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
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
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
Identification of novel markers of inflammation. This project will benefit Australia as it will increase basic understanding of inflammatory processes, result in a new generation of diagnostics for inflammatory diseases that could lead to earlier diagnosis and to monitor treatment, resulting in large economic and health benefit. It may lead to development of novel new therapies using monoclonal antibodies to regulate processes in immune, cardiovascular and infectious diseases. The work will gene ....Identification of novel markers of inflammation. This project will benefit Australia as it will increase basic understanding of inflammatory processes, result in a new generation of diagnostics for inflammatory diseases that could lead to earlier diagnosis and to monitor treatment, resulting in large economic and health benefit. It may lead to development of novel new therapies using monoclonal antibodies to regulate processes in immune, cardiovascular and infectious diseases. The work will generate significant economic spin-offs to the Australian biotechnology industry and will further relationships and training between research and development.Read moreRead less
Development of an effective vaccine for chlamydial infection: optimisation of a non-toxic cholera toxin-based adjuvant to generate a protective mucosal response. Chlamydial genital infections are the most common sexually transmitted infection in Australia and the world and impose a major health burden on the community. Chlamydial infections are also associated with cardiovascular disease, Australia's biggest killer and asthma, another condition that has increased significantly in prevalence in t ....Development of an effective vaccine for chlamydial infection: optimisation of a non-toxic cholera toxin-based adjuvant to generate a protective mucosal response. Chlamydial genital infections are the most common sexually transmitted infection in Australia and the world and impose a major health burden on the community. Chlamydial infections are also associated with cardiovascular disease, Australia's biggest killer and asthma, another condition that has increased significantly in prevalence in the past 10 years. This project will evaluate the effectiveness of a new adjuvant as a first step towards the development of a vaccine to target these important infections.Read moreRead less
Novel lipid-based adjuvants for induction of mucosal immunity. The project will determine if needle-free oral and transcutaneous immunisation using LipoVax, a novel lipid-based antigen delivery system developed by the industry partner, can protect mice against the mucosal pathogens Chlamydia and Helicobacter. We expect to show that this immunisation method can induce protective mucosal immunity against two of the most common infectious organisms affecting mankind. If successful this will allow u ....Novel lipid-based adjuvants for induction of mucosal immunity. The project will determine if needle-free oral and transcutaneous immunisation using LipoVax, a novel lipid-based antigen delivery system developed by the industry partner, can protect mice against the mucosal pathogens Chlamydia and Helicobacter. We expect to show that this immunisation method can induce protective mucosal immunity against two of the most common infectious organisms affecting mankind. If successful this will allow us to develop LipoVax as a new platform technology that can be applied to the development of human vaccines, veterinary vaccines, vaccines for companion animals and vaccines to target infections in feral animals and native wildlife population populations.Read moreRead less
Enhancing immunogenicity of DNA vaccines by targeted delivery to antigen presenting cells. Vaccines have proven to be one of the most effective means of preventing infection and also provide promise as a treatment for cancer. However, the range of effective technologies that make possible the delivery of vaccines that can protect against a broad range of infections is limited. DNA based vaccines are attractive because they are relatively easy to produce against a wide range of infections. Howeve ....Enhancing immunogenicity of DNA vaccines by targeted delivery to antigen presenting cells. Vaccines have proven to be one of the most effective means of preventing infection and also provide promise as a treatment for cancer. However, the range of effective technologies that make possible the delivery of vaccines that can protect against a broad range of infections is limited. DNA based vaccines are attractive because they are relatively easy to produce against a wide range of infections. However, DNA vaccines often provide poor protection against infections. This project will explore a unique technology developed in Australia and that will greatly improve the effectiveness of DNA vaccines against a broad range of diseases. Read moreRead less
Molecular Mechanisms of NOD signalling. Alterations in NOD1 and NOD2 (nucleotide-binding oligomerization domain containing 1 and 2) signalling have been implicated in various human inflammatory diseases. Therefore, a clear understanding of the molecular signalling pathways is important to gain further insights into potential drug targets for the treatment of these diseases. Using novel experimental approaches, this project aims to identify new members of the NOD signalling pathway. It will test ....Molecular Mechanisms of NOD signalling. Alterations in NOD1 and NOD2 (nucleotide-binding oligomerization domain containing 1 and 2) signalling have been implicated in various human inflammatory diseases. Therefore, a clear understanding of the molecular signalling pathways is important to gain further insights into potential drug targets for the treatment of these diseases. Using novel experimental approaches, this project aims to identify new members of the NOD signalling pathway. It will test the effect of pharmacological inhibition of established molecules such as RIPK2 or IAPs in NOD dependent models for human diseases. Outcomes of this study will be of the utmost interest for the treatment of NOD driven diseases such as Crohn's disease, Blau syndrome or asthma.Read moreRead less