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
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
Inflammatory skin disorders, such as psoriasis and dermatitis, are responsible for a large burden of human disease and affect people across alldemographics. Knockout (KO) of TNF signalling members in mice is known to induce skin inflammation. This project proposes to use these genetic mouse models to investigate how and why disruption of particular TNF superfamily members leads to disease and potentially identify new targets for treatment.
Many white blood cells have an innate ability to sense infection, and trigger inflammation to fight invading microbes. These innate immune cells use particular receptors to sense pathogens and we have now identified a new pathway that leads to the activation of one of these, known as Pyrin. Genetic mutations can activate this pathway, and our project will determine the molecular basis for this, and how it can be targeted to treat inflammatory disease.
Prof Carbone’s laboratory specialises in the study of immunity at the body surfaces. These surfaces include skin and mucosal tissues such as respiratory and gastrointestinal tract, all of which are the common points of entry for a variety of infectious agents. He has found that there exist cells at these peripheral sites that are separate from the immune components that one finds in the blood and, more importantly, that provide a profound level of protection during new infection. He now propose ....Prof Carbone’s laboratory specialises in the study of immunity at the body surfaces. These surfaces include skin and mucosal tissues such as respiratory and gastrointestinal tract, all of which are the common points of entry for a variety of infectious agents. He has found that there exist cells at these peripheral sites that are separate from the immune components that one finds in the blood and, more importantly, that provide a profound level of protection during new infection. He now propose to determine how best to induce this type of peripheral immune protection and how one can exploit these mechanisms for the purpose of infection control.Read moreRead less
Predictors And Consequences Of Allergies That Impact On Children Getting A Healthy Start To Life:a Prospective Study
Funder
National Health and Medical Research Council
Funding Amount
$893,559.00
Summary
Allergic diseases prevent Australian children getting a healthy start to life by causing long term illnesses. This group of diseases includes asthma, hay fever, eczema and food allergies. Half of all Australian children are born into families with a history of these conditions and these children are at increased risk. Some of these children develop allergies while the others do not. It is also known that allergic conditions change over time, but we have no information on causes of these changes. ....Allergic diseases prevent Australian children getting a healthy start to life by causing long term illnesses. This group of diseases includes asthma, hay fever, eczema and food allergies. Half of all Australian children are born into families with a history of these conditions and these children are at increased risk. Some of these children develop allergies while the others do not. It is also known that allergic conditions change over time, but we have no information on causes of these changes. For example some infants with eczema continue to have eczema or develop hay fever and asthma, while others do not. The aim of this study is to determine what factors cause allergies and what factors influence these changes. This will provide evidence to guide health policy and clinical practice. Looking at the different conditions in family members over time is a good way to answer these types of questions, because parents and siblings share similar exposures, but not all the same genes. This helps to disentangle the effects of the environment and genes. The Melbourne Atopic Cohort Study (MACS) is amongst the world�s major studies on the development of allergies. MACS commenced in 1991-94 by recruiting 620 babies prior to birth. Only infants born into families with a history of allergic disease were included. MACS is unique because all family members and the home environment were assessed at the time of birth of the child. These children have been followed regularly over the first ten years of their life. The MACS now provides a unique opportunity to conduct a family study that can examine genes, childhood environment and individual risk factors for allergies. This will also allow exploration of the impact of allergies on families and the health care system, and how we can reduce that impact. Such information will provide evidence to guide health care policy and clinical practice. Also, the current study will provide a platform for future studies to investigate the progression of allergies in this family cohort. This will be the world's only longitudinal family follow-up of allergies that spans all of childhood. It will assist in reducing the impact of these common conditions, and the findings will be original and significant not only in Australia but also internationally.Read moreRead less
Molecular Basis For The Emergence Of Community Acquired Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$427,518.00
Summary
Golden Staph is a major problem in our hospitals but serious Golden Staph infections are increasingly common in the community, among otherwise healthy people who have had no contact with hospitals. This project will find out how Golden Staph is evolving to become more likely to cause disease in the community. This knowledge can then be used to design new strategies for early detection, prevention and treatment.
Defining The Contribution Of Skin Gamma Delta T Cells To Cutaneous Immunosurveillance, Immunity And Disease After HSV Infection.
Funder
National Health and Medical Research Council
Funding Amount
$601,386.00
Summary
Herpes simplex virus (HSV) causes genital herpes and encephalitis. Disease is severe in the immunocompromised and the newborn. HSV enters through breaks in the skin or mucosa, where it first encounters gamma delta T cells. We have recently made the key finding that HSV can infect gamma delta T-cells shortly after inoculation. Here we will study how they contribute to the immune response when a virus enters the skin in mice and human tissues. This may lead development of new topical antiviral vac ....Herpes simplex virus (HSV) causes genital herpes and encephalitis. Disease is severe in the immunocompromised and the newborn. HSV enters through breaks in the skin or mucosa, where it first encounters gamma delta T cells. We have recently made the key finding that HSV can infect gamma delta T-cells shortly after inoculation. Here we will study how they contribute to the immune response when a virus enters the skin in mice and human tissues. This may lead development of new topical antiviral vaccines.Read moreRead less
Broad spectrum nanomedicine for Meningitis treatment. Brain inflammatory diseases are among the top ten infectious causes of death. The project aims to provide Australian doctors with a superior alternative of treating infections that do not respond to conventional antibiotics. The nanomedicine developed will reduce the burden of hospital and boost Australia economy in the biomedical sector.
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.