Therapeutic Potential Of The IL-3-IL-5-GM-CSF Common Beta Receptor To Treat Upper And Lower Allergic Airway
Funder
National Health and Medical Research Council
Funding Amount
$150,442.00
Summary
This research aims to develop new treatments for allergic diseases such as asthma and allergic rhinitis, which remain significant public health problems in Australia. We will develop new therapies with the potential to completely suppress acute and chronic allergic disease targeting a common receptor protein that controls multiple facets of allergic inflammation. We will test antibodies intended to treat human asthma using a novel mouse strain expressing the human form of this receptor.
Fetomaternal Immunological Interactions In The Aetiology Of Allergic Disease.
Funder
National Health and Medical Research Council
Funding Amount
$195,990.00
Summary
There is accumulating evidence that immune abnormalities that lead to allergy are present at birth, and may be linked with maternal factors in pregnancy. This study examines how immune interactions between the fetus and the mother during pregnancy predispose to allergic immune responses in the infant. Allergic diseases result from inappropriate Type 2 responses to the environment whereas Type 1 response dominate immune responses of nonallergic people. Type 2 immune responses are first initiated ....There is accumulating evidence that immune abnormalities that lead to allergy are present at birth, and may be linked with maternal factors in pregnancy. This study examines how immune interactions between the fetus and the mother during pregnancy predispose to allergic immune responses in the infant. Allergic diseases result from inappropriate Type 2 responses to the environment whereas Type 1 response dominate immune responses of nonallergic people. Type 2 immune responses are first initiated before birth when they are actually normal for fetal survival. In normal infants maturation of Type 1 immune responses plays a central role in switching off the Type 2 responses of fetal life. Allergic disease appears to be due to abnormal persistence of this Type 2 response pattern beyond the newborn period. One of the most striking abnormalities in allergic individuals is immature Type 1 function at birth. With rising rates of allergy, there is an urgent need to identify how the balance of Type 1 and Type 2 responses is regulated during this early period. Maternal factors appear to play a critical role. There is already evidence that Type 1 responses are lower in babies of allergic mothers compared to babies of allergic fathers, suggesting direct effects of the mother in pregnancy. Although pregnancy normally favours Type 2 immunity, there appears to be normal variation in the balance of Type 1 and Type 2 responses in pregnancy. We plan to determine if variations in this balance affect the fetal capacity for Type 1 responses. We propose that minor degrees of tissue mismatch (present in all pregnancies) will activate low grade Type 1 responses and enhance maturation of fetal Type 1 responses. We will determine if allergic mothers (prone to stronger Type 2 responses) have less developed Type 1 responses in pregnancy and if this plays a direct role in abnormal Type 1 responses observed in their babies.Read moreRead less
Initiating Events In The Development Of Allergic Airway Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$452,545.00
Summary
Despite recent advances we still do not understand the basic mechanisms which underlie the development of allergic airway inflammatory diseases such as rhinitis and asthma. It has been previously shown that when pollen are exposed to water they release a large number of very small starch granules which contain a number of potent allergens as well as plant steroids. In addition house dust mite allergens which are strongly associated with asthma are mostly located in small faecal pellets. Both the ....Despite recent advances we still do not understand the basic mechanisms which underlie the development of allergic airway inflammatory diseases such as rhinitis and asthma. It has been previously shown that when pollen are exposed to water they release a large number of very small starch granules which contain a number of potent allergens as well as plant steroids. In addition house dust mite allergens which are strongly associated with asthma are mostly located in small faecal pellets. Both these particles are ideally sized to enter the respiratory tract and initiate inflammatory responses. We have shown that these responses appear to be of the type that is needed to initiate allergic reactions. We intend to further study the interactions of these small inhaled allergen containing particles with cells of the respiratory tract. In this proposal we will look at both alveolar macrophages and respiratory epithelial cells. These approaches will not only provide new information about the processes of airway inflammation caused by allergens but may also define new therapeutic approaches to the treatment of these diseases.Read moreRead less
Effects Of Enteric Microflora On Mucosal And Systemic Immune Development In Infants At Risk Of Allergic Disease
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
The increase in allergic diseases over the last 20-30 years has been attributed to an increased immunological propensity to Type-2 allergic immune responses in the postnatal period. It has been proposed that this may be due to a relative deficiency of counter-regulatory Type 1 immune responses in early life. Thus, there is growing interest in factors that might affect Type 1 maturation in this early period. It has been proposed that progressively cleaner societies may have more allergies because ....The increase in allergic diseases over the last 20-30 years has been attributed to an increased immunological propensity to Type-2 allergic immune responses in the postnatal period. It has been proposed that this may be due to a relative deficiency of counter-regulatory Type 1 immune responses in early life. Thus, there is growing interest in factors that might affect Type 1 maturation in this early period. It has been proposed that progressively cleaner societies may have more allergies because there is less stimulation of the Type 1 responses during immune development. Bacterial products provide important maturation signals to the developing immune system, and may favour Type 1 responses. The largest early exposure to bacteria in occurs in the human gut, which is colonised with bacteria soon after birth. These bacteria play an important role in maintaining health, both in the protection from harmful bacteria, and in the development of food tolerance. There is evidence that infants in cleaner sociaeties may have alterations in bowel flora. For many years probiotic formulations (containing strains of these healthy bacteria) have been used safely to treat children with gastroenteritis to reduce the duration of diarrhoea. More recently it has been suggested that these formulations have a role in treating and even preventing allergic disease. Further research is needed to confirm this, and to define the underlying immunological processes. This randomised double blind control study will determine if supplementation with probiotic flora (in late pregnancy and in early infancy) can favourably influence gut colonisation, alter subsequent immune development, and help prevent allergic disease in infants at high risk (from allergic families).Read moreRead less
This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on hu ....This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on human mast cells grown in culture. We will characterise the chemical nature of this receptor and verify that it is functionally important in mast cell activation. Because mast cells reside in almost all body tissues and are also important mediators of host responses to infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. Another key cell in allergic and parasitic diseases is the eosinophil. We have found that two other S100 proteins are expressed in eosinophils from the blood of normal individuals and that the genes that encode these proteins are regulated by mediators that regulate eosinophil migration and survival at allergic sites. However although the numbers these cells are high in lung biopsies from patients with asthma, we find that these proteins are generally not expressed. Because one of the S100 proteins, S100A9, was recently found to be important in the ability of other blood cells to migrate to signals that recruit them into tissues, we will examine whether this protein regulates the ability of eosinophils to migrate. Results from this project will provide new knowledge concerning mechanisms of allergy and may lead to the design of novel strategies to regulate the process. Results may have broader ramifications applicable to other inflammatory and infectious diseases.Read moreRead less
Perioperative Administration Of Dexamethasone And Infection- The PADDI Trial
Funder
National Health and Medical Research Council
Funding Amount
$4,832,815.00
Summary
The PADDI Trial is a large (8,800 patients) international, multicentre, randomised, controlled, non-inferiority safety and effectiveness study that will run for five years. It will examine the benefits and complications of administering 8mg of a steroid drug (dexamethasone) to adult patients undergoing non-urgent surgical procedures who receive general anaesthesia. The main outcome is surgical site infection 30 days after surgery. The influence of diabetes will also be investigated.
Inhibition Of Allergic Airway Inflammation By Nanoparticles
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Inhaled air pollution particulate matter causes asthma exacerbations, with 'ultrafine' nanoparticles thought to play a major role. Unexpectedly, we recently found that, by contrast, administration of inert ultrafine nanoparticles prevents allergic airway inflammation. We will identify the key particle physical and chemical properties associated with this novel type of disease inhibition, study particle effects in clinically-relevant disease models and identify mechanisms of action.
Mechanisms And Treatment Of Early Life Chlamydial Infection And Associated Asthma
Funder
National Health and Medical Research Council
Funding Amount
$616,195.00
Summary
Asthma is a serious respiratory disease that results from certain immune responses to allergens and there are no cures. Immune responses and lung structure may be permanently altered by respiratory chlamydial infection early in life that leads to reduced lung function and asthma but how this occurs is unknown. In this project we will determine how early life infections affect immune responses, lung function and asthma and test novel treatments and preventions for infection-associated asthma.
‘Granny was never the same after her operation’ is a strong public perception. These reports of persistent memory and concentration loss following surgery are now supported by a body of scientific research recording an incidence of ‘postoperative cognitive decline’ (POCD) as high as 75% in cardiac surgery patients. At present the cause is unknown but recently anaesthesia has been implicated. Our research team will investigate these claims.