Identifying The Ontogeny And Fate Of T Follicular Helper Cells By Two-photon Photoconversion
Funder
National Health and Medical Research Council
Funding Amount
$623,070.00
Summary
The aim of this proposal is to investigate immune cells called T follicular helper cells using a novel microscopy-based method that we have developed. This method lets us ‘tag’ these cells in a way that enables us to distinguish them from all other cells and follow them as they migrate to different immunological compartments during the response. T follicular helper cells are important for protective immune responses against pathogens and a better understanding of this T cell subset will aid vacc ....The aim of this proposal is to investigate immune cells called T follicular helper cells using a novel microscopy-based method that we have developed. This method lets us ‘tag’ these cells in a way that enables us to distinguish them from all other cells and follow them as they migrate to different immunological compartments during the response. T follicular helper cells are important for protective immune responses against pathogens and a better understanding of this T cell subset will aid vaccine design.Read moreRead less
Acute Alerting Effects Of Daytime Exposure To Specific Wavelengths Of Light
Funder
National Health and Medical Research Council
Funding Amount
$446,367.00
Summary
Excessive sleepiness is the greatest identifiable and preventable cause of accidents in all modes of transportation. Shift workers working outside the 8am-5pm day, make up about 20% of the urban working population. These individuals often report excessive daytime sleepiness caused by irregular sleep-wake patterns and long-term sleep loss. Excessive sleepiness is also common in individuals with sleep disorders. While there are many stimulant and wake-promoting drugs available to counteract daytim ....Excessive sleepiness is the greatest identifiable and preventable cause of accidents in all modes of transportation. Shift workers working outside the 8am-5pm day, make up about 20% of the urban working population. These individuals often report excessive daytime sleepiness caused by irregular sleep-wake patterns and long-term sleep loss. Excessive sleepiness is also common in individuals with sleep disorders. While there are many stimulant and wake-promoting drugs available to counteract daytime fatigue such drugs have problems of side effects, interactions and in some cases dependence. Light has many beneficial effects for a wide range of medicinal, physiological, psychological, and social purposes. One well known effect is as a stimulant so that exposure to bright light, both during the night and in the middle of the day, improves alertness and attention, and decreases reaction times thus improving performance. These effects can also be measured as changes in brain activity. However we do not understand the mechanisms in the eyes which control these effects. While certain cells in the eyes called rods and cones are necessary for seeing objects clearly and for detecting colour, there appears to be another system in the eyes which may involve different specialized cells or photoreceptors that are important for the alerting effects of light. White light is made up of different wavelengths or colours of light. This study will examine which wavelength (blue, violet, red or green) of light best improves alertness and learning during the daytime. Various performance tests will be used in addition to measures of brain wave activity. By identifying the most effective wavelength of light for improving alertness in healthy young adults and better understanding the mechanisms in the eyes involved, we will be able to develop light treatment strategies in patient groups with sleep disorders and in individuals like shift workers who experience sleep loss.Read moreRead less
CONTINUING MECHANISTIC STUDIES OF UVA PHOTOIMMUNOPROTECTION
Funder
National Health and Medical Research Council
Funding Amount
$261,113.00
Summary
The UVB portion of sunlight causes sunburn, tanning, skin cancer, and suppresses immune function. Longer wavelength UVA is significantly less damaging, may contribute to photoageing and damage to deeper skin layers, but has been much less well studied. UVB-induced immunosuppression appears to be a prerequisite for skin cancer, and experimental protection from the immunosuppression results also in reduced severity of the long-term skin cancer outcome. We have identified a protective effect by UVA ....The UVB portion of sunlight causes sunburn, tanning, skin cancer, and suppresses immune function. Longer wavelength UVA is significantly less damaging, may contribute to photoageing and damage to deeper skin layers, but has been much less well studied. UVB-induced immunosuppression appears to be a prerequisite for skin cancer, and experimental protection from the immunosuppression results also in reduced severity of the long-term skin cancer outcome. We have identified a protective effect by UVA radiation against UVB-immunosuppression when UVA is administered to mice at non-burning environmentally relevant doses. This was an important and unprecedented finding, and is supported by recent observations also in humans. The aim of the present study is to clarify the mechanisms by which this resistance to UVB-induced immunosuppression is achieved, according to 2 main hypotheses: 1. UVA interferes with the actions of cis-urocanic acid, a natural epidermal UV-photoproduct that appears to initiate the immunosuppression by interacting with histamine. 2. UVA alters the balance of immunological control and thus activates normal antioxidant defences of the skin such as metallothionein and haem oxygenase, which antagonise the apparent oxidative requirement for UVB-immunosuppression. These pathways lead to the prediction that increasing the UVA component of the incident radiation will reduce skin cancer development. Humans typically receive disproportionately large UVA doses sunbathing through a UVB-sunscreen, or in cosmetic sunparlours. The assumption that UVA contributes to UVB skin damage may not be true at moderate UV doses, and a potential for UVA to protect from UVB-suppressed immunity and risk of skin cancer would suggest that broad spectrum sunscreens are contraindicated, and that the UVA effects need to be exploited.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
DNA Damage Induced By UVA And UVB In Squamous Cell Carcinoma Progression
Funder
National Health and Medical Research Council
Funding Amount
$65,000.00
Summary
Australia has the highest incidence of skin cancer in the world. This results from immigration of individuals with fair skin to Australia. Skin cancer is three times as common as all other cancers combined. Overall, the incidence of skin cancer continues to rise in Australia and it will be several years before the true effectiveness of preventative programs are known. In the meantime, 1000 Australians die each year from skin cancer. Modern sunscreens, even those with high SPF and labelled as bro ....Australia has the highest incidence of skin cancer in the world. This results from immigration of individuals with fair skin to Australia. Skin cancer is three times as common as all other cancers combined. Overall, the incidence of skin cancer continues to rise in Australia and it will be several years before the true effectiveness of preventative programs are known. In the meantime, 1000 Australians die each year from skin cancer. Modern sunscreens, even those with high SPF and labelled as broad spectrum do not protect very well from UVA, though they are very effective UVB filters. Most sunscreens absorb or reflect only about 50% as much UVA as UVB. Thus sunscreen use alters the spectrum of UV received. This is an important issue, because if sunscreens are used to prolong sun exposure they will selectively increase the amount of UVA reaching the skin, and the sun contains a lot more UVA than UVB. There is only limited evidence to suggest they protect from skin cancer in humans whereas there is good evidence that they protect from precursor lesions. We have developed a new hypothesis, that UVB is primarily responsible for development of preneoplastic lesions (solar keratosis and dysplastic nevi) whereas UVA plays a relatively more important role in their progression to malignancy. This hypothesis would explain why sunscreens are more effective at preventing nevi and solar keratosis formation than they are at preventing melanoma and squamous cell carcinoma. Until the action spectrum defining the wavelengths responsible for skin cancer induction is known, the optimal methods for protection from skin cancer will be difficult if not impossible to design. That different wavelengths may be involved in different phases of skin cancer development in humans is a novel hypothesis: if it is correct it will have profound implications for both the design of sunscreens and our current public health programmes for skin cancer prevention.Read moreRead less