Molecular mechanisms and interventions in allergy and asthma

Lead Research Organisation: King's College London
Department Name: Asthma Allergy and Lung Biology

Abstract

The health and economic burden of allergic diseases, including asthma, on the nation emphasizes the importance of research that tries to understand the mechanisms of these disorders. Allergy is caused by the presence of a specific antibody in the body, named IgE. The current research looks at ways in which the body makes this substance and how to switch it off. In asthma, one of the commonest allergic conditions, previous evidence has suggested that inflammation in the bronchial tubes in the lungs of patients play an essential role in perpetuating and causing severe disease. The proposed research analyses the control for the production of a number of substances, named cytokines, which are believed to be central to orchestrating bronchial inflammation in asthma. The results of the proposed work may provide new ideas on how to develop strategies for treatment of this common condition. Tak Lee (lead applicant) is the National Asthma Campaign Professor. The Charity can therefore help to publicize, in conjunction with the MRC, discoveries originating from the proposed research to its extensive lay membership through its news letters and to the wider public via its well established contacts in the media, whenever appropriate.

Technical Summary

IgE plays a critical role in the pathogenesis of asthma and allergic disease, not only through the sensitisation of mast cells and basophils through binding of IgE to the high-affinity IgE receptor FceRI, which provides a mechanism for acute exacerbation of asthma on allergen exposure, but also by binding of IgE to the low-affinity IgE receptor (CD23) on langerhans cells and monocytes. Thus, IgE is also involved in allergen capture, processing and presentation. It is therefore central to investigate the mechanisms regulating IgE synthesis and the interaction of IgE with its receptors. Glucocorticoids remain the cornerstone of therapy for asthma and allergic disease. One of the principal actions of these drugs is to inhibit the production of cytokines by Th2 cells such IL-4 and IL-13 that control IgE synthesis.


The overall strategy of our Cooperative group has always been to elucidate the molecular mechanisms of allergic disease and to identify new therapeutic targets. Creation of the group has permitted established groups of investigators to focus collectively and synergistically on a number of critical and unresolved issues in allergic disease. Significant contributions have been made to each of the original objectives identified approximately four years ago and substantial additional funding has been attracted. The work proposed in our renewal application is particularly timely because the molecular and other technologies developed in our earlier work can be used to progress proposed studies in an expeditious manner. Our renewal application addresses : (a) structural studies of protein-protein interactions of the IgE network; (b) the role of CD23 in the commitment of B cells to IgE synthesis; (c) domain folding in IgE; (d) molecular structure recognition and regulation of IgE; (e) localised IgE switching of the bronchial mucosa of intrinsic asthmatics; (f) the mechanisms of glucocorticoid action on IL-4 and IL-13; Th2 cytokines that regulate IgE production.

Publications

10 25 50

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Corrigan CJ (2009) The ADMIT series--issues in inhalation therapy. 3) Mild persistent asthma: the case for inhaled corticosteroid therapy. in Primary care respiratory journal : journal of the General Practice Airways Group

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Durham SR (2008) Sublingual immunotherapy: what have we learnt from the 'big trials'? in Current opinion in allergy and clinical immunology

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Durham SR (2007) Tradition and innovation: finding the right balance. in The Journal of allergy and clinical immunology

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Durham SR (2006) Allergen immunotherapy (desensitisation) for allergic diseases. in Clinical medicine (London, England)

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Erin EM (2006) Effects of a reversible beta-tryptase and trypsin inhibitor (RWJ-58643) on nasal allergic responses. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

 
Description BBSRC grant
Amount £458,249 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2010 
End 06/2013
 
Description MRC Co-operative collaborations 
Organisation Imperial College London
Department National Heart & Lung Institute (NHLI)
Country United Kingdom 
Sector Academic/University 
PI Contribution The co-opertaive funding encouraged numerous colaborations between resrachers at King's and |imperial Colleges, leading ultimately in a successful application to the MRC to found the MRC Centre in Allergic Mechanisms of Asthma. Ther output of research from these collaborations has been vast (see publication list).
Collaborator Contribution Collaboration between King's and Imperial Colleges increased (1) The patient database for our clinical studies on asthma and allergy (2) The range of laboratory expertise, especially with animal models of asthma
Impact See section 2