Co-administration Of DNA Encoding Co-stimulatory Molecules Enhances The Efficacy Of Immune Response To Foreign Antigen
Funder
National Health and Medical Research Council
Funding Amount
$182,000.00
Summary
Vaccines to prevent or treat infectious diseases and some cancers are urgently needed. Infected cells and some cancer cells display unique proteins which the body's immune system can recognises as 'foreign'. The body will then mount an immune response, which, if successful, will eradicate the infected or cancerous cells. Dendritic cells (DCs) initiate the body's immune response by instructing other immune cells to mount a response. For a vaccine to be successful it is important that the vaccine ....Vaccines to prevent or treat infectious diseases and some cancers are urgently needed. Infected cells and some cancer cells display unique proteins which the body's immune system can recognises as 'foreign'. The body will then mount an immune response, which, if successful, will eradicate the infected or cancerous cells. Dendritic cells (DCs) initiate the body's immune response by instructing other immune cells to mount a response. For a vaccine to be successful it is important that the vaccine activates the DCs in the right way. We propose to activate DCs by vaccinating with DNA encoding recently identified costimulatory molecules, as well as DNA encoding the foreign antigen. Our earlier work leads us to believe that this will enhance the immune response, and lead to a more effective state of immunityRead moreRead less
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.
Modulating Immune Responses By Targeting Dendritic Cells Using Dendritic Cell Specific Markers.
Funder
National Health and Medical Research Council
Funding Amount
$197,750.00
Summary
The ability to modulate immune responses would have major health benefits. Dendritic cells (DC) are key regulators of the immune system. Different types of DC possess different cell surface molecules and have differing regulatory functions. We have identified four novel DC surface molecules that can be used to target different types of DC. We aim to use antibodies against these molecules to either enhance the effectiveness of vaccines or to suppress autoimmune diseases.
Antigen Receptor Sharing By Lymphocytes During An Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$286,328.00
Summary
A successful immune response relies on the ability of immune cells to quickly mount a specific offensive against invading foreign pathogens like bacteria or viruses. The specificity of this offensive is governed by receptors that can recognise pathogens. To survive an infection the immune system must rapidly expand the number of immune cells that have receptors that recognise, and can therefore specifically combat, the infection. The underlying theory of immunology, the clonal selection theory, ....A successful immune response relies on the ability of immune cells to quickly mount a specific offensive against invading foreign pathogens like bacteria or viruses. The specificity of this offensive is governed by receptors that can recognise pathogens. To survive an infection the immune system must rapidly expand the number of immune cells that have receptors that recognise, and can therefore specifically combat, the infection. The underlying theory of immunology, the clonal selection theory, states that this expansion is mediated by the proliferation of immune cells selected on the basis of expressing a pathogen specific receptor. We hypothesise that in addition to this proliferation the immune system may also expand the number of immune cells expressing pathogen-specific receptors by transferring these receptors between cells by a means of cell-membrane sharing. Indeed, we have evidence that this does occur both in the test tube and in animals and can function to amplify the number of immune cells that can specifically recognise a pathogen and thereby help with immune response development. This grant aims to further advance our understanding of this novel phenomenon.Read moreRead less
Cells of the immune system need to recognise characteristic viral and bacterial molecules, in order to identify infection. Some immune cells can detect the presence of viral and bacterial DNA. The cells respond by making a number of anti-viral or anti-bacterial molecules, as well as activating other cells to fight the infection. The effect of bacterial DNA can be mimicked by certain short synthetic pieces of DNA. The potent activity of this synthetic DNA (termed CpG DNA ) is being exploited in a ....Cells of the immune system need to recognise characteristic viral and bacterial molecules, in order to identify infection. Some immune cells can detect the presence of viral and bacterial DNA. The cells respond by making a number of anti-viral or anti-bacterial molecules, as well as activating other cells to fight the infection. The effect of bacterial DNA can be mimicked by certain short synthetic pieces of DNA. The potent activity of this synthetic DNA (termed CpG DNA ) is being exploited in a number of clinical trials for treatment of cancer and allergy, as well as to improve vaccinations. Despite the rapid advance towards clinical application, there is still much basic information to learn about how CpG DNA acts on cells. The molecule to which DNA binds in order to activate the cells is called TLR9. TLR9 is not on the surface of cells, but within cells. In a bacterial infection, cells called macrophages engulf and digest bacteria and release the bacterial DNA within the cell, where it binds to TLR9. In other cases, including when CpG DNA is used therapeutically, the DNA needs to be taken up into the cell. Evidence shows that there is a receptor on the cell surface which binds DNA, and takes it into the cell. In this project we propose to identify this DNA uptake receptor. Apart from the use of CpG DNA, there are a number of other proposals for the therapeutic use of DNA. Although it is known that DNA enters into cells, the route for this has not been established. Whilst CpG DNA can activate immune cells, some other distinct DNA molecules can prevent the activation. We will examine whether these inhibitory DNA molecules bind more effectively to TLR9 than the CpG DNA, but do not activate the cell. These inhibitory molecules are proposed as a therapy for the autoimmune disease lupus, which involves inappropriate responses to DNA, and is thought to involve TLR9. In order to develop therapies, a detailed knowledge of how they work is essential.Read moreRead less
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
Regulation Of T Cell Effector Function In Peripheral Tissues
Funder
National Health and Medical Research Council
Funding Amount
$698,550.00
Summary
Protection from infections relies on different types of immune cells. While some of these cells are found in the blood, others reside in peripheral tissues such as the skin. We will analyse the function of these peripheral immune cells to understand how they work to fight off infections. We will also investigate how so-called memory cells that permanently reside in peripheral tissues can protect from re-infection with similar bacteria or viruses.
The Molecular And Cellular Trajectories Of Clonal Dendritic Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$826,742.00
Summary
Dendritic cells (DCs) are a blood cell type with a crucial role in our immune system. They are made in the bone marrow from stem and progenitor cells. How each of these cells individually makes DCs is complex and dynamic. We seek to understand this using cutting edge technologies to track each cell’s step-by-step role in this important process. This knowledge may help the use of DCs in the treatment of several diseases including autoimmunity and cancer.
The Role Of CD1-restricted T Cells In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$431,000.00
Summary
The human immune system requires T cells for survival. Specialised populations of T cells exist that patrol the body and target unwanted lipid molecules expressed by bacteria or by cells that have become abnormal or cancerous. I will identify these T cells in human blood and skin and determine their role in protection against disease. I will explore the types of lipids molecules recognised by these T cells and use this information to help prevent human diseases.