Epigenetic Regulation Of CD8+ T Cell Function And Memory.
Funder
National Health and Medical Research Council
Funding Amount
$578,171.00
Summary
Upon virus infection, a subset of white blood cells, called killer T cells, are recruited to fight the infection. This proposal aims to examine molecular changes that occur within killer T cells and impart their specific function. We also aim to understand how killer T cells are _programmed� as they establish immunological memory. This proposal will provide insights important for the design and improvement of vaccine strategies to fight pathogens such as influenza, HIV and even tumors.
Analysis Of The Molecular Functions Of Perforin: A Critical Role In Tumor Immunosurveillance
Funder
National Health and Medical Research Council
Funding Amount
$318,916.00
Summary
Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer ....Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer cell function in these models. But the role for perforin expressing killer cells in tumor surveillance against spontaneous tumorigenesis is still hotly debated. Our proposal to study tumor development in perforin-deficient p53-mutant tumor prone mice will enable us to answer this question. Furthermore, the molecular mechanisms by which perforin functions are poorly understood. We therefore also propose to complete a structure-function analysis of perforin using unique tools and information that our laboratory has at its disposal. The long-term goal will be to better understand the function of perforin at the molecular level such that the rationale design of therapeutic perforin inhibitors may become a reality for future regulation of killer cell effector functions in disease.Read moreRead less
A Polyepitope HPV16 E7 DNA Vaccine Restricted Through Multiple Class 1 Haplotypes Protects Against E7-expressing Tumour
Funder
National Health and Medical Research Council
Funding Amount
$218,244.00
Summary
Evidence that cervical cancer is caused by Human Papillomavirus is compelling. Once the virus enters the cells of the cervix, it produces a protein named E7 which functions to make the cells cancerous. Cervical cancer is the 5th commonest cause of death in women in Australia, and the major killer of women world-wide.The disease is particularly severe in those women whose immune systems are impaired, indicating immunological control of the cancerous cells . Current therapies including surgical re ....Evidence that cervical cancer is caused by Human Papillomavirus is compelling. Once the virus enters the cells of the cervix, it produces a protein named E7 which functions to make the cells cancerous. Cervical cancer is the 5th commonest cause of death in women in Australia, and the major killer of women world-wide.The disease is particularly severe in those women whose immune systems are impaired, indicating immunological control of the cancerous cells . Current therapies including surgical removal are frequently inadequate, and the r is no effective drug to combat the virus.These observations indicate that a vaccine is warranted, and that the E7 protein may be an ideal target for the vaccine. Cervical tumour cells are killed by specialised immune system cells named CTLs which recognise fragments of foreign antigen(E7) on their surface bound to selfMHC molecules. Our work has shown that multiple antigen fragments can be encoded and stitched together in a genetic vaccine which will stimulate CTLs to function in a number of 'self'molecule situations Our laboratory has developed several mouse models of human cervical cancer , and (along with others) has worked out which parts of the E7 protein are importatnt in developing an appropriate immune response to control tumour growth when given as a vaccine. One animal model consists of mice which are genetically engineered to produce several types of selfmolecules and also E7. Thes mice develop skin tumours as result of E7 expression. This system provides model of cervical epithelial tumours caused by E7 expression in women.Thus we can ask the questions o can we elicit CTL responses which function in the context of humanself ? o Will these CTL responses prevent the growth of E7-induced epithelial tumours? The OUTCOME of the project will be a vaccine which will prevent the establishment of cervical cancer which can progress directly into clinical trials in women bearing appropriate selfmolecules.Read moreRead less
Enhanced Translation Of Epstein-Barr Virus Nuclear Protein, EBNA1, As A Target For T Cell-based Immunotherapy.
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
Epstein-Barr virus, (EBV) is a human herpesvirus associated with a range of human cancers. EBNA1, an important EBV antigen, was thought to be immunologically silent however, recent studies from our laboratory show that EBNA1 is recognized by our body's defence system and these observations raise the possibility that EBNA1 may be an exploitable, immuno-therapy target for treating EBV-associated cancers.
The Biology Of Events Following Reactivation Of Herpes Simplex Virus.
Funder
National Health and Medical Research Council
Funding Amount
$388,522.00
Summary
Herpes simplex virus causes genital herpes, severe disease in neonates, cold sores and occasionally fatal encephalitis. It lies doemant within nerve cells near the spine and reactivates intermittently, travelling down nerves to cause the characteristic ulcers in the skin, including the genitals. This grant has two major components. In the first we aim to continue studies which are defining the way in which Herpes simplex viruses assemble within nerve cells. These processes have always been the s ....Herpes simplex virus causes genital herpes, severe disease in neonates, cold sores and occasionally fatal encephalitis. It lies doemant within nerve cells near the spine and reactivates intermittently, travelling down nerves to cause the characteristic ulcers in the skin, including the genitals. This grant has two major components. In the first we aim to continue studies which are defining the way in which Herpes simplex viruses assemble within nerve cells. These processes have always been the subject of much debate and have never been properly studied in the nerve cells in which the virus lives. Furthermore the way in which herpes simplex virus enters the processes of nerve cells and moves to the cell body will be studied by similar techniques. Such studies may contribute to the development of herpes simplex virus as a vector for gene therapy for treatment of diseases of the nervous system. The second part of the grant will examine the immune processes that occur in the skin during the early stages of a recurrent herpes simplex lesion. In particular there is a linkage between nerves and the major cells in the skin which present viral antigen to defensive T-cells. This link may provide a route for direct access of herpes simplex virus to these cells. In previous work the viral protein targets in infected skin cells for killer T-cells which infiltrate the skin have been defined. In this grant we also aim to find the stretches of amino acids which are specifically targetted by these cells.Read moreRead less
Novel Approaches For Activation And Expansion Of Genetically Modified T Cells In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$115,660.00
Summary
Killer T lymphocytes can penetrate tumors and their propagation and transfer into cancer patients has demonstrated some encouraging results, but this form of adoptive immunotherapy remains ineffective in most cancer patients. We propose to improve the tumor trafficking and anti-tumor activities of killer cells by genetically engineering them with proteins that will enable them to recognise and destroy cancer cells. Our previous work has indicated that killer T lymphocytes can be genetically engi ....Killer T lymphocytes can penetrate tumors and their propagation and transfer into cancer patients has demonstrated some encouraging results, but this form of adoptive immunotherapy remains ineffective in most cancer patients. We propose to improve the tumor trafficking and anti-tumor activities of killer cells by genetically engineering them with proteins that will enable them to recognise and destroy cancer cells. Our previous work has indicated that killer T lymphocytes can be genetically engineered in culture with tumor recognition receptors. When transferred into mice, these genetically engineered cells can release toxic and inflammatory proteins that cause tumor destruction. In this proposal we wish to further test this approach in mice by enginneering the mouse killer T cells with (i) receptors that provide stronger signals for killing and proliferation; and (ii) with receptors targeting other structures on tumor cells including the tumor vasculature as a means to overcome tumor escape. In addition, we wish to test a novel approach of combining both genetic engineering and vaccination strategies for expanding gene-modified cells after adoptive transfer. These studies will allow the best receptor genes to be transferred to human white blood cells and examined for anti-tumor effects in immune-deficient mice.Read moreRead less
The Impact Of Granzyme B On Cytotoxic T Cell Migration Through Tissue
Funder
National Health and Medical Research Council
Funding Amount
$605,963.00
Summary
Cytotoxic T cells (CTL) are white blood cells that move in an orchestrated way into body tissues to target, and destroy, virus-infected or cancer cells. Destruction of these abnormal cells is achieved when they ingest cytotoxic enzymes (proteases) released by CTL. We propose that one of these cytotoxins, granzyme B, has a dual function, and that it is also involved in helping CTL to efficiently move towards the target cells by clearing a path through the local tissue structure.
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