody is a sensitive and specific marker for human narcolepsy and might lead to a clinically useful diagnostic test. In another part of the project, experimental approaches willl be used to identify an antibody called an antiidiotype that can neutralise the narcolepsy autoantibody and therefore be developed as a therapeutic agent. Finally, experiments have been designed to examine the effect of the autoantibody on neurotransmitters in the brain that are believed to result in cataplexy.Read moreRead less
Innovative Stem Cell-based Strategies To Establish Immune Tolerance And Tissue Repair
Funder
National Health and Medical Research Council
Funding Amount
$5,554,618.00
Summary
Diseases such as autoimmune gastritis, multiple sclerosis and diabetes arise because a rogue immune system has turned inwards to attack our organs. The organ destruction follows from recognition by the immune system of specific molecules in these organs. These autoimmune diseases are incurable and controlled mainly by long-term administration of substances that suppress the immune system, often with serious side-effects. A rational approach is to render the rogue immune system harmless by removi ....Diseases such as autoimmune gastritis, multiple sclerosis and diabetes arise because a rogue immune system has turned inwards to attack our organs. The organ destruction follows from recognition by the immune system of specific molecules in these organs. These autoimmune diseases are incurable and controlled mainly by long-term administration of substances that suppress the immune system, often with serious side-effects. A rational approach is to render the rogue immune system harmless by removing the cells that recognize these particular molecules. This can be achieved by a Trojan horse approach in which the molecules are delivered to the immune system such that that the immune cells that recognize them are removed. To deliver these molecules to the immune system we will genetically engineer bone marrow stem cells, or embryonic stem cells that generate these stem cells, because they are precursors of mature immune cells. Rejection of organ transplants arise in a similar way and also require long-term immunosuppression. A similar approach can therefore be taken to promote acceptance of foreign organ grafts. In the aged, we will combine these approaches with rejuvenation of the immune system by blockade of sex steroid production and-or by creation of a new immune organ.Read moreRead less
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
Organ-specific Autoimmunity: The Role Of The Thymus And Periphery In Shaping The Gastric-specific T Cell Repertoire
Funder
National Health and Medical Research Council
Funding Amount
$579,763.00
Summary
The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own tissues. White blood cells, called T lymphocytes are responsible for attacking our own tissues in autoimmune diseases. Our studies will employ a range of molecular, genetic and imaging technologies to track the rare and potential harmful white blood cells. Our studies should reveal the me ....The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own tissues. White blood cells, called T lymphocytes are responsible for attacking our own tissues in autoimmune diseases. Our studies will employ a range of molecular, genetic and imaging technologies to track the rare and potential harmful white blood cells. Our studies should reveal the mechanisms by which these self destructive T lymphocytes are silenced in healthy individuals on the one hand, and on the other hand escape to cause destruction in individuals with autoimmune diseases. This fundamental information will allow the development of therapeutic strategies to selectively turn-off these destructive T lymphoctyes in individuals with autoimmune disease and thereby remove the damaging immune response and cure the disease.Read moreRead less