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.

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.

Publications

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Chen JB (2017) Antibodies and superantibodies in patients with chronic rhinosinusitis with nasal polyps. in The Journal of allergy and clinical immunology

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Correia LL (2017) SOX2 Drives Bronchial Dysplasia in a Novel Organotypic Model of Early Human Squamous Lung Cancer. in American journal of respiratory and critical care medicine

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Dhariwal J (2017) Mucosal Type 2 Innate Lymphoid Cells Are a Key Component of the Allergic Response to Aeroallergens. in American journal of respiratory and critical care medicine

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Dhariwal J (2017) Mucosal Type 2 Innate Lymphoid Cells Are a Key Component of the Allergic Response to Aeroallergens. in American journal of respiratory and critical care medicine

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Farne H (2016) Are emerging PGD2 antagonists a promising therapy class for treating asthma? in Expert opinion on emerging drugs

 
Description MRC Centenary Celebration (Science Festival & Open Week, June 2013) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Centre took part in the MRC Centenary Celebrations on 15th-16th June 2013 (Science Festival at the Science Museum) and on 20th June 2013, when we organised a day-time event as part of the Centenary Open Week.


Some outcomes of our Open Day event on 20th June 2013 by the Observation Point in London's South Bank:

• 12ft inflatable lungs from The Roy Castle Lung Cancer Foundation were probably our most significant model for the Open Week event. Centre scientists worked in shifts, presenting the anatomy and function of normal lungs and also spoke of lung diseases
• Asthma themed sand sculptures on the banks of Thames were of great interest. MRC Centenary hash tag #100mrc was also drawn in sand
• The desk size balloon model of lungs demonstrated how lungs work in a healthy individual and what happens in the lungs of asthmatics
• Members of the public were introduced to most common allergens at home ('Allergen House' poster game with magnetic allergens). Allergens such as dustmites and mold were placed in rooms where one would most likely encounter them. Afterwards scientists corrected the answers and explained the reasons why
• We ran an interactive game of Respiratory Olympics where peoples' lung capacities were measured using a spirometer. Men and women competed in different categories and the biggest lung capacity in each category won a prize, which was a pair of tickets to the Open East Festival (the first official opening of the Olympic Park since the 2012 Olympics)
• Overall we felt that our event was very well received, judging by the footfall and the fact that we did not experience many quiet moments. We felt that people were interested in our work and found our research of great significance

Other information:

• Collaboration and interaction with our partners (MRC, Asthma UK, Imperial and King's Colleges) as well as the other London based MRC Centres
• The Biomedical Research Centre (BRC) and the British Society for Immunology (BSI)
• Great learning exposure and enthusiasm for the Centre trainees (students and Post Docs)
• Our Open Day event was attended by Dr. Alfred William Frankland, one of the early pioneers of allergen immunotherapy
• Asthma UK Visit on12th Nov 2013 to the Centre Headquarters. Asthma UK have since requested further events for patients and donors. There are likely to be some as yet unknown impacts.
Year(s) Of Engagement Activity 2013
URL http://www.centenary.mrc.ac.uk/