This program application seeks to draw on the skills of a world leading group of Australian researchers to bring novel HIV vaccine designs to clinical trials, improve vaccine design and create new opportunities for commercialisation. The Chief Investigators, Prof David Cooper, Prof Peter Doherty (Nobel Prize winner), A-Prof Stephen Kent and Prof Ian Ramshaw, have achieved major scientific developments including: innovative collaborative clinical trials, cutting edge research in T cell immunology ....This program application seeks to draw on the skills of a world leading group of Australian researchers to bring novel HIV vaccine designs to clinical trials, improve vaccine design and create new opportunities for commercialisation. The Chief Investigators, Prof David Cooper, Prof Peter Doherty (Nobel Prize winner), A-Prof Stephen Kent and Prof Ian Ramshaw, have achieved major scientific developments including: innovative collaborative clinical trials, cutting edge research in T cell immunology, the establishment of the only PC3-level nonhuman primate facility in the Southern hemisphere, T cell immunogenicity of the DNA-viral vector prime-boost vaccine regimens and ground-breaking research on cytokine co-expressing viral vector vaccines. The Principle Investigators also have a record of substantial achievement in relation to HIV and T cell biology as well as novel vaccination technologies. There is a strong history of successful collaboration among this group leading to the award of major NIH funding.Read moreRead less
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.
Regulation Of Perforin And Granzyme Expression In The Primary Cytolytic T Lymphocyte Response
Funder
National Health and Medical Research Council
Funding Amount
$756,000.00
Summary
The white blood cells known as cytolytic T lymphocytes (CTL) play important roles in elimination of some viruses, bacteria and tumours. Many vaccines and new therapies to prevent or control infections and cancer therefore seek to improve the production and activities of CTL. CTL kill infected cells and tumours by releasing packets of toxic molecules, including the pore-forming protein perforin and enzymes known as granzymes. However, while the roles of perforin and one granzyme, granzyme B, in c ....The white blood cells known as cytolytic T lymphocytes (CTL) play important roles in elimination of some viruses, bacteria and tumours. Many vaccines and new therapies to prevent or control infections and cancer therefore seek to improve the production and activities of CTL. CTL kill infected cells and tumours by releasing packets of toxic molecules, including the pore-forming protein perforin and enzymes known as granzymes. However, while the roles of perforin and one granzyme, granzyme B, in cell killing are now quite well understood, little is known about the other granzymes and how they contribute to immune protection. We have recently discovered that production of perforin and the three most prominent granzymes (A, B and C) can be separately controlled and that they are produced in different levels in different types of immune response. This suggests that they may each serve a different purpose and are therefore required in different amounts depending on the nature of the immune challenge. We have also found that an important hormone of the immune system, interleukin 4, has a profound effect on CTL, preventing their production of perforin and granzymes B and C and hence limiting their ability to kill target cells. In this project we plan a comprehensive analysis of perforin and granzyme production by CTL in response to different signals under controlled conditions in cell culture, and in response to different types of immune challenge in mice. We will also explore how interleukin 4 inhibits perforin and granzyme production and whether this has an impact on the effectiveness of the immune response. Mice in which one or more of the genes coding for perforin and granzymes has been damaged will be used to investigate how the absence of these molecules affects the immune response. We anticipate that these studies will suggest new strategies to improve therapeutic CTL induction by regulating perforin and granzyme production.Read moreRead less
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.
Regulation Of Macrophage Function And Gene Expression By The Th2-Promoting Stimulus, ES-62
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
White blood cells are responsible for co-ordinating the immune response against foreign micro-organisms. Macrophages are a particular type of white blood cell that attempt to destroy microbes during the initial stages of an infection, but also release toxic substances that are responsible for pathology and side effects during many immune responses. This project aims to address how macrophages are involved in a particular type of immune response that develops when individuals are susceptible to c ....White blood cells are responsible for co-ordinating the immune response against foreign micro-organisms. Macrophages are a particular type of white blood cell that attempt to destroy microbes during the initial stages of an infection, but also release toxic substances that are responsible for pathology and side effects during many immune responses. This project aims to address how macrophages are involved in a particular type of immune response that develops when individuals are susceptible to certain diseases including asthma and diseases associated with intracellular infections. We are identifying genes expressed in macrophages during these immune responses that are likely to be involved in susceptibility to such diseases.Read moreRead less
Contribution Of Dendritic Cell Paralysis To The Immunosuppression Associated With Systemic Infections
Funder
National Health and Medical Research Council
Funding Amount
$490,051.00
Summary
The immune system fights viruses and other infections mobilising antibody-producing B cells and killer T cells. The B cells and killer T cells are recruited by specialysed cell of the immune system called Dendritic Cells (DC). The DC are distributed all over the body, where they play an immunosurveillance role: they constantly monitor their sorroundings for the presence of pathogens. When DC detect these pathogens they become activated . They capture the pathogen, break it into small pieces call ....The immune system fights viruses and other infections mobilising antibody-producing B cells and killer T cells. The B cells and killer T cells are recruited by specialysed cell of the immune system called Dendritic Cells (DC). The DC are distributed all over the body, where they play an immunosurveillance role: they constantly monitor their sorroundings for the presence of pathogens. When DC detect these pathogens they become activated . They capture the pathogen, break it into small pieces called antigens, and display these antigens on their surface, where they can be seen by helper T cells, which in turn mobilise the B cells, and by killer T cells. This chain of reactions initiates an immune response. The DC undergo profound changes after they detect pathogens. They stop monitoring their sorroundings, and concentrate on displaying to T cells the antigens that belonged to the pathogen that triggered their initial activation. Indeed, they do not respond to new pathogen encounters. In normal conditions few DC are activated by each pathogen encounter, so there are always enough DC ready to respond to new infections. However, there are situation that activate nearly all the DC at the same time. This can happen during sepsis (bacterial infection of the blood) and malaria. It has been recognised for a long time that these two conditions can be immunosuppressive they shut-down the immune system. Our previous work has demonstrated that this is in part due to the excessive number of DC that sepsis or malaria activate, leaving no more DC capable of responding to subsequent infections. This work has focused on the immediate effects of sepsis or malaria -within the first 24 hours or so; now we want to investigate the efffect of these conditions on the reconstitution of the DC network. We think this will help us to find treatments to restore immunocompetence a functional immune system- in sepsis or malaria patients.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
Understanding Interactions Between Eosinophils And Tissue-Invasive Parasitic Helminths
Funder
National Health and Medical Research Council
Funding Amount
$227,545.00
Summary
Eosinophils are blood cells which contribute to our defences against parasitic worms. Given the right opportunity, eosinophils can cause damage to some parasites within just a few hours of contact. This is quite a feat because parasitic worms are multicellular organisms which are much larger than eosinophils and which have evolved to live in the presence of active immune responses. To do it's job properly an eosinophil probably makes use of small soluble molecules in the blood and others fixed t ....Eosinophils are blood cells which contribute to our defences against parasitic worms. Given the right opportunity, eosinophils can cause damage to some parasites within just a few hours of contact. This is quite a feat because parasitic worms are multicellular organisms which are much larger than eosinophils and which have evolved to live in the presence of active immune responses. To do it's job properly an eosinophil probably makes use of small soluble molecules in the blood and others fixed to it's own cell surface, to recognize the parasite and to promote adhesion to the target. You might like to consider these molecules as hands grabbing onto handles on the surface of the parasite. The more hands there are, the better the grip and some hands grip more strongly than others. We are investigating what these molecules are and how they work. By understanding how eosinophils operate, we may be able to devise ways in which we can make them more effective. We are also trying to understand why some species of parasite are resistant to attack by eosinophils. We think that resistant parasites secrete substances which either block the binding of eosinophils to the parasite surface, or prevent the functioning of eosinophils that do bind. It is possible that these inhibitory substances may even kill the eosinophils before they can do their job. Resistant parasites might induce eosinophils to commit suicide, a useful property for us when we no longer need these cells, but a definite drawback if they still have a job to do. Parasitic worms have evolved to avoid at least some of our defences and sometimes they do this by mimicing natural processes important for regulating immune responses. In some diseases like asthma and allergy eosinophils slip from normal controls which regulate them and then they can cause tissue damage. Inhibitors of eosinophils which are produced by parasites might form the basis of new drugs to control these cells in diseases like asthma.Read moreRead less
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
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