The world has suddenly been alerted to the threat of pandemic influenza with the recent deaths in Asia of patients and their close contacts from which the avian influenza H5N1 virus has been isolated. Experts believe that it is only a matter of time before this virus mutates and acquires the ability to rapidly spread within the human population. The currently available vaccines have virtually no capacity to prevent infection by a new pandemic virus. Once the virus strikes appropriate vaccines ca ....The world has suddenly been alerted to the threat of pandemic influenza with the recent deaths in Asia of patients and their close contacts from which the avian influenza H5N1 virus has been isolated. Experts believe that it is only a matter of time before this virus mutates and acquires the ability to rapidly spread within the human population. The currently available vaccines have virtually no capacity to prevent infection by a new pandemic virus. Once the virus strikes appropriate vaccines can be made against it but this procedure takes at least 6 months, the time predicted for the virus to have already spread throughout the globe. We are proposing that a vaccine designed to induce killer T cells (called CTLs) that target the conserved regions shared by all influenza viruses, could be used as a preventative measure without prior knowledge of the exact type of virus that will emerge. This sort of vaccine will not prevent against infection but will greatly lessen the severity of the disease. We have already designed a vaccine that that will induce high levels of CTLs that can greatly speed up the clearance of viruses of the type that are currently in the human population, when tested in animal models. However, we predict that a new pandemic virus will be much more vigorous in its growth and so our vaccines will have to be improved to cope with this. This project looks at ways of increasing the number and effectiveness of the CTLs that are induced by our vaccines. This will require an understanding of how we can modulate the function of other specialised cells, dendritic cells and helper T cells, that play a role in starting and maintaining the CTL response, as well as modulating the CTLs themselves.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
Biology Of The Novel C-type Lectin Receptor DCL-1 In Innate And Adaptive Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
The innate immune system is the first line of defense in protecting the body from infection. Phagocytic (meaning eating) white blood cells, which include dendritic cells and macrophages are equipped with cell surface proteins These bind the many types of microbes that cause infection, allowing the phagocytes to destroy them (innate immune response). Furthermore, dendritic cells and macrophages have mechanisms to activate additional specific responses (adaptive immune response) mediated by lympho ....The innate immune system is the first line of defense in protecting the body from infection. Phagocytic (meaning eating) white blood cells, which include dendritic cells and macrophages are equipped with cell surface proteins These bind the many types of microbes that cause infection, allowing the phagocytes to destroy them (innate immune response). Furthermore, dendritic cells and macrophages have mechanisms to activate additional specific responses (adaptive immune response) mediated by lymphocytes (T and B cells). We have discovered a cell surface protein, termed DCL-1, which may play a role in uptake of microbes by phagocytes and activation of innate and adaptive immune responses. This project will examine the mechanisms whereby DCL-1 mediates these immune responses. Understanding the mechanism may allow us to exploit DCL-1 for tumor immunotherapy.Read moreRead less
I work on the molecular mechanisms of innate immunity. Priorities of my work are the immune response to pathogens such as viruses and bacteria and to cancer.