This research is directed by a team of medical and basic scientists with expertise in mechanisms of inflammation relevant to human disease. The program will investigate the molecular and cellular events that are responsible for inflammation in the kidneys, joints and blood vessels which lead to diseases such as glomerulonephritis, arthritis and atherosclerosis. The aim of the research is to find new therapeutic targets which may be specific to certain organs or disease processes, in order to dev ....This research is directed by a team of medical and basic scientists with expertise in mechanisms of inflammation relevant to human disease. The program will investigate the molecular and cellular events that are responsible for inflammation in the kidneys, joints and blood vessels which lead to diseases such as glomerulonephritis, arthritis and atherosclerosis. The aim of the research is to find new therapeutic targets which may be specific to certain organs or disease processes, in order to develop more effective and selective treatments ofchronic inflammatory disease in humans.Read moreRead less
Preclinical Development Of A Humanised Antibody To C5aR.
Funder
National Health and Medical Research Council
Funding Amount
$124,875.00
Summary
Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models of inflammation (rheumatoid arthritis, sepsis and colitis) ....Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models of inflammation (rheumatoid arthritis, sepsis and colitis) to determine the efficacy of the antibody, safety, the most effective dose, timing and route of administration. These studies are a necessary prelude to human clinical trials, which we hope to perform in approximately 24 months.Read moreRead less
Understanding and regulating autoimmune disease through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) family transcription factor, v-rel reticuloendotheliosis viral oncogene homolog B (RelB). This program is well-aligned with the national research priority: Promoting and Maintaining Good Health. The disabling conditions rheumatoid arthritis and type 1 diabetes affect over 1% of Australia's population. They are incurable, so disability and the need for treatment p ....Understanding and regulating autoimmune disease through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) family transcription factor, v-rel reticuloendotheliosis viral oncogene homolog B (RelB). This program is well-aligned with the national research priority: Promoting and Maintaining Good Health. The disabling conditions rheumatoid arthritis and type 1 diabetes affect over 1% of Australia's population. They are incurable, so disability and the need for treatment persist into old age and life expectancy is reduced. The program focuses on more effective and safer treatment, and future disease prevention, with immune therapy. This will have social and economic benefits to Australia. The research will advance Australia's intellectual leadership in Immunology, providing research training and career opportunities, and will lead to strong collaborations between basic scientists, clinicians and industry.Read moreRead less
A T Cell-Specific GR Promoter Determines Responsiveness To Glucocorticoids In Different Immune Compartments
Funder
National Health and Medical Research Council
Funding Amount
$417,500.00
Summary
Synthetic glucocorticoids, such as dexamethasone and prednisolone, are commonly used as potent anti-inflammatory steroid drug during the treatment of major human trauma and cancer. A side-effect of these very high steroid doses is a major down-regulation of the immune system, particularly massive death of important immune cells called T-cells, which can have a major impact on patient recovery and potential mortality. These T cells are particularly sensitive to glucocorticoid-induced cell death a ....Synthetic glucocorticoids, such as dexamethasone and prednisolone, are commonly used as potent anti-inflammatory steroid drug during the treatment of major human trauma and cancer. A side-effect of these very high steroid doses is a major down-regulation of the immune system, particularly massive death of important immune cells called T-cells, which can have a major impact on patient recovery and potential mortality. These T cells are particularly sensitive to glucocorticoid-induced cell death and have very high levels of receptors for these steroids called glucocorticoid receptors (GRs). We have discovered a unique GR gene promoter (designated 1A) that is active in T cells. Very little is known about how this gene promoter is regulated. This promoter may be a useful therapeutic target to block T cell death (caused by steroids) during recovery from injury, infection and cancer. Separation of anti-inflammatory and side-effects such as high T-cell death or blockade of these effects on T cells would have a major impact on patient immune status and recovery, and reduce the incidence of debilitating side-effects. Therapeutic down-regulation of this T cell-specific GR gene promoter could lead to targeted blockade of steroid-induced T cell death and help maintain a strong immune system. This application brings together a unique team of investigators (CIs) that have a strong history of collaboration in this area with recent publications in very high ranking international journals. The CIs bring a multi-disciplined approach combining endocrinology, molecular biology and cellular immunology to determine the underlying mechanisms of steroid actions and their effects on immune function. Both Dr Cole (CIA) and Dr Godfrey (CIB) have excellent track records in this area.Read moreRead less
IgA Mediated Activation Of FcalphaRI, An Fc Receptor And A Leukocyte Ig-like Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$535,500.00
Summary
Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites, these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate with the outside and are the major route of pathogen entry into the ....Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites, these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate with the outside and are the major route of pathogen entry into the body. Here IgA forms a rather passive, but pathogen specific, sticky barrier to prevent microbial pathogens attaching to these large surfaces. In an everyday analogy this IgA behaves somewhat like fly-paper. This subdued response is appropriate as we are constantly exposed to micro-organisms living in our gut, or breathed into our lungs, and our immune system would make us ill if it aggressively attacked our innocuous microbial neighbours. The second type of IgA is found in the blood where it attaches to pathogens that have breached the body's barriers. These IgA tags are actively sought by white blood cells whose function is to protect the body from infection by recognising and engulfing the tagged pathogens and destroying them with killer molecules, including bleach. The IgA-Fc receptor is the sensor on the surface of white blood cells which seeks the IgA tags as they attach to pathogens. In order to survive in this hostile environment some of our pathogens, such as Staphylococcus, have their own strategies to make themselves invisible to the immune system. These strategies include cutting up the IgA tags or blocking the sensors for IgA. In this project we will study how IgA tags turn on white blood cells to destroy pathogens. We will also be looking at two Staphylococcal proteins which block up the sensor for IgA tags. Finally we are endeavouring to understand how it is the mucosal type IgA does not activate the white cells nearly as much as the IgA from the blood.Read moreRead less
Innate Immunity And Chlamydia Infection: Bacterial:epithelial Cell Cross-talk At The Mucosal Surface.
Funder
National Health and Medical Research Council
Funding Amount
$593,340.00
Summary
Chlamydial infections are the most common sexually transmitted disease in Australia. Infection induces short term immunity that is only partially protective. Furthermore, in many infected individuals the immune response causes inflammation of the fallopian tubes leading to pelvic inflammatory disease, ectopic pregnancy and infertility. In these individuals the initial chlamydial infection may not be cleared and a chronic infection may develop that can be reactivated, perhaps many times, contribu ....Chlamydial infections are the most common sexually transmitted disease in Australia. Infection induces short term immunity that is only partially protective. Furthermore, in many infected individuals the immune response causes inflammation of the fallopian tubes leading to pelvic inflammatory disease, ectopic pregnancy and infertility. In these individuals the initial chlamydial infection may not be cleared and a chronic infection may develop that can be reactivated, perhaps many times, contributing to the ongoing inflammatory response. Evidence from in vitro studies suggests that antibiotics routinely used to treat Chlamydia infection may actually contribute to the development of chronic infection. The stage of menstrual cycle at the time of exposure and oral contraceptive use can also influence susceptibility to infection suggesting that sex hormones influence infection outcomes. The innate or early immune response to infection by reproductive tract epithelial cells, the target cells of chlamydial infection, is believed to initiate the pro-inflammatory immune responses that will develop in some individuals following primary infection, however very little is known regarding this early epithelial cell immune response. In the proposed studies we will use reproductive tract epithelial cell lines, freshly isolated epithelial cells and cervical biopsy explant cultures to define this early innate immune response to chlamydial infection. Using gene-profiling techniques we will identify the types of innate immune response that predispose to long-term inflammatory sequelae. Gene-profiling techniques will also be used to determine why chronic chlamydial infections develop in some individuals and whether antibiotics influence this. Our ultimate aim is to be able to predict which infected individuals are likely to develop long term inflammatory disease and may therefore need more intensive antibiotic therapy or treatments such as therapeutic vaccination.Read moreRead less
Toll-like receptors in infectious and inflammatory diseases: the double-edged sword of innate immunity. The innate immune system is the first line of defence against invading microorganisms. This project will explore the role of specific innate immune genes in the control of infections and the development of inflammatory diseases.