The Influence Of Glucocorticoid Hormones In T Cell Development And Function
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
The defence of the body to disease is a very complex process involving multiple interactions between subsets of white cells, in particular lymphocytes. This immune system, however, does not act in isolation but is subject to constant regulation by a variety of other cells and soluble factors. Particularly important in this regard is the impact of glucocorticoids which are normally associated with stress conditions. These steroids have been proposed to act at several levels in the immune system, ....The defence of the body to disease is a very complex process involving multiple interactions between subsets of white cells, in particular lymphocytes. This immune system, however, does not act in isolation but is subject to constant regulation by a variety of other cells and soluble factors. Particularly important in this regard is the impact of glucocorticoids which are normally associated with stress conditions. These steroids have been proposed to act at several levels in the immune system, usually causing suppression but they can also modify in a positive sense. Defining the targets of glucocorticoids and their precise functional impact will thus have very important implications for not only understanding the regulation of the immune response but also in the clinic. This project will make use of mice which have had the receptor for glucocorticoids genetically deleted. Focussing on T cells (the most important cells of the immune system) these mice will be examined in detail for alterations in the development of T lymphocytes and their function in defending the body against virus and tumours and their involvement in self destruction (autoimmune) diseases including multiple sclerosis.Read moreRead less
Adenosine Receptor Antagonists As Immunotherapeutic Agents For Cancer
Funder
National Health and Medical Research Council
Funding Amount
$555,779.00
Summary
We have shown that drugs that block immunosuppressive adenosine receptors can improve anti-tumour immune responses and consequently enhance the effectiveness of chemotherapy. These drugs are already known to be well-tolerated in humans and so have great potential for clinical development. We propose to determine the therapeutic response achieved with these drugs in combination with established cancer treatments involving radiotherapy and immune based therapies.
Molecular And Cellular Mechanisms Of Cytotoxic Lymphocyte Perforin
Funder
National Health and Medical Research Council
Funding Amount
$419,223.00
Summary
Cytotoxic lymphocytes are immune cells, which recognise and kill virus-infected or cancer cells. Perforin is essential for the activity of cytotoxic lymphocytes. The loss of perforin function results in an inherited immune deficiency, or may lead to the development of cancer. Despite a key role of perforin, its mechanism of action and the regulation of activity are unknown. I propose to elucidate these aspects of perforin biology. This is important for understanding immune regulation in humans.
My research straddles biochemistry, cell biology and immunology. I am interested in the mechanisms of antigen presentation by dendritic cells, and the functions of the cystatin family of protease inhibitors.
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
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
Using Genetically Manipulated Mice To Study The Pathophysiologic Consequences Of Castration-induced Prostatic Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
Prostate cancer is the second leading cause of cancer death among Australian men. The disease is incurable once it spreads beyond the confines of the prostate gland. Hormonal treatments can keep the cancer at bay for a number of years until they are no longer effective. Hormonal treatments cause shrinkage of prostate cancer because they interfere the function of the male hormone, testosterone, which encourages growth of prostate cancer. Hence, there is a need for other treatments that may improv ....Prostate cancer is the second leading cause of cancer death among Australian men. The disease is incurable once it spreads beyond the confines of the prostate gland. Hormonal treatments can keep the cancer at bay for a number of years until they are no longer effective. Hormonal treatments cause shrinkage of prostate cancer because they interfere the function of the male hormone, testosterone, which encourages growth of prostate cancer. Hence, there is a need for other treatments that may improve the quality of life and survival of prostate cancer patients. It appears that a cancer patient can make immune cells known as T cells, which can recognise his own tumour but which are prevented from destroying the tumour. Using a mouse model of prostate cancer, we wish to understand how prostate tumours act to prevent immune destruction in circumstances that are common to the treatment of human prostate cancer. For example, hormonal treatments produce dead prostate cancer cells that will be cleared by the body's professional scavenger cells in a way that suppresses an active immune response against the tumour. To learn how the removal of dead cells suppresses the immune response, we propose to perturb the normal clearance of dead prostate cells by at least two means. First, we will study mice that have an inherited deficiency in the removal of dead cells. Second, these mice will be given a growth factor to produce an excess of immune stimulating cells known as dendritic cells in the prostate gland. The dendritic cell is the main type of cell that initiates immune responses. We will investigate whether the greater number of dendritic cells, which were put into the prostate gland by the growth factor, can remove the dead prostate cells in a way that excites rather than suppresses the anti-tumour immune response. Positive results obtained from these studies may lead to the design of new treatments for advanced prostate cancer.Read moreRead less
Immune reactions are mediated by the expansion of white blood cells, and the progeny of this expansion is steered down different developmental pathways depending upon the nature of the initial infection or insult. We have recently identified a new means for control of the developmentwhite blood cells, and will here define this mechanism. These studies will open new opportunities for autoimmune therapeutics and vaccine development.