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
Sunscreen Immune Protection Factor Prediction Of Inhibition Of Anti-tumour Immunity And Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$186,372.00
Summary
Despite sunscreens having been used in Australia for more than 25 years the incidence of skin cancer continues to increase. This is partly due to the long lag time in developing a skin cancer, so that the current incidence reflects sun exposure patterns of many years ago. However this is also partly due to sunscreens not being as effective at preventing skin cancer as they are at preventing sunburn. The ultraviolet wavelengths found in sunlight are the prime cause of skin cancer. Australians are ....Despite sunscreens having been used in Australia for more than 25 years the incidence of skin cancer continues to increase. This is partly due to the long lag time in developing a skin cancer, so that the current incidence reflects sun exposure patterns of many years ago. However this is also partly due to sunscreens not being as effective at preventing skin cancer as they are at preventing sunburn. The ultraviolet wavelengths found in sunlight are the prime cause of skin cancer. Australians are exposed to high levels of sunlight, and consequently 66% of Australians develop skin cancer throughout their lifetime. For this reason, Australia has been dubbed the Skin Cancer Capital of the World. To reduce the incidence of skin cancer in Australia, it is recommended that individuals use sunscreens. The means of assessing the effectiveness of sunscreens is based on an SPF system, which measures the ability of sunscreens to prevent sunburn (erythema). However sunburn is induced by particular ultraviolet wavelengths, and may not be as important for skin cancer assessment as other damaging effects of sunlight, such as immunosuppression and genetic mutations. Sunscreens should be tested for protection from immunosuppression as well as sunburn, as this would aid the development of better sunscreens. We have developed the technology to measure protection of the immune system, and intend to investigate the usefulness of this new sunscreen test.Read moreRead less
The Role Of Dermal Mast Cells In Limiting The Pathology Associated With Chronic Low-dose UVB Irradiation Of The Skin.
Funder
National Health and Medical Research Council
Funding Amount
$513,945.00
Summary
Australians are subject to high levels of sun exposure , that consequently can lead to skin damage and skin cancer. The specific aims of our reseearch are to investigate the role of skin mast cells in the limitation of skin alterations associated with chronic low-dose ultraviolet B exposure. Understanding the innate mechanisms that protect against excessive skin damage and cancer might aid the development of better treatment modalities in the future.
Targeting Inflammatory Skin Disease Using An Immune-modulatory Human Signal Peptide
Funder
National Health and Medical Research Council
Funding Amount
$698,836.00
Summary
Effective drugs are desperately needed for the improved treatment of inflammatory diseases. We will determine how a modified human peptide, which we have discovered and can make, works to suppress harmful skin inflammation. We will design new formulations to deliver our drug to the skin in order to better treat psoriasis, an autoinflammatory skin disease. We will also trial our new drug in models of atopic dermatitis a debilitating skin disease for which there is limited treatment options.
Cellular And Molecular Mechanisms Of Transcutaneous Immunisation
Funder
National Health and Medical Research Council
Funding Amount
$190,490.00
Summary
Vaccines are among the most effective medical interventions. The recent discovery that cholera toxin, when applied to the normal skin of humans and laboratory animals, stimulates powerful and protective immune responses to itself, and to other proteins has opened up the possibility of needle-free vaccines in the form of skin patches. How CT brings about this effect is currently unknown. We have discovered that the immune stimulating effect of CT depends upon the production of an immune protein ( ....Vaccines are among the most effective medical interventions. The recent discovery that cholera toxin, when applied to the normal skin of humans and laboratory animals, stimulates powerful and protective immune responses to itself, and to other proteins has opened up the possibility of needle-free vaccines in the form of skin patches. How CT brings about this effect is currently unknown. We have discovered that the immune stimulating effect of CT depends upon the production of an immune protein (cytokine) called tumour necrosis factor (TNF). TNF is known to activate specialised immune cells within the skin (Langerhan's Cells ) and we hypothesise that the interaction beween CT and LC via TNF is the pathway to the potent immune response. In this project we propose to investigate the cells and molecules involved in the immune effects of CT in the skin with a view to the development of new skin based vaccine strategies.Read moreRead less
Determining Regulators Of ILC3 In Mucosal Barrier Function And Immune Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$705,209.00
Summary
Innate lymphoid cells (ILCs) are specialized cells that defend the body against invading microorganisms at the body’s surfaces, mediate pathogen clearance and tissue repair but may also drive inflammatory conditions such as allergic asthma and inflammatory bowel disease. We will investigate the molecular switches that regulate this novel cell type and potentially uncover novel molecules or pathways for therapeutic targets.