The Phenotype Of Protective Cytotoxic T Cell Responses During Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$841,114.00
Summary
T cell responses are important to establish protection against pathogens and some cancer via generation of memory cells that can be maintained long term and defeat promptly re-infections. This proposal aim at determining important factors that drive the success of immunological memory by employing single cell technologies and unique longitudinal samples from subjects infected with hepatitis C virus. The finding of this study will inform current vaccine research and immunotherapies.
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
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
Interactions Between Adaptable Pathogens, Drugs And The Human Host
Funder
National Health and Medical Research Council
Funding Amount
$5,727,327.00
Summary
The Centre for Clinical Immunology and Biomedical Statistics (CCIBS) represents a collaboration between Royal Perth Hospital and Murdoch University that has brought together internationally recognised expertise in clinical immunology, experimental biology and innovation in biostatistics and computing. These resources have been applied to a broad range of research issues within the broad framework of HIV and hepatitis C disease and treatment. CCIBS has become a leading centre of research excellen ....The Centre for Clinical Immunology and Biomedical Statistics (CCIBS) represents a collaboration between Royal Perth Hospital and Murdoch University that has brought together internationally recognised expertise in clinical immunology, experimental biology and innovation in biostatistics and computing. These resources have been applied to a broad range of research issues within the broad framework of HIV and hepatitis C disease and treatment. CCIBS has become a leading centre of research excellence internationally, establishing a reputation for innovative approaches to host-viral interactions that are built on a long tradition of research into the population genetics of both human and viral genomes, combined with a willingness to negotiate complex computation and statistical challenges in order to faithfully reflect dynamic biological processes at a population level. An early recognition that large and integrated repositories of genetic and clinical data are fundamental to the research success in the genomic era has also led to the creation of the single most comprehensive repository of HIV genetic sequencing data in the world. The contributions that CCIBS has made to several distinct areas of research, including understanding viral adaptation to host immune responses, the development of genetic testing to predict drug hypersensitivity reactions, and causes of antiretroviral drug-associated toxicities, have been published in prestigious journals including Science, Nature, Nature Immunology, The Lancet, Proceedings of National Academy of Sciences, and The American Journal of Human Genetics, and have also resulted in numerous international collaborations that recognise the unique attributes that CCIBS has been able to bring to the global research effort aimed at understanding fundamental aspects of HIV and hepatitis C biology and treatment.Read moreRead less
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.
Defining The Roles Of The Chemotactic Receptor EBI2 For The Regulation Of Leukocyte Migration And The Generation Of Immunity
Funder
National Health and Medical Research Council
Funding Amount
$421,747.00
Summary
The proposed study aims at improving our understanding of the role of the immune cell receptor Epstein-Barr virus-induced gene 2 (EBI2) in guiding the movement of white blood cells during immune responses. The project will investigate the function of EBI2 in the control of infectious diseases and its regulation on human immune cells. These insights have the potential to create new therapeutic approaches to treat human autoimmune and inflammatory diseases and improve vaccine design.