Characterisation of the role of T cells in the pathogenesis of atopic disease

Lead Research Organisation: MRC Human Immunology Unit

Abstract

Eczema or atopic dermatitis is very common, affecting approximately 1 in 10 people in the United Kingdom. As with the related conditions asthma and hayfever, none of the current treatments offer permanent cure and all carry potential side effects. Although much of the tendency to develop eczema is inherited within a family, it is now understood that the environment also plays an important role. Evidence suggests that a particular type of cell, which is normally involved in fighting infections, can react to environmental triggers and contribute to the development of disease.||The proposed research will be a detailed study of how such T cells react to certain triggers including house dust mite, and how this might produce inflammation in the skin. By examining the blood and skin of affected patients we will attempt to define key central events in the development and function of the reactive T cells. Through helping to understand the precise causes of disease, we hope to be able to identify new potential treatment targets that are relevant not only for eczema but also for asthma and hayfever.

Technical Summary

Atopic dermatitis, asthma and allergic rhinitis now account for a combined prevalence of up to 30% in Western countries. Although there is considerable circumstantial evidence suggesting that T cells might be important in the pathogenesis of atopic disease, little is known of the underlying mechanisms.||The overall objective of the research is to quantify and characterise the allergen-specific CD4+ and CD8+ T cell responses in individuals with atopic dermatitis (AD). The design of the laboratory-based research project will be the analysis of allergen-specific T cell reactivity in the blood of a cohort of 40 patients with symptomatic AD, 20 atopic patients without AD, and 20 non-atopic controls. T cell reactivity will also be analysed in lesional skin biopsies taken from 10 patients after standard cutaneous antigenic challenge. Using class I and class II tetrameric complexes, ELISpot and intracellular cytokine flow cytometry, allergen-specific T cells will be quantified and characterised. The principle measures will be the number of allergen-specific T cells in the blood or lesional tissue and the proportion expressing structural and functional phenotypes. These measures will be correlated with clinical disease severity scores and other laboratory indices of atopic disease and known genetic associations.||All of these studies have been granted ethical approval by the Oxford local research ethics committee.||The initial published results show that individuals with atopic dermatitis have high circulating frequencies of allergen-specific T cells and that local staphylococcal superantigen facilitates epithelial presentation of allergen to such T cells. These data link infection and allergic reactivity which are two of the most common associations of atopic dermatitis, and raise a number of possibilities for new translational approaches to disease management.||By characterising the involvement of T cells, we hope that the project will contribute to our understanding of AD pathogenesis and also identify novel therapeutic strategies for the atopic diseases.

Publications

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Ardern-Jones MR (2007) Bacterial superantigen facilitates epithelial presentation of allergen to T helper 2 cells. in Proceedings of the National Academy of Sciences of the United States of America

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Aslam A (2006) Defining the T cell antigen proteome of wasp venom. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

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Aslam A (2011) Common filaggrin null alleles are not associated with hymenoptera venom allergy in Europeans. in International archives of allergy and immunology

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Baldo M (2010) T cells reactive with the NC16A domain of BP180 are present in vulval lichen sclerosus and lichen planus. in Journal of the European Academy of Dermatology and Venereology : JEADV

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Bateman EA (2008) Identification of an immunodominant region of Fel d 1 and characterization of constituent epitopes. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

 
Description new approaches to investigation and treatment of atopic disease
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description British Skin Foundation Grant
Amount £62,000 (GBP)
Organisation British Skin Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2014 
End 12/2015
 
Description British Skin Foundation Large Research Awards
Amount £70,000 (GBP)
Organisation British Skin Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description Comprehensive Research Network
Amount £1,700,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Clinical Research Network (CRN)
Sector Public
Country United Kingdom
Start 04/2007 
End 03/2017
 
Description Janssen collaborative research grant
Amount $1,600,000 (USD)
Organisation Johnson & Johnson 
Department Janssen Pharmaceuticals
Sector Private
Country United States
Start 10/2013 
End 09/2015
 
Description MRC Experimental Medicine 2
Amount £380,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description MRC/UCB Antibody Discovery Initiative
Amount £250,000 (GBP)
Funding ID MC_EX_MR/R022550/1 
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 02/2019 
End 12/2019
 
Description NIHR Senioe Investigator
Amount £60,000 (GBP)
Organisation University of Leicester 
Department NIHR Biomedical Research Centre
Sector Hospitals
Country United Kingdom
Start 04/2018 
End 03/2022
 
Description Oxford Biomedical Research Centre
Amount £1,000,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2007 
End 03/2017
 
Description Wellcome Trust Collaboratiev Award
Amount £3,000,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2018 
End 04/2023
 
Title Allergen-specific T cells 
Description Allergen-specific T cells were derived from human peripheral blood and used to show an interaction with S.aureus. This has lead to the award of an MRC Experimental Medicine 2 grant for a proof of concept clinical trial. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2008 
Provided To Others? Yes  
Impact many outputs - see relevant sections 
 
Title HLA peptide tetrameric complexes 
Description I was involved in the later stages of HLA peptide tetrameric complex development and refinement of their use (first developed by John Altman, Mark Davis, Andrew McMichael, John Bell et al) and their application to the study of human disease 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Vast number of publications have now used the technology 
 
Description Andrew McKenzie LMB Cambridge 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Public 
PI Contribution We are working with Andrew McKenzie to identify nuocytes in human and model skin and relate to clinical disease. we provide knowhow and expertise for access to human skin cells.
Collaborator Contribution Andrew McKenzie provides knowhow and expertise for access to model skin
Impact new collaboration
Start Year 2011
 
Description Biomedical Research centre Oxford 
Organisation University of Oxford
Department Nuffield Department of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided many of the samples and technology for analysis of samples using Biomedical Research Centre equipment.
Collaborator Contribution Access to equipment and individuals
Impact Many outputs as detailed in relevant sections
Start Year 2007
 
Description Branch Moody Harvard 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution We collaborate on CD1a-restricted T cell responses. We have contributed ideas, samples, experimental work and technical advances.
Collaborator Contribution We collaborate on CD1a-restricted T cell responses. Branch Moody and his team have contributed ideas, samples, experimental work and technical advances.
Impact Multiple publications and conference presentations
Start Year 2012
 
Description Judy Breuer 
Organisation University College London
Department MRC Centre for Medical Molecular Virology
Country United Kingdom 
Sector Public 
PI Contribution Analyses of T cell responses to varicella zoster virus
Collaborator Contribution Provision of samples and analyses
Impact see relevant sections
Start Year 2008
 
Description Paul Klenerman VZV 
Organisation Medical Research Council (MRC)
Department MRC Molecular Haematology Unit
Country United Kingdom 
Sector Public 
PI Contribution Analysis of varicella zoster virus specific immune respoonses after vaccination
Collaborator Contribution Access to samples and discussions.
Impact Publications and presentations
Start Year 2008
 
Description Transduction of TCR 
Organisation University College London
Department Division of Infection and Immunity
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of T cell clones
Collaborator Contribution Help with cloning TCR into primary T cells
Impact Still early stages
Start Year 2009
 
Description University of Sri Jayawardanapura 
Organisation University of Sri Jayawardanapura
Country Sri Lanka 
Sector Academic/University 
PI Contribution Analyses of samples
Collaborator Contribution Contribution of samples and some analyses
Impact see relevant sections
Start Year 2008
 
Title Idea that combined allergen and anti-bacterial approaches may benefit patients with atopic disease 
Description We observed that staphylococcal superantigen facilitates antigen presentation of allergen by epithelial cells. This potentially explains a clinical observation seen in individuals with atopic dermatitis, that flares of disease are often associated with infection. The underlying mechanisms were characterised. I believe this is important for understanding of disease and for the development of new treatment approaches (recent award of MRC Experimental Medicine 2 funding to take this into a proof-of-principle clinical trial). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2007
Development Status Under active development/distribution
Impact We hope that this will provide patient benefit 
 
Description CRN Podcast 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Podcast highlighting medical problems in dermatology and our strategies for developign new approaches to treatment.
Year(s) Of Engagement Activity 2019
 
Description MRC Festival of Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact MRC Festival of Science exhibuit taken to many cities in 2017, describgin our work on skin inflammation and new approaches to treatment.
Year(s) Of Engagement Activity 2017
 
Description National Science Week 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Approximately 150 members of public attended lectures and displays

I have many school children who wish to have lab attachments
Year(s) Of Engagement Activity 2009,2010