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The Regulation Of Monocyte Derived Dendritic Cells (moDCs) During Allograft Rejection
Funder
National Health and Medical Research Council
Funding Amount
$110,218.00
Summary
Islet transplantation can cure type 1 diabetes, but the required drugs for immunosuppressing graft rejection have side effects. Therefore understanding how immune rejection occurs so that we can suppress in a more discreet selective way is our goal. A type of cell that is prominent during graft rejection is the monocyte derived dendritic cell. We propose that this cell is critical for orchestrating immune responses during rejection. Therefore we wish to determine how such cells are controlled.
Antigen-presenting cells control immune responses. Different types of these cells do different jobs and affect different diseases. We wish to control these processes by determining how the cells live and die. In particular we are interested in controlling the local immune responses during rejection of islet transplantation, which can cure type 1 diabetes.
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
Upregulation Of Chemokine Receptor Expression And Function On CD4+ T Cells In Primary And Secondary Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
This research will begin to determine the significance of changes in the amount of recently-discovered proteins on the surface of cells called T lymphocytes. These cells control immune responses and move throughout the body to do this. Sometimes, they are activated inappropriately and cause diseases like asthma, arthritis and multiple sclerosis and other times they need assistance for activation (vaccination). It is therfore important to understand how the movement of these cells through the bod ....This research will begin to determine the significance of changes in the amount of recently-discovered proteins on the surface of cells called T lymphocytes. These cells control immune responses and move throughout the body to do this. Sometimes, they are activated inappropriately and cause diseases like asthma, arthritis and multiple sclerosis and other times they need assistance for activation (vaccination). It is therfore important to understand how the movement of these cells through the body is controlled. A better understanding of this process shuld allow us to design better ways to control it, thereby controlling the negative aspects of T lymphocyte activation.Read moreRead less
Targeting CD40L(CD154) On Dendritic Cells For CD8 T Cell-mediated Immunity And Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Killer T cells fight infection but also participate in transplant rejection. Activation of killer T cells often requires helper T cells. However, in the absence of helper cells, we have found an alternative pathway by which killer cells can be activated. We will explore this new pathway in enhancing vaccine responses and in modulating transoplant rejection.
This research aims to understand the early developmental events in human blood cell diversi?cation that generate cells involved in oxygen transport, wound healing and protecting us from cancer and infection. The ?ndings will assist in diagnosing and treating human immune system and blood cell disorders such as leukaemia, chronic infection and autoimmunity through understanding the mechanisms of how normal, healthy blood cells are generated.
Do NK Cells Limit The Long Term Burden Of CMV In Older Australians And Transplant Recipients?
Funder
National Health and Medical Research Council
Funding Amount
$413,864.00
Summary
Most people are infected with cytomegalovirus at an early age. The virus is not naturally cleared from the body but becomes latent and may be reactivated by stress or inflammation. Repeated immune responses to these reactivations causes more inflammation and wears out the immune system resulting in diseases of aging (eg: cardiovascular disease). Here we investigate which aspects of the immune system can control CMV in healthy people and in renal transplant recipients. We focus on a population of ....Most people are infected with cytomegalovirus at an early age. The virus is not naturally cleared from the body but becomes latent and may be reactivated by stress or inflammation. Repeated immune responses to these reactivations causes more inflammation and wears out the immune system resulting in diseases of aging (eg: cardiovascular disease). Here we investigate which aspects of the immune system can control CMV in healthy people and in renal transplant recipients. We focus on a population of cells called natural killer (NK) cells.Read moreRead less
Controlling Life And Death Of Dendritic Cell Subsets For Immunomodulation
Funder
National Health and Medical Research Council
Funding Amount
$639,577.00
Summary
Dendritic cells are pivotal in orchestrating immune responses; for example, they can turn immune cells into assassins to kill virus infections. Their function is so diverse that different dendritic cells do different jobs. There are many genes that control life and death of cells but those that are important for each specialised dendritic cell have not been comprehensively studied. Drugs that affect the proteins made by such genes selectively may be a new way of controlling immune responses.
Antigen Presentation, Recognition And The Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$15,738,750.00
Summary
The early events in immunity require various molecular interactions. We will examine the structural and biophysical basis for some of these interactions, including those associated with transplant rejection and autoimmunity. We will explore the impact of variation in immune response genes on immune evasion and disease susceptibility. Our basic research will determine the mechanisms by which the immune system discriminates between different self and micro-organism associated determinants. We will ....The early events in immunity require various molecular interactions. We will examine the structural and biophysical basis for some of these interactions, including those associated with transplant rejection and autoimmunity. We will explore the impact of variation in immune response genes on immune evasion and disease susceptibility. Our basic research will determine the mechanisms by which the immune system discriminates between different self and micro-organism associated determinants. We will address the structural and biochemical basis for operation of an immune molecule called tapasin and unravel the basis for how some viruses escape the function of this molecule, thus allowing their immune evasion. We will also explore the use of modified small proteins called peptides in a humanized model of gluten hypersensitivity resembling that of Celiac disease. The molecular basis of the natural human immune system's capacity to recognise and reject grafts will be examined. This complements work aimed at improving the prediction of clinical graft rejection in transplantation. Dendritic cells play a central role in immunity, responsible for capturing material, whether from micro-organisms or self tissues, and presenting it to cells of the immune system. Our program will study the development and immunological function of the different dendritic cell subtypes. We will determine the relative contribution of each to the maintenance of immune tolerance and to the induction of immunity to several pathogens, including herpes simplex virus and malaria. Novel dendritic cell surface molecules that we have discovered will be tested for their ability to enhance the effectiveness of vaccines. Overall, this program utilises a broad array of immunological techniques designed to dissect the development and function of various immune system cell types and determine the structure-function relationships between important cell surface molecules involved in immunity.Read moreRead less