Cell-mediated Immune Responses In Cytomegalovirus-induced Myocarditis
Funder
National Health and Medical Research Council
Funding Amount
$238,407.00
Summary
The proposed research will provide a clearer understanding of the body's immune response to virus and self tissues in inflammatory heart disease. Inflammation of the heart, myocarditis, can occur following virus infection. The condition may be chronic and persist for a long time even after the virus infection has resolved. The autoimmune response attacks the body's own tissues and involves reactivity to a heart protein, namely myosin. Important immune cells (B and T cells) play a role in the dis ....The proposed research will provide a clearer understanding of the body's immune response to virus and self tissues in inflammatory heart disease. Inflammation of the heart, myocarditis, can occur following virus infection. The condition may be chronic and persist for a long time even after the virus infection has resolved. The autoimmune response attacks the body's own tissues and involves reactivity to a heart protein, namely myosin. Important immune cells (B and T cells) play a role in the disease process. Antibodies are produced by B cells during the virus infection which react to myosin but we do not know the reactivity of T cells in this disease. Natural molecules (cytokines) produced by our body are important for shaping our immune response (T and B cell-mediated) in virus infections and diseases. Autoimmune disease is a result of a mistake by our immune system. Such diseases can be triggered by virus infection and require immunotherapy for correction. In the project, we propose to : 1. Investigate immunological responses of immune cells (T cells) in the heart using an experimental mouse model of cardiovascular disease. 2. Examine the response of T cells to myosin using the mouse model of infection with a herpesvirus, cytomegalovirus (CMV). 3. Study the role of cytokines and immunotherapy in our CMV-triggered myocarditis model. Determination of the events leading to cardiovascular disease will allow developments of improved treatment and potential vaccinations against inflammatory heart disease. The findings from the proposed project are expected to have broader impact for other viruses invading the heart and their associated diseases in man.Read moreRead less
The Generation And Function Of Tissue-specific Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$488,577.00
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. We will discover how regulatory lymphocytes, are able to protect against autoimmune disease. Such regulatory lymphocytes are attractive therapeutic agents to prevent a variety of immune-mediated diseases, including autoimmune diseases, allergy and transplantation rejection.
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
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
Immunopathogenesis Of Organ-specific Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$284,638.00
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. Our studies will employ state-of-the art technologies to further our knowledge of this class of diseases and to uncover the normal mechanisms that allow the immune system to differentiate foreign and self components.
The Role Of NKT Cell Subsets In The Regulation Of EAE
Funder
National Health and Medical Research Council
Funding Amount
$455,899.00
Summary
Multiple sclerosis (MS) is the most cause of paralysis amongst young adults. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that recapitulates many features of the human disease. NKT cells are a group of T cells, whose actiavtion protects against EAE, in an as yet unidentified manner. These studies will provide critical information on the way in which NKT cells regulate immunity and will enhance development of therapies for MS.
Novel Approaches To Pathogenesis, Diagnosis &treatment Of Autoimmune Diseases Based On New Insights Into Thymus-dependen
Funder
National Health and Medical Research Council
Funding Amount
$1,045,422.00
Summary
An individual relies upon their immune system to protect against invasion by hostile organisms. The system usually works well. Invading agents (the 'non-self') are detected and attacked by the immune system's patrolling killer T cells. These normally beneficial cells are called T cells because they were formed and educated in an organ called the thymus, which kick-starts our immune system in childhood, but falls into inactivity by adolescence. Sometimes the education system in the thymus goes wr ....An individual relies upon their immune system to protect against invasion by hostile organisms. The system usually works well. Invading agents (the 'non-self') are detected and attacked by the immune system's patrolling killer T cells. These normally beneficial cells are called T cells because they were formed and educated in an organ called the thymus, which kick-starts our immune system in childhood, but falls into inactivity by adolescence. Sometimes the education system in the thymus goes wrong and it releases T cells that mistakenly attack 'self' instead of 'non-self'. This causes autoimmune diseases, such as type1 diabetes, multiple sclerosis and rheumatoid arthritis. The Euro-Thymaide project aims to determine why and how self-attacking T cells are mistakenly released from the thymus into the body. Usually such errant T cells are detected and destroyed within the thymus, before they have the opportunity to escape and cause autoimmune diseases. The ultimate objective is to learn about the thymus recognition process and help the immune system detect and destroy faulty T cells that patrol the body, thereby preventing the onset of autoimmune diseases.Read moreRead less
Investigating T Cell Tolerance And Organ-specific Auotimmunity Using Autoantigen Deficient Mice
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
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. Our studies will employ technologies to genetically manipulate mice to further our knowledge of this class of disease and to uncover the normal mechanisms that allow the immune system to prevent autoimmune attack. In particular we will gain information on the way that a new class ....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. Our studies will employ technologies to genetically manipulate mice to further our knowledge of this class of disease and to uncover the normal mechanisms that allow the immune system to prevent autoimmune attack. In particular we will gain information on the way that a new class of lymphocytes, known as regulatory lymphocytes, are able to protect against autoimmune disease. Such regulatory lymphocytes have been identified in humans and are attractive therapeutic agents to prevent a variety of immune-mediated diseases, including autoimmune diseases, allergy and transplantation rejection.Read moreRead less