Mast Cells Determine Susceptibility To Induction Of Systemic Immunomodulation By UVB Radiation
Funder
National Health and Medical Research Council
Funding Amount
$194,993.00
Summary
The ultraviolet B component of sunlight causes an immunosuppression in humans such that UV-induced tumours develop. In a murine model, we have shown that dermal mast cells at the irradiated site are crucially important in the mechanisms by which UVB stimulates this immunosuppression. In this project we wish to study in more depth the mechanisms by which sunlight stimulates mast cells to produce molecules which in turn signal immunosuppressive events. We hypothesise that there is an intermediary ....The ultraviolet B component of sunlight causes an immunosuppression in humans such that UV-induced tumours develop. In a murine model, we have shown that dermal mast cells at the irradiated site are crucially important in the mechanisms by which UVB stimulates this immunosuppression. In this project we wish to study in more depth the mechanisms by which sunlight stimulates mast cells to produce molecules which in turn signal immunosuppressive events. We hypothesise that there is an intermediary by which sunlight stimulates mast cell activity; we hypothesise that cis-urocanic acid may be involved directly or indirectly in this process. There is considerable evidence that histamine may be the major product of mast cells involved in this process; however it is unknown whether its primary action is on keratinocytes (stimulating prostanoid production), antigen presenting cells or lymph node cells. This project will also investigate the relationship of studies with mice to UVB-induced systemic immunosuppression in humans. Non-sun-exposed skin from controls and patients with non-melanoma skin cancers will be examined and dermal mast cell prevalence evaluated; we hypothesise that people with high dermal mast cell numbers are more prone to immunosuppression and thus, the outgrowth of UV-induced non-melanoma skin cancers. We hypothesise that there may also be qualitative differences in the mast cells of UV-sensitive and UV-resistant individuals; variations may occur in the granule contents of neutral proteinases or cytokines. It is necessary that we better understand the basis of immune system modulation by UVB that allows non-melanoma skin cancer development as these patients have a 20-30% higher risk of death from other cancers.Read moreRead less
The Role Of PAC-1 In Leukocyte Activation And Inflammatory Responses
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
The MAP kinase pathway is fundamental for signalling a variety of cellular responses. This pathway is particularly important for immune responses ie. cytokine signalling, chemotaxis, and proliferation. PAC-1, a MAP kinase phosphatase, is an important regulator of this pathway. Extensive gene profiling of various immune cells using Affymetrix GeneChips identified PAC-1 as a highly regulated molecule in activated mast cells. Mast cells are important inflammatory cells, particularly for rheumatoid ....The MAP kinase pathway is fundamental for signalling a variety of cellular responses. This pathway is particularly important for immune responses ie. cytokine signalling, chemotaxis, and proliferation. PAC-1, a MAP kinase phosphatase, is an important regulator of this pathway. Extensive gene profiling of various immune cells using Affymetrix GeneChips identified PAC-1 as a highly regulated molecule in activated mast cells. Mast cells are important inflammatory cells, particularly for rheumatoid arthritis and asthma. We have shown that PAC-1 deficient mice are highly protected from inflammation and disease in a mouse model of rheumatoid arthritis. This grant aims to extend these exciting initial findings to other inflammatory diseases, particularly asthma and type 1 Diabetes, and to establish the basis for PAC-1 inhibition of disease. This research should establish PAC-1 as a new and important target for inflammatory disease, provide understanding on inflammatory processes, and possibly lead to improved therapies for diseases such as rheumatoid arthritis.Read moreRead less
Improving Adaptive Anti-viral Responses: A Key To Eliminating Persistent Viral Infection
Funder
National Health and Medical Research Council
Funding Amount
$402,391.00
Summary
Cytomegalovirus (CMV) can cause a persistent infection that can result in adverse clinical outcomes. Our previous work established that suboptimal adaptive immunity is responsible for viral persistence. This proposal will define the defect in adaptive immunity, its causes and how to improve it. The understanding gained from the proposed studies will provide crucial information for the development of improved anti-viral therapies and vaccines.
Role Of NK Cell-dendritic Cell Interactions In The Induction Of T Cell Responses Involved In Malarial Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$338,154.00
Summary
Cerebral malaria is a devastating neurological syndrome. Recent data indicate that NK cells are involved in disease induction. NK cell function is controlled by receptors encoded by a genetic region named the Natural Killer Complex (NKC). We showed that the differential expression of NKC genes controls the degree of susceptibility to cerebral malaria. Here we will identify and characterise NKC receptors involved in pathogenesis and the mechanism by which these molecules mediate disease.
Mechanisms Of Virally-induced Immunosuppression: Effects On DC-NK Networks
Funder
National Health and Medical Research Council
Funding Amount
$566,308.00
Summary
Cytomegalovirus (CMV) infection induces immunosuppression that often results in adverse clinical outcomes. Our previous work established that dendritic cells (DC), cells involved in the initiation of immune responses, are a principle target for CMV. This proposal will test the hypothesis that CMV-induced immunosuppression is mediated by viral interference with DC. Understanding the mechanisms involved in the induction of immunosuppression is a crucial step towards developing better therapies.
A Congenic Approach To Analysing The Genomic Control Of Innate Immunity In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$240,156.00
Summary
In addition to the lymphocytes, which are specialised white cells that can learn to defeat the infections that the body has been previously exposed, the body has a number of other defences. These non-learning systems have been honed by evolution and usually form an effective first-line of defence. This proposal deals with three: complement, and two highly specialised types of white blood cell, the Natural Killer cells and the NKT cells. The project will study mice especially bred to carry differ ....In addition to the lymphocytes, which are specialised white cells that can learn to defeat the infections that the body has been previously exposed, the body has a number of other defences. These non-learning systems have been honed by evolution and usually form an effective first-line of defence. This proposal deals with three: complement, and two highly specialised types of white blood cell, the Natural Killer cells and the NKT cells. The project will study mice especially bred to carry different versions of the genes which control these defences. Particular attention will be paid to their involvement in the autoimmune diseases, type 1 diabetes and lupus.Read moreRead less