Tolerance Induction By Antigen-presenting Cell-targeted Antigen
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
We have found that by ‘targeting’ antigen to the cells that ‘train’ the immune system we have been able to prevent the development of autoimmune disease. In the research proposed here we aim to develop new ways in which antigens can be targeted to these cells so that this approach can be applied clinically. The proposed studies will also determine how antigens targeted in this way restore self-tolerance and prevent autoimmune disease.
Novel Vaccine Formulation For Immunotherapy Of Adenocarcinomas
Funder
National Health and Medical Research Council
Funding Amount
$178,400.00
Summary
We have designed a vaccine based on a unique delivery system. Mice immunised with vaccine were protected from a tumour challenge. We will now design a vacine with a cancer associated protein so that people once immunised can make killer cells. Since humans have different genetic makeup we will produce a vacine which is more effective and will benefit everyone. This vaccine will be more effective than a current vacine in that has yielded promising results in humans.
Immunological Therapies For Cancer, Chronic Infection And Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$10,891,788.00
Summary
The team comprises five leading scientists with a history of successful investigation into the role of the immune system in cancers, chronic viral infections, and autoimmune diseases. There is a large unmet need for effective solutions with fewer side effects in these diseases which cause a high disease burden in our society. In this program, we particularly seek to develop novel vaccines for chronic infections and autoimmune diseases, and to improve the safety of bone marrow transplantation.
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
Developmental Stages Of In Vivo And In Vitro-generated Dendritic Cell Subsets And Regulation Of T Cell Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$88,087.00
Summary
Dendritic cells (DC) represent a diverse family of white blood cells that form a sentinel network throughout the body involved in the detection and eradication of pathogens and cancer cells. DC can originate from different precursor cells in the bone marrow. It is therefore possible that different types of DC perform differing functions. For instance, DC not only initiate immune responses but are also able to silence them. However, the ability of DC to instruct and orchestrate the immune respons ....Dendritic cells (DC) represent a diverse family of white blood cells that form a sentinel network throughout the body involved in the detection and eradication of pathogens and cancer cells. DC can originate from different precursor cells in the bone marrow. It is therefore possible that different types of DC perform differing functions. For instance, DC not only initiate immune responses but are also able to silence them. However, the ability of DC to instruct and orchestrate the immune response may not only depend upon their origins but also on where they encounter pathogens or cancer cells and what other signals are associated with this encounter. Due to their specialized capacity to instruct the immune response (e.g. T cells, B cells and NK cells) of impending danger, DC are used experimentally to more efficiently deliver vaccines to the immune response so as to eradicate cancer or infectious disease. However, in order to successfully use DC to deliver vaccines, one must first understand how these cells normally behave in the body and what signals can alter their functional ability to orchestrate immune responses. We can generate DC outside the body from their precursors. We can also isolate DC from the circulation. This project seeks to identify how various physiologic stimuli differentially regulate the functional behaviour of DC subsets and how this then influences the DC's ability to instruct the developing T cell immune response. Furthermore, whether these signals are the same for DC generated outside the body with those isolated from the blood. Of particular interest is whether differing types of DC and differing stages of their maturity will differentially influence the T cell's ability to secrete immune response hormones and to recognize and kill cancer cells. The findings of this study have direct implications of how to best harness DC to effectively deliver vaccines and generate potent immune responses against cancer and infectious disease.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
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