Population Dynamics Of Tissue-specific Effector And Regulatory CD4+ T Cells
Funder
National Health and Medical Research Council
Funding Amount
$394,250.00
Summary
Survival of white blood cells in the body is an active process and is important for the maintainence of a T cell population which can recognise a wide variety of foreign antigens. At present the fate of T lymphocytes which recognise self antigens is unclear. Knowledge of the survival kinetics of self-reactive T lymphocytes and the mechanism by which they are regulated in the normal individual is crucial to be able to control the development of various diseases, including autoimmune diseases. Fro ....Survival of white blood cells in the body is an active process and is important for the maintainence of a T cell population which can recognise a wide variety of foreign antigens. At present the fate of T lymphocytes which recognise self antigens is unclear. Knowledge of the survival kinetics of self-reactive T lymphocytes and the mechanism by which they are regulated in the normal individual is crucial to be able to control the development of various diseases, including autoimmune diseases. From our previous studies of autoimmune gastritis we have generated cell lines of lymphocytes that recognise stomach-specific antigens and with these unique reagents we will perform experiments to determine the fate of these self-reactive T cells in a normal individual. Also we will determine the impact of different amounts of the tissue antigens on the survival and activation of self-reactive T cells, and finally how a special class of lymphocytes, know as regulatory lymphocytes, act in vivo to control the activity of self-reactive T cells. We will use not only classical immunological approaches to address these issues but also state of the art imaging, to visualise the nature of the cell interactions in living tissues. The information arising from this work will underpin strategies to selectively turn off self-reactive lymphocytes that cause disease, will form the basis of clinical development of cell based therapies to treat autoimmune diseases, and the imaging technologies developed in this grant will have wide applicability to the study of a range of immune responses.Read moreRead less
Understanding Rapid T-cell Clearance By The Liver: A Critical Step Towards Improved Liver Transplantation.
Funder
National Health and Medical Research Council
Funding Amount
$412,134.00
Summary
The liver has paradoxical properties: it is the site of effective immune responses to pathogens, but under some circumstances, it is known to induce harmless immune responses. Poor responses can be beneficial in a transplantation setting because, in the absence of immunosuppressive drugs, liver transplants are more readily accepted than other organ allografts. Not only are liver transplants well accepted, they can induce secondary acceptance of kidney or heart grafts from the same donor that wou ....The liver has paradoxical properties: it is the site of effective immune responses to pathogens, but under some circumstances, it is known to induce harmless immune responses. Poor responses can be beneficial in a transplantation setting because, in the absence of immunosuppressive drugs, liver transplants are more readily accepted than other organ allografts. Not only are liver transplants well accepted, they can induce secondary acceptance of kidney or heart grafts from the same donor that would otherwise be rejected. However, this ability of the liver to induce unresponsiveness may allow some viruses to persist, particularly , Hepatitis B and C. Four in every five patients infected with hepatitis C develop a chronic disease due to the inability of the immune system to clear the virus. Although it is known that white blood cells enter the liver and become unresponsive, little is known about the mechanisms that prevent an effective response. The CIA s work has been at the forefront of liver immunology and transplantation by demonstrating that the architecture and vasculature of the liver, and therefore the type of unique cellular interactions taking place within it, are essential to gain an understanding of its unique immunological properties. Using the CIB s unique protocols for solid-organ transplantation in rodents, we will provide evidence for a new mechanism that occurs at very early stages after antigen encounter in the liver. We propose to unravel this mechanism using well characterised transgenic mouse models and advanced analytical technology. We will determine the role of this mechanism in liver transplantation. Our preliminary data point to a very high chance of success. This project will have important implications for transplantation studies and for the development and treatment of food allergies and chronic hepatitis C and other of immune-mediated liver diseases.Read moreRead less
The Axis Of Bcl-2, Plasmacytoid DCs And Lupus As A Basis For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$712,172.00
Summary
Systemic lupus erythematosus (SLE) affects 1 in 1000 Australians, mostly women. Here the immune system goes awry and makes antibodies against the body’s own components including the body’s DNA. This leads to damage to many parts of the body including kidneys, joints, brain and heart. It is incurable. A particular immune cell controls the development of this disease and we have found this cell is selectively killed by an inexpensive drug, which we hope will be a better way of treating SLE.
Our research has identified unprecedented communications between the microbes that colonize our body’s surfaces and killer T cell immunity. Our findings indicate that microflora is key to a healthy balance between two immune mediator systems that have opposing effect on T cell immunity. The project will extend our understanding of how this regulated and seeks to harness these novel insights to explain the well known, but poorly understood role of microbes in autoimmune diseases.
Functional Aspects Of CD52 Signalling In Immune Regulation
Funder
National Health and Medical Research Council
Funding Amount
$133,351.00
Summary
Autoimmune disease, such as Rheumatoid arthritis, Type 1-Diabetes, Lupus and Multiple Sclerosis, is caused by disruptions in the normal control of the immune system. A type of cell called a regulatory T-cell can prevent these damaging immune reactions. However, we do not know how T-cells do this. CD52 is a protein found on the surface of T-cells. Our preliminary work shows that CD52 also suppresses these damaging immune responses. This project researches how CD52 influences the immune system.
Control Of Pathogenic Antibody Responses In Humans
Funder
National Health and Medical Research Council
Funding Amount
$763,845.00
Summary
Deficient or inappropriate antibody responses are at the core of many autoimmune diseases, allergies, food intolerances, and often explain the failure of vaccination strategies. Specialised follicular T cells control the quality of antibodies produced by B cells. This fellowship will combine basic studies investigating B cell helper or regulatory follicular T cells in humans with genetic studies identifying the causes of autoantibody-driven diseases. The results will uncover targeted therapies.
Interleukin Signalling In CD4+ T Cell Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$663,919.00
Summary
Our bodies rely on the production of antibodies to fight infection. The cytokine IL-21 is produced by immune cells called T follicular helper (Tfh) cells that help B cells make antibodies. Tfh cells, in turn, are controlled by regulatory (Tfr) cells. Our findings demonstrate that IL-21 supports Tfh cells and limits Tfr cells, thus favoring antibody production and long term immunity. Using genomic and cellular approaches, the mechanism(s) underlying these observations will be explored.
NK Cell Subsets And Their Role In Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$173,522.00
Summary
Natural killer (NK) cells are 5-10% of white blood cells of the immune system that represent one of our first lines of defense against microbes and cancer development. Recent evidence strongly suggests that NK cells are major cells of importance in the immune system, not only in acting as killers of cancer cells or virus-infected cells, but also in regulating the adaptive memory components of the immune response. Despite our greater knowledge of NK cell biology, we still know very little about t ....Natural killer (NK) cells are 5-10% of white blood cells of the immune system that represent one of our first lines of defense against microbes and cancer development. Recent evidence strongly suggests that NK cells are major cells of importance in the immune system, not only in acting as killers of cancer cells or virus-infected cells, but also in regulating the adaptive memory components of the immune response. Despite our greater knowledge of NK cell biology, we still know very little about the diversity that exists within the NK cell population. The development and maturation of NK cells requires far greater study and this proposal aims to examine this question in the best experimental model, the mouse. We have recently made an important breakthrough concerning the distinct functional behavior of newly discovered NK cell subsets. We now aim to develop a more integrated model of NK cell development, such that vaccines and adjuvants designed to prevent and ameliorate lethal and chronic infectious diseases and cancer can be more rationally designed.Read moreRead less
Transcriptional Control Of Peripheral T Cell Differentiation During Pathogen Infection And Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$92,314.00
Summary
White blood cells, specifically helper and killer T cells, play an important role in fighting infection. They are tightly regulated and if not properly controlled can lead to aggressive autoimmune diseases such as diabetes and multiple sclerosis. My studies will elucidate the mechanisms behind the regulation of T cells at steady-state and during disease. Insights gained from this project will have implications for the design of new approaches to combat infectious and autoimmune diseases.
Mechanisms Of Dendritic Cell-induced T-cell Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$314,773.00
Summary
Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic suceptibility to autoimmune disease, the mechanisms fail and the body's immune sytem attacks normal tissues or organs. We have developed a new approach to using the cells which train the immune system to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. Thes ....Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic suceptibility to autoimmune disease, the mechanisms fail and the body's immune sytem attacks normal tissues or organs. We have developed a new approach to using the cells which train the immune system to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. These cells (dendritic cells) are genetically modified to express the molecular targets of the autoimmune response. This in turn switches off the response to these targets. In this project we will explore how these cells can be used to turn off cells of the immune system and if cells of the immune system in turn control the dendritic cell's ability to do this.Read moreRead less