UNDERSTANDING HEPATITIS C VIRUS-SPECIFIC T CELL TOLERANCE
Funder
National Health and Medical Research Council
Funding Amount
$429,710.00
Summary
Most individuals who are infected with hepatitis C virus (HCV) develop a persistent infection that is lifelong and are at risk of developing serious liver disease, including liver cancer. The evidence suggests that an inadequate immune response is responsible for the inability of the patient to resolve the infection, but it is not clear which stage of the immunological cascade might be targeted. In this project, we will test the hypothesis that HCV antigen induce supressor T cells This will have ....Most individuals who are infected with hepatitis C virus (HCV) develop a persistent infection that is lifelong and are at risk of developing serious liver disease, including liver cancer. The evidence suggests that an inadequate immune response is responsible for the inability of the patient to resolve the infection, but it is not clear which stage of the immunological cascade might be targeted. In this project, we will test the hypothesis that HCV antigen induce supressor T cells This will have the effect of inhibiting the immune response and result in the outcome that we currently recognise as persistent HCV infection.Read moreRead less
Modification Of Dendritic Cell Function And Priming Of Protective Immunity By Malaria Blood-stage Parasites
Funder
National Health and Medical Research Council
Funding Amount
$316,500.00
Summary
Approximately 2 billion individuals live in areas where malaria is a risk. Children and naive individuals who get infected for the first time, usually travellers, are most at risk of dying from a Plasmodium falciparum infection, with an estimated 2 million children under 3 years of age killed each year. Surviving adults living in malarial areas have partial immunity after a series of infections. It is unclear how this protective immunity, particularly cellular immunity is acquired, and also uncl ....Approximately 2 billion individuals live in areas where malaria is a risk. Children and naive individuals who get infected for the first time, usually travellers, are most at risk of dying from a Plasmodium falciparum infection, with an estimated 2 million children under 3 years of age killed each year. Surviving adults living in malarial areas have partial immunity after a series of infections. It is unclear how this protective immunity, particularly cellular immunity is acquired, and also unclear why it takes so long to develop. Recent advances in immunology have indicated that Dendritic Cells (DCs) are necesssary to induce effectively cellular immunity and prime memory responses. DCs take up foreign proteins and show them to T cells resulting in their activation. T cells are critical for the establishment of long-term protective immunity to malaria. However, it has not been known if DC can take up malaria parasites or malaria infected red-blood cells and process them to activate protective T cell responses. Our preliminary data shows that both human and mouse DC can take up parasitised red-cells, but that the interaction of parasite derived proteins on the surface of the red cell with DC receptors causes a defect in DC maturation. This defect may prevent effective priming of T cells during natural malaria infection, contributing to the poor development of immunity in malaria endemic areas. Given these novel fundamental findings, it is now important to elucidate: 1) The nature of the DC defect induced by the parasites 2) Assess whether this is a common feature of all Plasmodia, or whether it may relate to strain virulence 3) Determine the nature and extent of the malaria specific response induced by the defective DC. Understanding how parasites may be able to sabotage a critical inducing component of the immune system has wide implications for the use of any immuno-therapies in malaria endemic regions.Read moreRead less
Immune Regulation, Cellular Trafficking And Chemokine Receptors In Intestinal Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
The intestine is exposed to a vast array of foreign substances, or antigens, from food to the abundant bacteria that populate the gut. The gut immune system has developed elaborate and poorly understood mechanisms for preventing inflammation in response to these antigens. A breakdown in these control mechanisms may be partly responsible for the chronic intestinal diseases known as inflammatory bowel diseases, which cause abdominal pain, diarrhoea and bleeding. A recently described immune cell ty ....The intestine is exposed to a vast array of foreign substances, or antigens, from food to the abundant bacteria that populate the gut. The gut immune system has developed elaborate and poorly understood mechanisms for preventing inflammation in response to these antigens. A breakdown in these control mechanisms may be partly responsible for the chronic intestinal diseases known as inflammatory bowel diseases, which cause abdominal pain, diarrhoea and bleeding. A recently described immune cell type, known as a regulatory T cell (T reg), is a powerful candidate cell as a master controller of intestinal inflammation. We know that T cells move to various sites in the body under the influence of hormone-like proteins known as chemokines, but the existence of T reg cells in the intestine, their characteristics, their behaviour and their specific response to chemokines, are all unknown. These studies aim to examine the presence and nature of T reg cells in human and mouse intestine, in both health and inflammation, and to explore how these cells migrate into the gut under the influence of chemokines. This knowledge will help in our understanding of intestinal immunity and endogenous regulation of immune responses, and will provide new targets for treatment of inflammatory bowel disease, and potentially other inflammatory diseases.Read moreRead less
Immunopathological Role Of Monocyte-macrophages In Flavivirus Encephalitis.
Funder
National Health and Medical Research Council
Funding Amount
$445,011.00
Summary
Viral encephalitis is a life-threatening infection of the brain for which there are no reliable treatments. White cells called monocytes enter the brain from the blood and although important in the immune response that destroys the virus, can also damage the brain. Our work focuses on determining how monocytes migrate into the brain in viral infection, what functions they have once inside the brain, and how to exclude a certain types of monocytes that we have found to be particularly damaging.
The Role Of Epigenetic And Transcriptional Regulation In CD8+ T Cell Effector Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$72,571.00
Summary
All cells contain DNA that is tightly wrapped around proteins, whereby changes in the structure allow for the expression of proteins. Cells of the immune system express proteins that can resolve viral infections. This study plans to examine the factors mediating the changes in DNA that allow for the expression of these proteins in immune cells. Insights will enable a greater understanding of how these proteins are generated and maintained, and hence will have implications for vaccine design.
Evaluation Of Immune Correlates For Virus-specific CD8+ T Cells Following Prime-boost Vaccination
Funder
National Health and Medical Research Council
Funding Amount
$397,889.00
Summary
This project will use cutting-edge technology to evaluate the quality of virus-specific white blood cells generated following vaccination. Clinically relevant vaccination strategies will be analysed in a well characterised mouse model of infection to produce correlates associated with protective vaccine efficacy, particularly in an immunosupressed setting. This will lead to more focused research and ultimately the development of prophylactic and therapeutic HIV vaccines.
Immunodominance In Vaccinia Virus And Recombinant Vaccinia Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$388,455.00
Summary
When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do ....When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do not understand well, T cells that recognize only a few out of the many peptides will dominate an entire immune response. As a result, immune responses are focused in such a way that they recognize only a tiny portion of an invading microbe. Focusing of immune responses also occurs during immunization with vaccines. Some new, genetically engineered vaccines use a harmless microbe to carry small parts of more dangerous pathogens. The parts chosen will not cause any disease by themselves, so the whole vaccine is safe. Vaccines built in this way are in clinical trials for diseases such as AIDS and malaria, but do not work as well as was hoped. These new vaccines are largely made up of the carrier and the parts of the microbe we wish to immunize against (e.g. a part of the AIDS virus) will be only a small fraction of the whole vaccine. Ideally we would like the immune system to focus on this small part of our choosing, but the few studies done suggest that this is not the case. In this project we will study vaccines that use a carrier called vaccinia virus. We will test to what extent immune responses are focused inappropriately. We will then genetically alter the virus and use new immunisation strategies to try and shift the focus of the immune response so that it targets the right parts of the vaccine. The ultimate aim is to improve vaccines, but in the process we may learn more about how the immune system chooses its targets.Read moreRead less
Using Mathematical Models Of Infection To Inform The Design And Analysis Of Epidemiologic Studies.
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Childhood immunisation has been enormously successful at preventing death and disease. Not all vaccines provide life-long protection, however, and booster doses may be required for older children or even adults. Deciding when and how often doses are required depends on how a particular infection is spread within families and the community both before and after vaccine use. We want to understand more about this process and its implications for the ongoing effectiveness of vaccine programs.