A Dendritic Cell Subset Targeting Approach For Defining Immune Function And Tailoring Immunotherapy
Funder
National Health and Medical Research Council
Funding Amount
$692,753.00
Summary
Dendritic cells are important sentinel cells of the immune system that orchestrate our immune responses against invading pathogens. There are different types of dendritic cells and they perform different jobs. We have a series of antibodies that can recognise markers on the surface of different dendritic cells populations. We can use these antibodies as homing devices to deliver foreign material to individual dendritic cell subpopulations and thereby manipulate the type of immune response genera ....Dendritic cells are important sentinel cells of the immune system that orchestrate our immune responses against invading pathogens. There are different types of dendritic cells and they perform different jobs. We have a series of antibodies that can recognise markers on the surface of different dendritic cells populations. We can use these antibodies as homing devices to deliver foreign material to individual dendritic cell subpopulations and thereby manipulate the type of immune response generated. Effectively, we aim to tailor immune responses to fight a particular bacteria, virus, parasite, or even cancer cells. The current proposal will extend the number of antibodies we test for their ability to generate tailored immunity. We will examine a number of new molecules for their ability to shuttle foreign material to dendritic cells and their ability to stimulate immune responses. Next, we will test these homing devices as vaccines and their ability to prevent or treat cancer. Our aim is to develop a robust, highly efficient, generic, vaccination approach for cancer immunotherapy.Read moreRead less
Perforin Trafficking And Activation In Killer Lymphocytes
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
Perforin (PRF) is a protein essential for the function of cytotoxic lymphocytes during an immune response in humans. Humans deficient in PRF are severely immunosuppressed and fall critically ill if they contract a viral infection. The partial loss of PRF function can also predispose an individual to cancer. We aim to investigate the functional and biochemical properties of PRF. The outcomes of this study will determine how PRF influences the immune system and immune homeostasis in humans.
My research straddles biochemistry, cell biology and immunology. I am interested in the mechanisms of antigen presentation by dendritic cells, and the functions of the cystatin family of protease inhibitors.
Molecular And Cellular Mechanisms Of Cytotoxic Lymphocyte Perforin
Funder
National Health and Medical Research Council
Funding Amount
$419,223.00
Summary
Cytotoxic lymphocytes are immune cells, which recognise and kill virus-infected or cancer cells. Perforin is essential for the activity of cytotoxic lymphocytes. The loss of perforin function results in an inherited immune deficiency, or may lead to the development of cancer. Despite a key role of perforin, its mechanism of action and the regulation of activity are unknown. I propose to elucidate these aspects of perforin biology. This is important for understanding immune regulation in humans.
Aldehyde-modified Antigens For The Immunotherapy Of Adenocarcinomas
Funder
National Health and Medical Research Council
Funding Amount
$284,250.00
Summary
The incidence of breast cancer in women is 1 in 8 and the frequency of other cancers are rising. Even with conventional approaches such as surgery, cytotoxic therapy, radiotherapy and combination therapy only a few cancers are treatable. The development of a cancer vaccine will greatly benefit humanity similar to childhood and adult vaccinations for preventing infectious disease. In this proposal we intend to chemically modify a synthetic protein called mucin 1 (MUC1) which is exprssed on cells ....The incidence of breast cancer in women is 1 in 8 and the frequency of other cancers are rising. Even with conventional approaches such as surgery, cytotoxic therapy, radiotherapy and combination therapy only a few cancers are treatable. The development of a cancer vaccine will greatly benefit humanity similar to childhood and adult vaccinations for preventing infectious disease. In this proposal we intend to chemically modify a synthetic protein called mucin 1 (MUC1) which is exprssed on cells in breast cancer to make it more immunogenic - that is make it look more like a foreign protein so that the immune cells can make antibodies or killer cells that recognise it. These activated cells can now migrate to the tumour sites and kill the invading tumour. In order to do this we are going to introduce mannose, a particular sugar that can bind to important white blood cells and an aldehyde group that can activate immune cells. We will test the effectiveness of the modified proteins in mice to see if they can generate an good immune. If this is satisfactory then we will see if mice are vaccinated with these modified proteins can reject implanted mouse or human tumours. If these experiments are successful further work can be done with human cells and later clinical trials. Any methods developed here will be applicable to other cancers and also infectious diseases.Read moreRead less
Investigation Into The Immunogenicity Of Dendritic Cell-derived Exosomes
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Dendritic cells are essential in immune responses. They have unique capacity to stimulate lymphocytes specific to viruses, bacteria and cancers. They are extremely rare and difficult to isolate. We have developed a method of culture which gives a continuous supply of dendritic cells. Cells produced in our culture also produce a high yield of acellular membranous particles called 'exosomes' which have been previously been very difficult to isolate and characterise. Some preliminary reports sugges ....Dendritic cells are essential in immune responses. They have unique capacity to stimulate lymphocytes specific to viruses, bacteria and cancers. They are extremely rare and difficult to isolate. We have developed a method of culture which gives a continuous supply of dendritic cells. Cells produced in our culture also produce a high yield of acellular membranous particles called 'exosomes' which have been previously been very difficult to isolate and characterise. Some preliminary reports suggest that exosomes can induce or modify immune responses and that they have enormous immunotherapeutic potential. Further study of their clinical application is limited by the difficulty of isolating enough dendritic cells from which to isolate exosomes. This study will involve production and characterisation of exosomes from our unique murine dendritic cell culture system. Exosomes isolated will be assessed in terms of potential for immunotherapeutic treatment of disease such as cancer, viral infection and autoimmunity.Read moreRead less
THE BIOLOGY OF HUMAN DEC-205: A POTENTIAL ANTIGEN LOADING RECEPTOR FOR DENDRITIC CELLS
Funder
National Health and Medical Research Council
Funding Amount
$227,017.00
Summary
Dendritic Cells (DC) represent a unique subset of white blood cells which play a critical role in initiating the immune response. Foreign material from bacteria-viruses and potentially cancer cells are recognised by DC, taken inside, processed and presented with other signals to T and B Lymphocytes for a response. Several DC surface molecules may beinvolved in the recognition of foreign material. We have cloned human DEC-205, a molecule which is predicted to bind the sugar groups associated with ....Dendritic Cells (DC) represent a unique subset of white blood cells which play a critical role in initiating the immune response. Foreign material from bacteria-viruses and potentially cancer cells are recognised by DC, taken inside, processed and presented with other signals to T and B Lymphocytes for a response. Several DC surface molecules may beinvolved in the recognition of foreign material. We have cloned human DEC-205, a molecule which is predicted to bind the sugar groups associated with bacteria-viruses and to act as a foreign material recognition and loading receptor. This project seeks to synthesise components of DEC-205 to test the binding capacities of its different components to different sugars and other molecules. We will also establish its expression pattern and how this is regulated on different white blood cell types. It is also possible that DEC-205 transmits signals which activate the DC, and we will test for that possibility. Finally, we will attempt to exploit this knowledge for loading cancer target molecules into DC via DEC-205 to initiate a cancer vaccine response.Read moreRead less