Proof of concept study of combined allergen immunotherapy and antibiotics for the treatment of chronic atopic dermatitis

Lead Research Organisation: University of Oxford
Department Name: Unknown

Abstract

Atopic dermatitis (eczema) affects up to 20% of the UK population and is strongly associated with asthma and hayfever. We have shown that a common skin infection, Staphylococcus aureus, can dramatically alter how the body reacts to harmless environmental proteins or allergens. Therefore individuals are more likely to react to an allergen, such as house dust mite, if they encounter it at the same time as staphylococcal infection. Our findings potentially provide a new mechanism for atopic dermatitis and also for atopic and other allergic diseases, including asthma, hayfever and peanut allergy. We will investigate whether by combining anti-bacterial treatment with allergen desensitisation it is possible to improve symptoms in adult individuals with severe atopic dermatitis. We will also take blood samples from study subjects to examine changes in the immune response during treatment. This will give us important insights into how the disease occurs and how we can improve on our results in future clinical trials.
We will present our findings at scientific meetings and through publications, but will also liaise with the public and press whenever appropriate. Dr Graham Ogg has been involved in the presentation of science to the public, for example at the Royal Society Summer Science Exhibition and through the national Public Understanding of Science events and promotes the importance of public engagement in science.

Technical Summary

We have recently shown that staphylococcal enterotoxin B acts as an adjuvant for allergen-specific Th2 responses in individuals with atopic skin disease. These data provide a novel pathogenesis for atopic disease and link together diverse existing genetic, epidemiological and clinical observations. We aim to translate the findings by testing the hypothesis that combined reduction of S. aureus adjuvant effect and allergen immunotherapy provides clinical benefit for individuals with severe chronic atopic dermatitis. We will undertake a proof of concept clinical evaluation of whether prolonged antibiotic/antiseptic use and allergen immunotherapy improves subjective and objective disease severity scores in adults with severe atopic dermatitis. Furthermore by monitoring changes in allergen-specific humoral and cellular immune responses during successful treatment, we will identify correlates of disease and methods to monitor novel therapeutic strategies. We will use cytokine detection, proliferation and HLA-peptide tetrameric complexes to identify and characterise antigen-specific T cells. The clinical data would translate back to the bench for the design of novel approaches to reduce bacterial adjuvancy, or allergen-specific immune responses and would be used to inform the design of large scale clinical trials to assess differential approaches to the reduction in bacterial load or novel approaches to immunotherapy. Compliant with the Experimental Medicine 2 remit, the proposed interventions are based on existing strategies that have not been studied together in the setting of chronic atopic dermatitis, we would therefore avoid the time and GMP and other development costs and issues (including animal work) required for novel compounds. Although the findings will have particular significance for atopic skin disease, it is also anticipated that the data will be relevant to the associated diseases asthma and allergic rhinitis. In summary, we are aiming to translate our molecular immunology findings into achievable interventions with rapid timelines for clinical benefit to patients.

Publications

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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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Crack LR (2011) Phenotypic analysis of perennial airborne allergen-specific CD4+ T cells in atopic and non-atopic individuals. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

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Gutowska-Owsiak D (2014) Histamine exerts multiple effects on expression of genes associated with epidermal barrier function. in Journal of investigational allergology & clinical immunology

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Gutowska-Owsiak D (2018) Orchestrated control of filaggrin-actin scaffolds underpins cornification in Cell Death & Disease

 
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 Medical Association
Amount £35,000 (GBP)
Organisation British Medical Association (BMA) 
Sector Learned Society
Country United Kingdom
Start 10/2012 
End 09/2014
 
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 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 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
 
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 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
 
Title new method to identify T cell epitopes 
Description Use of emulsion PCR and IVTT to identify T cell epitopes 
IP Reference  
Protection Protection not required
Year Protection Granted 2010
Licensed No
Impact Early days
 
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 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 the public attended including many school children.

I get frequent requests for school children to join the group for attachments
Year(s) Of Engagement Activity 2010
 
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