Tumour Antigen Cross-presentation: Efficiency, Biology And Role Of Inhibitory B7 Homologue Molecules
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
It is now known that the body s immune system often attempts to attack cancers but this response is generally fairly weak. It was previously thought that one of the main reasons for this failure was that the immune system was ignorant of the presence of the cancer until too late. Our recent work over the past few years has shown that this is not the case. A process called cross-presentation seems to efficiently and continuously expose the cancer to the body s anti-cancer killer T-cells. This gra ....It is now known that the body s immune system often attempts to attack cancers but this response is generally fairly weak. It was previously thought that one of the main reasons for this failure was that the immune system was ignorant of the presence of the cancer until too late. Our recent work over the past few years has shown that this is not the case. A process called cross-presentation seems to efficiently and continuously expose the cancer to the body s anti-cancer killer T-cells. This grant will work out exactly how efficient that process is, which cells are responsible and some aspects of how it happens. We will also study whether some recently-discovered braking molecules, which slow down immune responses and which could be 'applying the brakes' to anti-cancer responses. This could lead to new approaches to therapy eg by removing these brakes during vaccination therapy.Read moreRead less
Characterisation Of The Biochemical And Cell Biological Mechanisms Of Cross-presentation In Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
The immune system possesses several mechanisms to fight viruses and cancer. One of these mechanisms consists of recruiting anti-virus or anti-cancer killer cells. These killer cells are recruited by specialized cells known as Dendritic Cells (DC). The DC are distributed all over the body, and can detect the presence of viruses or cancer cells. When they do, they take up chunks of the virus or cancer cells, break them into small pieces called antigens, and display these antigens on their surface, ....The immune system possesses several mechanisms to fight viruses and cancer. One of these mechanisms consists of recruiting anti-virus or anti-cancer killer cells. These killer cells are recruited by specialized cells known as Dendritic Cells (DC). The DC are distributed all over the body, and can detect the presence of viruses or cancer cells. When they do, they take up chunks of the virus or cancer cells, break them into small pieces called antigens, and display these antigens on their surface, where they can be seen by the killer cells. This initiates an immune response whereby the killer cells seek and destroy the viruses and cancer cells. We are trying to harness the ability of DC to initiate immune responses in order to design more efficient vaccines to fight viruses and cancer. Our goal is to deliver vaccines that will directly target the DC and induce the formation of protective killer cells. These strategies require us to overcome two problems. The first is that we possess different types of DC, which play distinct functions, but we do not know which type is the most effective at recruiting killer cells, or why. The second problem is that we need to understand which vaccine design is the most effective at promoting presentation of the antigens that will be used to induce killer cells. The goal of this research project is to learn how we should deliver antigens to which DC type to generate the best possible vaccine.Read moreRead less
Evaluation Of Immune Responses To Multiple Tumour Antigens During Tumour Growth
Funder
National Health and Medical Research Council
Funding Amount
$451,980.00
Summary
It is becoming increasingly clear that cancerous tissues are not hidden from the body's immune system and yet, despite the generation of tumour-specific T cells and antibodies, the immune system does not often destroy solid tumour. Tumours express a large number of potential antigens (molecules in or on cancer cells that can be recognised by the immune system), but T cell responses to tumour antigens may be limited to only a few of these antigens (the dominating ones). These T cells could compet ....It is becoming increasingly clear that cancerous tissues are not hidden from the body's immune system and yet, despite the generation of tumour-specific T cells and antibodies, the immune system does not often destroy solid tumour. Tumours express a large number of potential antigens (molecules in or on cancer cells that can be recognised by the immune system), but T cell responses to tumour antigens may be limited to only a few of these antigens (the dominating ones). These T cells could compete with any other T cells that have been, or are being, generated, preventing their expansion and development into fully functional T cells. If this is true, then tumours will 'escape' immune mediated destruction, as a T cell response to only a few antigens is not likely to be enought to seriously perturb growing tumours. In this grant we will use a well established mouse model of cancer to evaluate immune responses to tumour antigens during tumour growth and try to understand why other potential antigens do not invoke a fully functional immune response. If we are successful, we will have made advances that could lead to new therapies for cancer.Read moreRead less
Crystallographic Studies Of Non-canonical Peptides Binding To MHC Class I Molecules.
Funder
National Health and Medical Research Council
Funding Amount
$489,750.00
Summary
Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called T-cell lymphocytes. This recognition process is the key step in the immune response and some fundamental questions in immunology are centred on the nature of this process. At the molecular level, the recognition is mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called t ....Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called T-cell lymphocytes. This recognition process is the key step in the immune response and some fundamental questions in immunology are centred on the nature of this process. At the molecular level, the recognition is mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called the MHC on the surface of the target cell. The target cell can be a cancer cell, or an infected antigen presenting cell (specialised cells in the body which present protein fragments (peptides) on their surface via MHC). The structure of a TCR and TCR-MHC have been solved in terms of the shape of the molecules at atomic resolution, bringing detailed information on how these two proteins interact with each other. In this proposal the structural basis of antigen presentation and recognition in cell-mediated immunity will be determined by three-dimensional structures of different peptides on MHC by x-ray crystallography. Cell surface antigen presentation by MHC molecules is crucial for initiating the cellular immune response against invading pathogens and cancer. This proposal encompasses a combined biochemical, immunological, and biophysical approach to understand the range of ligands which can bind to MHC which are subsequently recognised by the TCR. To understand the antigenic properties of modified peptides at the structure level, the x-ray structure of MHC with modified bound synthetic peptides will be determined.Read moreRead less
Tissue Specific Antigen Presenting Cell Functions During Infection.
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
T cell activation is often inefficient following infection or vaccination, resulting in poor control of pathogens. In this grant, we propose to investigate the cellular basis for sub-optimal CD4+ T cell activation following infection. Specifically, we will study the roles of antigen presenting cells in CD4+ T cell activation in an experimental model of visceral leishmaniasis caused by the human protozoan parasite Leishmania donovani.