Pathogenesis and treatment of cutaneous atopic disease; the interaction between the ipithelium and the innate and adaptive immune response

Lead Research Organisation: University of Oxford

Abstract

We are working towards treatment and prevention of immune-mediated skin disease. The skin is often the first point of contact with pathogens and allergens, but relatively little is understood about how the cutaneous immune system clears these challenges. Such knowledge is vitally important to understanding the mechanisms of skin disease and related diseases, and for developing more effective ways of cutaneous drug and vaccine delivery.
It is increasingly clear that skin barrier dysfunction is an important first step in the development of atopic eczema, one of the commonest skin diseases in the UK, and often associated with asthma and rhinitis. The barrier dysfunction promotes entry of allergens and microbes which eventually lead to skin inflammation. The latter is treated with topical immune suppressants, but these are not curative and also carry risks of side effects.
We wish to understand the steps linking barrier dysfunction and skin inflammation, as these will provide opportunities for new treatments. In particular, we will explore ways to repair barrier function and to understand the roles of novel immune cells in contributing to the inflammation.
These findings will have implications for atopic eczema, but also for other forms of inflammatory skin disease and indeed for the improvement of vaccine delivery in to the skin.

Technical Summary

Atopic disease affects 20-30% of the UK population and includes atopic eczema, asthma and rhinitis. Current treatments are suppressive, but not curative, and carry risks of side-effects. Since the identification of an association between atopic eczema and null mutations in the gene encoding filaggrin, it has become increasingly clear that events in the epithelium represent critical susceptibility factors in disease pathogenesis. We are working towards an understanding of the pathogenesis of atopic disease, in particular to explain how the epidermal dysfunction associated with filaggrin insufficiency contributes to atopic disease and whether this can be modified therapeutically. We capitalize on the ready access to lesional tissue in humans, and to function within networks and collaborations to maximize opportunities for success. The aim of the research is to understand the pathogenesis of cutaneous atopic disease in order to inform new approaches to disease prevention and treatment. The studies will also contribute to our understanding of the interaction between the epithelium and the innate and adaptive immune response. Emphasis will be focused on: 1) how filaggrin insufficiency promotes atopic inflammation and whether this can be therapeutically modified; 2) characterising innate IL-13 producing cells in human lesional atopic skin and after antigen challenge; 3) understanding mechanisms underlying antigen-specific immunotherapy to modulate immune responses in humans and to translate these findings to patient benefit; 4) investigating mechanisms underlying the cellular immune response to viral antigens in human skin. The experimental design is based on isolation of cells from blood and skin of patients and controls. The cells from skin include keratinocytes, dendritic cell family members (eg Langerhans cells), T cells, innate lymphoid cells. The patients will include those with cutaneous atopic disease and other inflammatory skin diseases, as well as individuals before and after cutaneous antigen challenge. Studies will be undertaken ex vivo and after culture. Interactions between keratinocytes, Langerhans cells and immune effector cells will include examination by expression analyses, mediator production and functional keratinocyte outcomes such as barrier function. Molecular mechanisms underlying these findings will be investigated. As well as contributing to disease and tissue specific questions, these studies will advance the broader University Unit aims of defining the interactions between the innate and adaptive immune responses and the local micro-environment, which in turn will support the development of new approaches to vaccination and treatment.

Publications

10 25 50

publication icon
Bourgeois EA (2015) Bee venom processes human skin lipids for presentation by CD1a. in The Journal of experimental medicine

publication icon
Fernando S (2016) Patterns and causes of liver involvement in acute dengue infection. in BMC infectious diseases

publication icon
Floudas A (2017) IL-17 Receptor A Maintains and Protects the Skin Barrier To Prevent Allergic Skin Inflammation. in Journal of immunology (Baltimore, Md. : 1950)

publication icon
Gutowska-Owsiak D (2013) Cytokine regulation of the epidermal barrier. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

publication icon
Gutowska-Owsiak D (2017) Therapeutic vaccines for allergic disease. in NPJ vaccines

 
Description Many local/regional clinical guidelines and GP training sessions
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Training and education fo GPs to improve health care delivery
 
Description Urticaria guidelines committee
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact The guidelines will impact on healthcare internationally
 
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 Anaptysbio Research Grant
Amount £700,000 (GBP)
Organisation AnaptysBio 
Sector Private
Country United States
Start 02/2017 
End 01/2019
 
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 Celgene Fellowship
Amount £500,000 (GBP)
Organisation Celgene 
Sector Private
Country United States
Start 01/2016 
End 01/2020
 
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 EXPLORATORY/DEVELOPMENT GRANT
Amount $137,000 (USD)
Funding ID 1R21AI125886-01 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 09/2016 
End 08/2018
 
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 Johnson and Johnson collaborative research
Amount £100,000 (GBP)
Organisation Johnson & Johnson 
Sector Private
Country United States
Start 01/2015 
End 12/2015
 
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 UCB Research grant
Amount £354,000 (GBP)
Organisation UCB Pharma 
Sector Private
Country United Kingdom
Start 09/2016 
End 08/2018
 
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 High throughput peptide display technology 
Description A high throughput method to identify peptides ligands of any target, form a large library. 
Type Of Material Technology assay or reagent 
Year Produced 2016 
Provided To Others? Yes  
Impact Orbit Discovery spin out has licensed 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 Del Besra 
Organisation University of Birmingham
Department Birmingham Clinical Trials Unit
Country Unknown 
Sector Academic/University 
PI Contribution Part of Wellcome Trust Collaborative Award
Collaborator Contribution lipid chemistry
Impact Not yet
Start Year 2018
 
Description Jamie Rossjohn 
Organisation Monash University
Department Monash Centre for Astrophysics
Country Australia 
Sector Academic/University 
PI Contribution Part of our Wellcome Trust Collaborative Award
Collaborator Contribution Biophysical and structural knowledge
Impact Not yet
Start Year 2018
 
Description Muzlifah Haniffa 
Organisation Newcastle University
Department Newcastle 85+ Study
Country United Kingdom 
Sector Academic/University 
PI Contribution Part of Wellcome Trust Collaborative Award
Collaborator Contribution Dendritic cell biology
Impact Not yet
Start Year 2018
 
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 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 Development of a test for T celllymphoma/leukaemia 
Description We have developed a potential test for T cell lymphoma which may have future theraeutic relevance. 
IP Reference WO2016051205 
Protection Patent application published
Year Protection Granted 2014
Licensed Commercial In Confidence
Impact Academic work continues in order to validate the technology. Commercial interactions currently under negotiation.
 
Title Method for peptide drug discovery 
Description New method for peptide drug discovery 
IP Reference  
Protection Patent granted
Year Protection Granted 2014
Licensed Yes
Impact studies ongoing
 
Title method to characterise T cell infiltrates 
Description New method to characterise whether T cell infiltrates are malignant or inflammatory. New diagnostic test. 
IP Reference  
Protection Patent application published
Year Protection Granted 2014
Licensed Commercial In Confidence
Impact early stage of development
 
Title method to determine previous dengue serotype infection 
Description technique to determine what serotypes of dengue a person has been infected with 
IP Reference Insufficient Information 
Protection Patent application published
Year Protection Granted
Licensed No
Impact further work and publication
 
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 
 
Title Many clinical trials 
Description I run many clinical trials in Oxford to translate our findings towards clinical practice 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact As trials progress, these will introduce new forms of treatment. 
 
Company Name Orbit Discovery Ltd 
Description Peptide drug discovery company 
Year Established 2015 
Impact None yet
 
Description BRC Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Members of public attended and took part in activities run by my group and others

further interest in our research an dsupport from potential participants
Year(s) Of Engagement Activity 2014
 
Description Blogs 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Blog discussion of our recent studies
Year(s) Of Engagement Activity 2015
 
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 Podcast 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Podcast available through university website and on Youtube
Year(s) Of Engagement Activity 2014
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public lecture describing the science and translational impact of our research. Much positive discussion and feedback - some example comments below:

"Difficult immunology issues presented in a comfortable and easy to understand way. Thank you. "

"Excellent presentation given the complexity of the subject."

"Very informative, excellent speaker. Thank you."
Year(s) Of Engagement Activity 2016
URL https://www.youtube.com/watch?v=aiFb8CWvy5k&list=PL8hacko-P1Wduo8gAf71vt30nuhpn8OtR
 
Description School visit Abingdon 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact 80 pupils attended

good informal feedback
Year(s) Of Engagement Activity 2013
 
Description WIMM Public Understanding of Science and Engagement committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact ongoing activity

ongoing
Year(s) Of Engagement Activity 2012
 
Description school visit oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact approx 40 students attended with many questions

Interest from students wanting to study science or medicine. work experience students
Year(s) Of Engagement Activity 2013