Enhancing Vaccine Efficacy By Harnessing Dendritic Cell Receptors And Their Unique Properties
Funder
National Health and Medical Research Council
Funding Amount
$687,519.00
Summary
Potent vaccination might be achieved by using monoclonal antibodies as magic bullets to target vaccines to special cells in the body. We show that targeting these special cells by using monoclonal antibodies that recognise Clec9A is effective, perhaps because it brings several different immune cells together so that they orchestrate very efficient immune responses. This application investigates how targeting Clec9A allows strong vaccination so that we can apply this to new generation vaccines.
Understanding The Mechanisms Of Action Of The ISCOMATRIX Adjuvant For The Development Of Human Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$401,361.00
Summary
CSL Limited, an Australian owned global biopharmaceutical company, is developing the ISCOMATRIX (IMX) adjuvant for vaccines to prevent and treat serious human disease of global concern (e.g. cancer, pandemic flu, HPV, HCV). This study will identify the mechanisms of action of IMX in generating strong cellular immunity, how to enhance it further by combining with other immuno-modulators so as to develop novel IMX vaccines for the treatment of established cancer and persistent viral infections.
TARGETING THE HUMAN CROSS-PRIMING DENDRITIC CELLS FOR IMMUNOTHERAPY
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Specialized white blood cells called dendritic cells (DCs) are essential to inducing the immune system to eradicate cancers and viral infections in mice. We have defined human DC subsets and related their functional capacities to the mouse DC subsets. We will now identify the human DC subsets involved in the induction of cancer and viral immune responses and use this information to develop clinical therapeutic cancer vaccination trials.
I am an immunologist determining the development and function of the dendritic cell system, including its role in autoimmunity and resistance to infection.
Antigen Presentation, Recognition And The Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$15,738,750.00
Summary
The early events in immunity require various molecular interactions. We will examine the structural and biophysical basis for some of these interactions, including those associated with transplant rejection and autoimmunity. We will explore the impact of variation in immune response genes on immune evasion and disease susceptibility. Our basic research will determine the mechanisms by which the immune system discriminates between different self and micro-organism associated determinants. We will ....The early events in immunity require various molecular interactions. We will examine the structural and biophysical basis for some of these interactions, including those associated with transplant rejection and autoimmunity. We will explore the impact of variation in immune response genes on immune evasion and disease susceptibility. Our basic research will determine the mechanisms by which the immune system discriminates between different self and micro-organism associated determinants. We will address the structural and biochemical basis for operation of an immune molecule called tapasin and unravel the basis for how some viruses escape the function of this molecule, thus allowing their immune evasion. We will also explore the use of modified small proteins called peptides in a humanized model of gluten hypersensitivity resembling that of Celiac disease. The molecular basis of the natural human immune system's capacity to recognise and reject grafts will be examined. This complements work aimed at improving the prediction of clinical graft rejection in transplantation. Dendritic cells play a central role in immunity, responsible for capturing material, whether from micro-organisms or self tissues, and presenting it to cells of the immune system. Our program will study the development and immunological function of the different dendritic cell subtypes. We will determine the relative contribution of each to the maintenance of immune tolerance and to the induction of immunity to several pathogens, including herpes simplex virus and malaria. Novel dendritic cell surface molecules that we have discovered will be tested for their ability to enhance the effectiveness of vaccines. Overall, this program utilises a broad array of immunological techniques designed to dissect the development and function of various immune system cell types and determine the structure-function relationships between important cell surface molecules involved in immunity.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
The Role Of Dendritic Cell Subsets In The Decision Between T Cell Tolerance And Immunity
Funder
National Health and Medical Research Council
Funding Amount
$445,009.00
Summary
The immune system protects the body against infection by means of a population of circulating white blood cells called lymphocytes. Each lymphocyte has on its surface its own particular receptor which recognises only one out of the universe of possible substances. Receptors are generated in a semi-random way, using a combination of elements encoded by the genes, and it is possible to generate receptors that react with the body itself, rather than with invading organisms. If the cells bearing the ....The immune system protects the body against infection by means of a population of circulating white blood cells called lymphocytes. Each lymphocyte has on its surface its own particular receptor which recognises only one out of the universe of possible substances. Receptors are generated in a semi-random way, using a combination of elements encoded by the genes, and it is possible to generate receptors that react with the body itself, rather than with invading organisms. If the cells bearing these self-reactive receptors become activated, an autoimmune disease ensues. The question of how lymphocytes can tell the difference between the body itself and foreign organisms is of major interest to immunologists. One of the first ideas was that self-reactive lymphocytes are inactivated by making reactions early in life. Despite the simplicity and intellectual appeal of this idea, it is inconsistent with a large body of experimental evidence. On the basis of number of new experiments, I have proposed an alternative model of self tolerance for one of the subsets of lymphocytes. In this model, the cells that help lymphocytes to recognise particular substances possess the property of distinguishing self from foreign, and pass that information on. The aim of this project is to provide direct experimental evidence in support of the model. Many of our attempts to deal with medical problems related to the immune system have been hampered by our lack of understanding of exactly how immune tolerance is controlled. If my model proves to be correct, it will be possible to manipulate immune responses with far greater effectiveness, providing new treatments for autoimmune disease, allergy, graft rejection and vaccination.Read moreRead less