Heterosubtypic T Cell-inducing Vaccines For Influenza In Humans
Funder
National Health and Medical Research Council
Funding Amount
$352,307.00
Summary
Bird flu virus poses a large risk to the world if it mutates to become easily spread between people. If this occurs vaccines will be made to the mutated strain but there will be a time lag before these are available. We have been working on a novel vaccine that induces protective T cell immunity to parts of the virus that are common to all influenza strains and will be effective against any new virus. Our information from animal models will be used to create a human vaccine of this type .
Transcriptional Regulation Of Terminal T Cell Differentiation By Blimp-1
Funder
National Health and Medical Research Council
Funding Amount
$411,404.00
Summary
Memory cells stand at the end of immune reactions and determine the success or failure of vaccination. T cells in are considered essential in tumour surveillance, clearance of infections and in providing help for antibody decretion. Blimp-1 is a major factor controling the differentiation of effector T cells. We aim to study its role in the generation of memory T cells which will help to develop better stratagies for immunization and for the treatment of immunodedeficiency and autoimmunity.
Making Signalling Through The Tumour Necrosis Factor Receptors Selective For Promoting Neutrophil Antimicrobial Activity
Funder
National Health and Medical Research Council
Funding Amount
$196,312.00
Summary
It is evident to the professional and general community that antibiotic and drug resistance displayed by bacteria is a continuing and growing problem in the treatment of infection with potentially casastrophic effect on the health of our community. This concern is only partly reduced by our potential to develop new antimicrobial agents and vaccines. If we were able to use immunomodulators in a relatively safe and appropriate manner to target and enhance the antimicrobial power of specific compon ....It is evident to the professional and general community that antibiotic and drug resistance displayed by bacteria is a continuing and growing problem in the treatment of infection with potentially casastrophic effect on the health of our community. This concern is only partly reduced by our potential to develop new antimicrobial agents and vaccines. If we were able to use immunomodulators in a relatively safe and appropriate manner to target and enhance the antimicrobial power of specific components of the immune system then this could be exploited in the treatment of infection. While body proteins formed (cytokines) which modify the behaviour of the immune system are being used as pharmaceuticals, their toxic side effects are problematic to the patient. Our project focusses on one of the cytokines, tumor necrosis factor (TNF), which increases the antimicrobial activity of phagocytic cells but in addition can have quite devastating effects on other tissues in the body. This is because when TNF binds to its receptor on cells and tissues it elicits a multitude of signals inside the cell which can also precipitate illness. The purpose of our investigations is to identify which signals are responsible for increasing resistance against infection and which are not. With this information we will then see if it is feasible to selectively stimulate this signal from outside the cell since this has a better chance of succeeding as a pharmaceutical. This task is likely to be achievable since our research team has made some unique observations about TNF signalling characteristics and we have developed a peptide TNF mimetic which shows only the characteristics of increasing antimicrobial activity.Read moreRead less
Pathophysiological Significance Of Reverse Signaling Through Membrane TNF
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surfac ....Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surface of the cell and then it is 'clipped off' and released as a smaller, soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We believe that binding of tumour necrosis factor receptors to the cytokine while it is in its membrane form can also send a message backwards, into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell. In this project we will investigate this phenomenon in detail. The results will be extremely relevant to new methods of treatment of diseases, that rely either on 'masking' tumour necrosis factor by administering soluble forms of its receptor or on blocking the release of the soluble form of the molecule from the surface of the cell. Our work will enable us to understand the consequences of these approaches more fully. We will also be looking at the role of the membrane form of tumour necrosis factor in a model of infectious disease. Influenza virus is responsible for a great deal of morbidity and mortality around the world. We, and others, have shown, in a mouse model, that some cells in the lungs make tumour necrosis factor during the course of viral pneumonia. Here we will determine whether the membrane form of this cytokine plays a role in clearing virus or causing some of the complications of this disease. This also may have relevance to other inflammatory and infectious disease.Read moreRead less
The Quantitative Regulation Of Antibody Forming Cell Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$336,500.00
Summary
B lymphocytes are the antibody-producing cells of the immune system. After they are made in the bone marrow, they are exported to the body to circulate, searching for signs of infection. When they encounter an invader, they change, with the help of other immune cells, into antibody-producing cells. A small proportion of the cells are set aside as memory cells that can rapidly become antibody-producing cells should the same infection occur again in the future. This is the basis of vaccination. Th ....B lymphocytes are the antibody-producing cells of the immune system. After they are made in the bone marrow, they are exported to the body to circulate, searching for signs of infection. When they encounter an invader, they change, with the help of other immune cells, into antibody-producing cells. A small proportion of the cells are set aside as memory cells that can rapidly become antibody-producing cells should the same infection occur again in the future. This is the basis of vaccination. The secretion into serum of antibodies that can bind to and eliminate an invader anywhere in the body is the main function of B lymphocytes. This project studies how a B cell changes into an antibody-producing cell. We will learn very basic and detailed quantitative aspects of the process, such as: -How long does it take to become an antibody-producer once a B cell detects an invader? -Do they-must they divide while they are changing? -How do hormones from other cells regulate the process? Do they increase division, survival, change the properties of the B cells, or improve their output? We will study all these responses in detail, so that we can make a model that can accurately predict the outcome of a particular set of circumstances. We will study the genes that are known to be required for antibody-producing cells to form, or to do their work. We will also study animals whose immune systems are under- or over-active, to find out what part of the antibody-producing process is faulty. We may be able to predict where the problem lies, by comparing these animals cells to our model, and therefore to suggest a remedy. Using this information, we hope eventually to be able to study diseases of antibody producing cells in humans (as occur in allergy, asthma, rheumatoid arthritis and leukaemia), to be able to identify the precise cause of the problem, and to suggest a therapy. This information may also be used to improve the outcome of vaccination.Read moreRead less
Influence Of TNF And TGF-beta On Langerhans Cell Mobilisation From Regressor And Progressor Skin Tumours
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Skin cancer is the most common type of cancer in humans. It is caused by the ultraviolet wavelengths found in sunlight. Australia has the highest incidence of skin cancer in the world, due to the large amount of sun exposure experienced by Australians during work and leisure. Considerable research needs to be directed towards this disease to understand how it forms and how it can be treated. Skin cancer can be controlled by the immune system, which in some cases is able to destroy the cancer, so ....Skin cancer is the most common type of cancer in humans. It is caused by the ultraviolet wavelengths found in sunlight. Australia has the highest incidence of skin cancer in the world, due to the large amount of sun exposure experienced by Australians during work and leisure. Considerable research needs to be directed towards this disease to understand how it forms and how it can be treated. Skin cancer can be controlled by the immune system, which in some cases is able to destroy the cancer, so that it disappears, or regresses. Other skin tumours fail to be destroyed by the immune system and therefore grow progressively. Differences between progressor and regressor tumours can help define why the immune system is able to destroy some but not other tumours. The cell of the immune system that is responsible for initiating immune responses against skin cancer is called the Langerhans cell. This cell migrates between the cancer and the local lymph node, where it activates lymphocytes to leave the lymph node and destroy the cancer. Our studies have shown that a major difference between progressor and regressor skin tumours is the ability of Langerhans cells to migrate from these tumours. Skin tumours produce cytokines (hormone like molecules) which enhance or inhibit Langerhans cell mobilization from the tumour. We have identified some of the cytokines involved, and plan to study how these cytokines interfere with this process and whether they do this by increasing the production of other factors, or by having a direct influence on the Langerhans cells. This knowledge would increase our ability to utilize these cells for treatment of cancer. This study will also further basic understanding of the biological factors which regulate the movement of this important cell from our tissues to the draining lymph node, which is of fundamental importance in the development of immunity.Read moreRead less
Critical Role Of TNF In Host-virus Interactions And Outcome Of Infection: Involvement Of Reverse Signalling Through MTNF
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two st ....Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two stages: First, the cytokine is exposed on the surface of the cell and then it is clipped off and released as a soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We have found that binding of tumour necrosis factor receptors to the cytokine, while it is in its membrane form, can also send a message backwards into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell and constitutes a major new route through which information transfer can occur. In this project we will characterize the biological changes that result from reverse signalling in specific types of leukocytes. We will be looking at the role of membrane tumour necrosis factor in two separate models of viral disease. The first is influenza pneumonia that is responsible for a great deal of morbidity and mortality worldwide. The second is a model of poxvirus infection (mousepox) that mimics the disease smallpox in humans. Human poxvirus infections are on the rise (e.g. monkeypox) and there is an increased threat of smallpox as a weapon of bioterrorism. Mousepox is a good model for the study of generalized viral infections and is also an excellent example of a virus that encodes proteins specifically designed to interfere with host tumour necrosis factor. Our studies will focus on the role of this cytokine in host-virus interactions and the outcome of infection.Read moreRead less