Induction Of Natural T-Regulatory Cells By Thymic Dendritic Cell Populations
Funder
National Health and Medical Research Council
Funding Amount
$413,775.00
Summary
In this study, we will determine the roles of the antigen presenting cells, namely denderitic cells, in the induction of T-regulatory cell (T-reg) developemnt in the thymus. T-reg cells play important roles in controlling the development of autoimmunity. This study will help to understand the possible causes of autoimmune diseases and to develop new treatments for these diseases.
Immune Dysregulation In HIV Patients With Immune Reconstitution After Highly Active Anti-retroviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
As HIV infection progresses to AIDS, there is a depletion of CD4 T-cells from the patient's blood and inhibition of the function of the remaining cells. Some immune defects resolve if the patient is given treatment with highly active anti-retroviral therapy (HAART), but it remains to be determined if the function of the imune system returns fully to normal. We have shown that problems with the regulation of the restored immune system in the first 6 months of treatment can lead to diseases associ ....As HIV infection progresses to AIDS, there is a depletion of CD4 T-cells from the patient's blood and inhibition of the function of the remaining cells. Some immune defects resolve if the patient is given treatment with highly active anti-retroviral therapy (HAART), but it remains to be determined if the function of the imune system returns fully to normal. We have shown that problems with the regulation of the restored immune system in the first 6 months of treatment can lead to diseases associated with Mycobacterial infections (eg: tuberculosis), CMV retinitis, hepatitis B virus or hepatitis C virus. We have defined these conditions as Immune Restoration diseases (IRD) and shown that they occur in one in four individuals who begin HAART from low baseline CD4 T-cell counts. IRD are likely to become common as therapy becomes available in Africa and Asia as patients begin treatment from low CD4 T-cell counts. There is also emerging evidence that dysregulated T-cell responses may cause disease later in the course of immune reconstitution. For example, some patients with undetectable HIV experience opportunistic infections or autoimmune disease after many months of HAART. This project will use West Australian patients receiving optimal therapy for their HIV infection. We will analyse immune activation and T-cell function in patients beginning HAART with low CD4 T-cell counts and patients who have had well-controlled HIV infection for at least 6 months. Blood samples will be collected for the measurement of immunological messengers (cytokines) known to be involved in different types of immune responses. The results will be correlated with the clinical outcome.Read moreRead less
The Role Of The Dendritic Cell Surface Molecule Clec9A In Dendritic Cell Subset Function And Dead Cell Recognition
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Dendritic cells (DC) are sentinels of the immune system. DC monitor the environment and regulate tolerance to self versus immunity to dangerous material. Different types of DC perform different jobs. We have identified a new surface molecule, Clec9A, on some mouse and human DC. We will investigate the function of Clec9A in the immune response. We will also use Clec9A to help unite mouse and human DC biology, since until now there have been few useful marker molecules common to both species.
The Role Of C-Cbl In The Regulation Of T Cell Signalling And Development
Funder
National Health and Medical Research Council
Funding Amount
$527,250.00
Summary
c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) ....c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) mice show that Cbl proteins are important in regulating the development of, and signalling by, cells of the immune system called T cells. c-Cbl knockout mice show greatly enhanced PTK-signalling responses and deregulated activity of a PTK called ZAP-70. The mechanism of this is not known, but analysis of a c-Cbl mutant mouse shows that this is not dependent on the tyrosine kinase binding (TKB) domain of c-Cbl. Therefore other functional domains of Cbl must be responsible for the increased signalling response in the c-Cbl knockout mouse. One candidate is the highly conserved RING finger domain which can modify Cbl-associated PTKs by addition of ubiquitin molecules. Ubiquitination of a protein often, but not always, leads to its degradation, and this could be how Cbl controls the strength and duration of signalling in T cells. However there may be other functions of the conserved RING finger yet to be identified. c-Cbl itself is prominently and very rapidly modified by tyrosine phosphorylation on tyrosine 737 by the Fyn PTK following T cell activation, but the role of this modification is not known and could also be essential for c-Cbl s function in T cells. We plan to investigate the roles of the RING finger domain and Fyn-mediated tyrosine phosphorylation in c-Cbl regulation of T cell signalling by analyzing knock-in mice that carry specific mutations disrupting the RING finger or tyrosine 737 in the c-Cbl gene.Read moreRead less
UNDERSTANDING HEPATITIS C VIRUS-SPECIFIC T CELL TOLERANCE
Funder
National Health and Medical Research Council
Funding Amount
$429,710.00
Summary
Most individuals who are infected with hepatitis C virus (HCV) develop a persistent infection that is lifelong and are at risk of developing serious liver disease, including liver cancer. The evidence suggests that an inadequate immune response is responsible for the inability of the patient to resolve the infection, but it is not clear which stage of the immunological cascade might be targeted. In this project, we will test the hypothesis that HCV antigen induce supressor T cells This will have ....Most individuals who are infected with hepatitis C virus (HCV) develop a persistent infection that is lifelong and are at risk of developing serious liver disease, including liver cancer. The evidence suggests that an inadequate immune response is responsible for the inability of the patient to resolve the infection, but it is not clear which stage of the immunological cascade might be targeted. In this project, we will test the hypothesis that HCV antigen induce supressor T cells This will have the effect of inhibiting the immune response and result in the outcome that we currently recognise as persistent HCV infection.Read moreRead less
Co-ordinating The Intrinsic And Extrinsic Arms Of Hematopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$615,286.00
Summary
The cell types of the blood, such as red and white blood cells, are produced in the bone marrow from a rare stem cell. The stem cell uses a handfull of important master-regulatory genes that act in a hierarchy to promote the blood cell differentiation process. This research aims to understand how these master-regulators function in isolation and together in producing the white blood cells that are required for our immune response to microbes, vaccination and to prevent cancer.
Regulation Of T Follicular Helper Cell Development And Effector Function In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,197.00
Summary
Immune cells mature into distinct populations with specialized functions. One subsets are T follicular helper (TFH) cells which are important for instructing B cells to produce antibodies following infection or vaccination. The means by which TFH cells are generated are unknown. We will determine mechanisms whereby TFH cells are produced and how they function. We hope to design approaches that will modulate the function of TFH cells in cases of immunodeficiencies, autoimmunity or vaccination.
Molecular Interactions Of The Tetraspanins CD37, TSSC6 And CD151 In T Cells
Funder
National Health and Medical Research Council
Funding Amount
$566,575.00
Summary
The tetraspanins are a new type of protein that are found at the surface of cells. Cells of the immune system, such as white blood cells, display at their surface, up to 20 different tetraspanin proteins. However, the precise contributions of these tetraspanin proteins to immunity is still not clear, nor is it clear exactly how tetraspanin proteins differ from one another and why white blood cells need to display so many different tetraspanins. Using genetic technology we have created mice which ....The tetraspanins are a new type of protein that are found at the surface of cells. Cells of the immune system, such as white blood cells, display at their surface, up to 20 different tetraspanin proteins. However, the precise contributions of these tetraspanin proteins to immunity is still not clear, nor is it clear exactly how tetraspanin proteins differ from one another and why white blood cells need to display so many different tetraspanins. Using genetic technology we have created mice which are unable to express certain individual tetraspanin proteins at their cell surface. Excitingly, the immune systems of these mice are not normal, in particular one type of white blood cell, the T cell responds in an exaggerated manner to stimulation. These results suggest a role for tetraspanins in the control and regulation of the immune system. This project will extend these results and work out the precise molecular mechanism by which the tetraspanins exert this control. In the future, a full understanding of how tetraspanins control T cells may ultimately lead to novel ways of controlling the immune system.Read moreRead less
Investigation Of The Roles Of TNFa-related Apoptosis-inducing Ligand, TRAIL, In The Immune System.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the t ....TRAIL, is a newly described member of the tumour necrosis factor (TNF)-family of cytokines, which can kill a wide range of tumour cells, and virus infected cells, but not most normal cells. TRAIL has proven to be safe when administered to normal, tumour bearing, and virally-infected mice, and causes no detectable side-effects in these animals. As such it holds huge potential and is being widely investigated for use as a new anti-cancer therapy. Despite these findings, little is known about the true physiological role of TRAIL in vivo. To define the normal roles of TRAIL, CIA has been characterising TRAIL gene knock-out mice. These studies have confirmed that TRAIL contributes to control of tumours in vivo, and in early events during anti-viral responses. However, these studies have also revealed novel roles for TRAIL in T cell biology, and B cell memory. Understanding how TRAIL contributes to these processes, will shed significant light on the potential of TRAIL to be used as a therapeutic agent for humans with lymphoproliferative disease, for illiciting better long-lived antibody responses such as after vaccination, and as an anti-viral reagent in immunocompromised individuals during virus infection.Read moreRead less
The Role Of The Intestinal Epithelium In Gliadin Peptide Influx In Coeliac Disease
Funder
National Health and Medical Research Council
Funding Amount
$503,566.00
Summary
Food products made from cereals such as wheat are part of the staple diet for much of the world but unfortunately they trigger coeliac disease in 1:100 individuals including more than 100,000 Australians. This project aims to determine where the disease inducing proteins cross the cells that line the intestine to enter the body. It also aims at increasing the health of these cells to produce a barrier that can prevent the disease inducing proteins from entering the body.