Cutaneous Immunology

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
 
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 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
 
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