MRC-GSK Alliance: Mechanisms of interplay between allergy and viruses in asthma
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
We apply to form an Alliance between GSK and the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma to discover and develop new approaches for prevention/treatment of asthma and asthma attacks. We will integrate research in areas of major strength for the Centre with the strengths in asthma drug discovery at GSK. The overall aim is to investigate mechanisms of interplay between allergy and virus infection in development of asthma and in acute asthma attacks.
The major cause of asthma attacks are human rhinovirus (RV) infections, these are also related to development of asthma when they occur in early life. We will investigate gene expression and how expression is regulated in lung cells during RV infection to identify molecules/pathways induced by RV infection that are implicated in promoting allergic responses.
We will determine whether RV induction/modification of these molecules/processes are related to pre-existing allergic responses, virus load and clinical severity of asthma exacerbation.
A major cause of asthma is failure of development of immunological tolerance to allergens. We have shown that tolerance can be reversed by a virus infection, but the mechanisms are unknown. We will purify lung cells from the virus-induced breakdown of tolerance model to identify genes implicated in tolerance breakdown and determine whether these are replicated in lung cells in the human.
Finally we will determine whether blocking or inducing molecules implicated in virus induced worsening of allergic responses/breakdown of tolerance, determines severity of RV induced allergic airway inflammation.
Accomplishment of these aims will identify targets for development of novel therapies for asthma and asthma attacks.
The major cause of asthma attacks are human rhinovirus (RV) infections, these are also related to development of asthma when they occur in early life. We will investigate gene expression and how expression is regulated in lung cells during RV infection to identify molecules/pathways induced by RV infection that are implicated in promoting allergic responses.
We will determine whether RV induction/modification of these molecules/processes are related to pre-existing allergic responses, virus load and clinical severity of asthma exacerbation.
A major cause of asthma is failure of development of immunological tolerance to allergens. We have shown that tolerance can be reversed by a virus infection, but the mechanisms are unknown. We will purify lung cells from the virus-induced breakdown of tolerance model to identify genes implicated in tolerance breakdown and determine whether these are replicated in lung cells in the human.
Finally we will determine whether blocking or inducing molecules implicated in virus induced worsening of allergic responses/breakdown of tolerance, determines severity of RV induced allergic airway inflammation.
Accomplishment of these aims will identify targets for development of novel therapies for asthma and asthma attacks.
Technical Summary
We apply to form an Alliance between GSK and the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma to discover and develop new approaches for prevention/treatment of asthma and asthma exacerbations. We will integrate research in areas of major strength for the Centre with the strengths in asthma drug discovery at GSK. The overall aim is to investigate mechanisms of interplay between allergy and virus infection in development of asthma and in acute asthma exacerbations. We will use human rhinovirus (RV) infection in asthmatic and healthy subjects to investigate roles of pre-existing/induced IgE, Th2 responses and RV infections in augmenting allergic responses in humans in vivo, alongside mouse models studies of breakdown of immune tolerance by virus infection and of virus exacerbation of allergic airway inflammation, to discover novel mechanisms where not technically possible in humans, and to investigate causal relationships with outcomes in vivo. Candidate mechanisms/drugs in GSK pipelines will then be tested in the mouse models above.
We will investigate:
1. epigenetic modifications induced by RV infection in bronchial epithelial cells (BECs) ex vivo and mRNA/miRNA expression profiles of BECs and bronchoalveolar lavage macrophages, dendritic cells (DCs) and CD4+ T cells at baseline and during RV infection in vivo to identify molecules/pathways implicated in promoting Th2 responses.
2. whether RV infection in vivo increases production and affinity of IgEs against previous allergens and generates new allergen specificities (epitope spreading) by somatic hypermutation, receptor revision, class switching and affinity maturation leading to expansion of allergen-specific high affinity IgE-expressing B and plasma cells.
We will determine whether RV induction/modification of these molecules/processes are related to pre-existing IgE levels/specificities or Th2 responses and virus load, clinical severity of asthma exacerbation (airway inflammation, symptoms, lung function and airway hyperresponsiveness) in vivo.
We will purify lung DCs from the virus-induced breakdown of tolerance model to identify mRNA/miRNAs in DCs implicated in tolerance breakdown and determine whether these are replicated in lung DCs in the human model in vivo.
Finally we will determine whether antagonism/agonism of molecules implicated in virus induced augmentation of Th2/IgE responses/tolerance breakdown in vivo, results in increased/decreased breakdown of immune tolerance or severity of RV induced exacerbation of allergic airway inflammation in mice in vivo.
Accomplishment of these aims will identify targets for development of novel therapies for asthma and asthma exacerbations and will provide early proof of concept testing of some of these targets.
We will investigate:
1. epigenetic modifications induced by RV infection in bronchial epithelial cells (BECs) ex vivo and mRNA/miRNA expression profiles of BECs and bronchoalveolar lavage macrophages, dendritic cells (DCs) and CD4+ T cells at baseline and during RV infection in vivo to identify molecules/pathways implicated in promoting Th2 responses.
2. whether RV infection in vivo increases production and affinity of IgEs against previous allergens and generates new allergen specificities (epitope spreading) by somatic hypermutation, receptor revision, class switching and affinity maturation leading to expansion of allergen-specific high affinity IgE-expressing B and plasma cells.
We will determine whether RV induction/modification of these molecules/processes are related to pre-existing IgE levels/specificities or Th2 responses and virus load, clinical severity of asthma exacerbation (airway inflammation, symptoms, lung function and airway hyperresponsiveness) in vivo.
We will purify lung DCs from the virus-induced breakdown of tolerance model to identify mRNA/miRNAs in DCs implicated in tolerance breakdown and determine whether these are replicated in lung DCs in the human model in vivo.
Finally we will determine whether antagonism/agonism of molecules implicated in virus induced augmentation of Th2/IgE responses/tolerance breakdown in vivo, results in increased/decreased breakdown of immune tolerance or severity of RV induced exacerbation of allergic airway inflammation in mice in vivo.
Accomplishment of these aims will identify targets for development of novel therapies for asthma and asthma exacerbations and will provide early proof of concept testing of some of these targets.
