Determination Of An Action Spectrum For Ultraviolet Radiation-induced Immunosuppression In Humans
Funder
National Health and Medical Research Council
Funding Amount
$213,500.00
Summary
Ultraviolet (UV) radiation causes mutations in the skin which can develop into cancers many years later. The skin's immune system is an important defence that prevents most potentially cancerous cells from developing into skin tumours. UV also suppresses skin immunity, allowing cancer cells to proliferate unchecked. There is also evidence that this UV-induced immunosuppression may have important effects on infectious diseases such as herpes virus, leprosy and tropical ulcers. Sunlight contains U ....Ultraviolet (UV) radiation causes mutations in the skin which can develop into cancers many years later. The skin's immune system is an important defence that prevents most potentially cancerous cells from developing into skin tumours. UV also suppresses skin immunity, allowing cancer cells to proliferate unchecked. There is also evidence that this UV-induced immunosuppression may have important effects on infectious diseases such as herpes virus, leprosy and tropical ulcers. Sunlight contains UVB, which causes sunburn, and UVA. Until recently, UVA was thought to have little effect on skin immunity. We have previously shown that both broadband UVB and UVA are immunosuppressive, even after single exposures equivalent to 8 minutes of sunlight. It is not known which UVA wavelengths are most immunosuppressive. These studies will use a xenon arc solar simulator and a series of interference filters to produce narrow UVB and UVA wavebands. The effects of these wavebands on humans can be studied by deliberately eliciting immune responses to substances which volunteers are already sensitive to. One model of skin immunity in these studies is allergy to nickel (in earrings and costume jewellery), which affects 10% of women. The volunteers' backs are exposed to different UV wavelengths, and then nickel patches are taped to both the UV-exposed areas and adjacent, unexposed areas. By comparing the intensity (redness and thickness) of these nickel reactions, immunosuppression caused by each waveband can be measured. Similarly, the Mantoux reaction (in people vaccinated against tuberculosis) provides another, complementary model of skin immunity. Knowledge of the immune effects of different UV wavelengths (an action spectrum for UV immunosuppression) would improve understanding of skin cancer and enable development of better sunscreens, which currently offer only partial immune protection.Read moreRead less
Targeted Redox Therapy For Photoageing Prevention And Treatment
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Our goal is to target natural reduction/oxidation (redox) modifiers, i.e. niacin and sulforaphane, to the skin deeper layers to treat photoageing. Both drugs have been separately shown to prevent UV induced skin cancer. The outcomes of this project will be safer and more effective prevention and treatment of sun damaged skin. This project can provide health benefits to Australians from improved treatment of sun damage, and economic benefits to the nation.
Dynamics And Mechanisms Of Neutrophil Migration During Tissue Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$529,577.00
Summary
Neutrophil granulocytes are central mediators of inflammatory conditions and infections. It is currently unclear how neutrophils navigate through inflamed tissues and how they detect damaged cells and/or pathogens. This proposal will use cutting-edge multi-photon microscopy to dissect the dynamics and mechanisms of neutrophil behaviour in real time in living animals. These experiments will provide a new understanding of the development of inflammatory diseases.
MPM Non-invasive Imaging Of Biological Interactions Following Drug Delivery With Micro-nanoprojection Patches.
Funder
National Health and Medical Research Council
Funding Amount
$403,612.00
Summary
The overarching aim of my research is to develop and evaluate effective, practical and reproducible physical methods for delivering genes and drugs to specific immunologically-sensitive cells in the skin to ultimately treat and vaccinate against human diseases. I recently patented a method using arrays of nano-scale projections on a patch to accurately, efficiently and safely deliver biomolecules not just to specific skin cells, but also to organelles within them. Conceptually, the delivery devi ....The overarching aim of my research is to develop and evaluate effective, practical and reproducible physical methods for delivering genes and drugs to specific immunologically-sensitive cells in the skin to ultimately treat and vaccinate against human diseases. I recently patented a method using arrays of nano-scale projections on a patch to accurately, efficiently and safely deliver biomolecules not just to specific skin cells, but also to organelles within them. Conceptually, the delivery device is a set of microscopic nanoneedles coated with drug substance and applied to the skin as a small patch. The device is practical, needle-free and pain-free. The aim of this current project is to use the micro-nanoprojection array patches-configured to uniquely deliver biomolecules to cells within given strata-to find: 1) what delivery sites of antigen-expression plasmid- toll like receptor (TLR) agonist lead to strong humoral immune responses in the intact animal. 2) whether delivery of different TLR agonists have different effects on the maturation and migration of the different professional antigen presenting cells (APCs) in the skin, as visualised locally by Multi-Photon Microscopy (MPM). 3) whether differences in APC maturation and migration are associated with different systemic antibody responses. We will identify optimal delivery sites of drugs-vaccines to the skin (layer, cells targeted, duration of delivery) with MPM for desired systemic immune responses. This will have important contributions towards improving immunotherapeutics of major diseases via skin targeting with micro-nanoprojection array patch technologies (and other methods).Read moreRead less
Immunoregulatory Immune Responses To A Peripherally Presented Tumour Antigen
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
Tumours express proteins which the body can recognise as foreign. However, the recognition process often goes wrong, leaving the body's defences against infection unable to respond to the tumour. This lack of response may become permanent, and the tumour may then be protected by the immune system. We have a model system, based on cervical cancer, in which we can determine the reasons why tumour tolerance can occur, and explore ways of overcoming the tolerance
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
Biological Function Of The Chemokine Receptor 6 Expression On B Cells
Funder
National Health and Medical Research Council
Funding Amount
$241,500.00
Summary
The correct movement of cells is important for the defence of the body against micro-organisms. White blood cells have to arrive quickly at the site of an infection and information about this infection has to be spread. White blood cells that navigate the body are using molecules on their surface termed as receptors which help them to detect the scent of their target. One of these receptors is located on white blood cells that produce antibodies and enables these cells to migrate to appropriate ....The correct movement of cells is important for the defence of the body against micro-organisms. White blood cells have to arrive quickly at the site of an infection and information about this infection has to be spread. White blood cells that navigate the body are using molecules on their surface termed as receptors which help them to detect the scent of their target. One of these receptors is located on white blood cells that produce antibodies and enables these cells to migrate to appropriate tissues . We want to know more about the biological role of this receptor and its functions during the immune response to pathogens. It would be of significant importance to understand the impact of these cell surface receptors in detail because this could open the possibility to new therapies of infectious diseases and chronic inflammation.Read moreRead less
Effect Of Ultraviolet Radiation On Development Of Effector And Memory T Cells To Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$498,328.00
Summary
Australia has the highest incidence of skin cancer in the world, due to our lifestyle that involves high levels of exposure to sunlight. Skin cancer, including melanoma can be destroyed by the immune system, but sunlight inhibits immunity, enabling skin tumours to grow. Our aim is to determine how sunlight affects the activation of effector anti-melanoma T cells, and their development into memory T cells, and the dose of sunlight required to have this effect. It is unknown whether ultraviolet ra ....Australia has the highest incidence of skin cancer in the world, due to our lifestyle that involves high levels of exposure to sunlight. Skin cancer, including melanoma can be destroyed by the immune system, but sunlight inhibits immunity, enabling skin tumours to grow. Our aim is to determine how sunlight affects the activation of effector anti-melanoma T cells, and their development into memory T cells, and the dose of sunlight required to have this effect. It is unknown whether ultraviolet radiation in sunlight suppresses the activation of effector cells that mediate rejection of skin tumours, or their development into memory cells, or migration of activated-memory lymphocytes into skin tumours. The number of antigen reactive T cells is a key issue for tumour immunity and the aim of many clinical immunotherapy trials is to boost these to levels that can effectively destroy the tumour. It is important to establish whether low doses of sunlight readily achievable during normal living, or only higher exposures received when sunbaking, inhibit the number of these effector T cells, and their migration into skin tumours. It is important to determine whether there is a relatively safe threshold level of sunlight exposure to be able to give better advice on sunlight doses that can be achieved without causing serious deleterious health effects. Also these levels of sunlight may interfere with immunotherapy trials and therefore need to be determined. An additional outcome will be to determine whether chemopreventative agents that enhance recovery from sunlight induced suppression of skin allergies are also protective for anti-tumour immunity. The establishment of procedures for prevention of suppression of anti-tumour immunity may enhance the number of T cells activated by natural immunity or during immunotherapy, thereby improving immune rejection of melanoma.Read moreRead less
Role Of The Mast Cell Product Histamine In Ultraviolet Radiation Induced Systemic Immunomodulation
Funder
National Health and Medical Research Council
Funding Amount
$393,750.00
Summary
The harmful effects of ultraviolet radiation on skin, as exemplified by sun exposure, are well recognised: sunburn, premature ageing of skin, and induction of skin cancer. Indeed, skin cancers are the most common cancers in Australia. Increasingly recognised now is that UV radiation can alter the immune system. This is of particular relevance to the development of skin cancer: alteration of the immune system is critical to outgrowth of UV-induced cancers. The intact immune system is otherwise ab ....The harmful effects of ultraviolet radiation on skin, as exemplified by sun exposure, are well recognised: sunburn, premature ageing of skin, and induction of skin cancer. Indeed, skin cancers are the most common cancers in Australia. Increasingly recognised now is that UV radiation can alter the immune system. This is of particular relevance to the development of skin cancer: alteration of the immune system is critical to outgrowth of UV-induced cancers. The intact immune system is otherwise able to reject the great majority of UV-induced skin cancers. This effect of UV radiation on the immune system may be relevant to other diseases. It may alter the course of some infections, change the way the body responds to vaccination, and may also have a role in some immune-related diseases such as multiple sclerosis. How it is that these wavelengths just beyond visible light can affect the immune system is the subject of this project. We know that UV radiation can penetrate only a short way into the skin, yet can have widespread effects on the immune system. Our research to now has shown that a particular cell type sitting just below the surface of skin, the dermal mast cell, is essential. We've also demonstrated some of the complexity of the early response to UV exposure - both a chemical (cis-urocanic acid) in the very outermost layer of skin, and nerves in the skin, have roles. Importantly, anti-histamines can inhibit UV effects on immune responses. Additional lines of evidence also point to histamine, a product of mast cells, as playing a pivotal role in the immune alterations following UV exposure. Our research aims to characterise the effects of histamine on cells central to the development of immune responses, known as dendritic cells, and define the mechanisms of the effect in experimental models. In collaboration with researchers in the UK, we will further characterise the role of mast cells in UV alterations to immunity in humans.Read moreRead less