Molecular Mechanisms In The Regulation Of Allergy And Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$4,977,215.00
Summary
To understand the fundamental cellular and molecular processes that underpin the development of allergic disorders, viral infections of the respiratory tract and chronic inflammatory diseases of the lung. There is particular interest in the role of immune cells, such T cells and granulocytes in these disorders, and in the processes that control their function. Understanding these processes will provide new insights into the immune system's role in health and disease, and help develop better ther ....To understand the fundamental cellular and molecular processes that underpin the development of allergic disorders, viral infections of the respiratory tract and chronic inflammatory diseases of the lung. There is particular interest in the role of immune cells, such T cells and granulocytes in these disorders, and in the processes that control their function. Understanding these processes will provide new insights into the immune system's role in health and disease, and help develop better therapies to treat inflammatory disorders.Read moreRead less
B-1 B Cells As A Source Of Polyreactive IgE Antibodies, In Allergic Individuals
Funder
National Health and Medical Research Council
Funding Amount
$331,320.00
Summary
Allergic disease results from the actions of antibody molecules that are produced by cells called B cells. Over the last fifteen years, it has been realised that there are at least two B cell subsets, called B-1 and B-2 cells. The B-1 cells and their antibody products have many unusual features, and they have been implicated in some disease processes. We have recently completed studies that strongly suggest that B-1 B cells may play an important role in some allergic disease. We wish to compare ....Allergic disease results from the actions of antibody molecules that are produced by cells called B cells. Over the last fifteen years, it has been realised that there are at least two B cell subsets, called B-1 and B-2 cells. The B-1 cells and their antibody products have many unusual features, and they have been implicated in some disease processes. We have recently completed studies that strongly suggest that B-1 B cells may play an important role in some allergic disease. We wish to compare groups of patients defined according to their allergic conditions and age, to see whether B-1 B cell activity is associated with particular allergic diseases. We hypothesise that patients with allergic skin conditions have raised numbers of allergy-inducing B-1 cells. Such patients will be compared with those with allergies to inhalent allergens and others with food allergies. Studies will be performed in adult groups as well as in children, for B-1 B cell numbers are known to vary with age. As most of our understanding of the regulation of B cell function, in the context of allergic disease, has arisen from studies conducted with conventional B-2 cells, we also wish to reconsider aspects of B cell regulation. We are specifically interested in the regulation of the 'switching' of B-1 B cells, when they change from the production of antibodies of a 'non-allergic' type (IgM antibodies) to allergy-promoting IgE antibodies. We wish to determine whether the B-1 B cells of allergic individuals are particularly susceptible to such switching, when under the influence of regulatory molecules called cytokines. We expect that B-1 B cells will be associated with some, though not all allergic conditions, and that these cells will emerge as a new target for therapies. Such a finding would be most important. The development of new therapies will require a better understanding of the regulation of these cells, and this will be another important outcome of this project.Read moreRead less
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
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
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