Regulation of dendritic cell function by the ocular microenvironment in uveitis

Lead Research Organisation: University of Birmingham
Department Name: Sch of Biosciences

Abstract

The immune system protects the individual from a large range of infections. Although the immune response is highly efficient, this can result in some damage to surrounding areas. For the majority of organs this does not present a problem. However, in certain organs any significant immune mediated damage could threaten the survival of the individual. For these organs the immune response is carefully controlled and they are described as having immune privilege. The eye is a well studied example of an organ with immune privilege. It is clear that when inflammation occurs in the eye (uveitis) this contradicts the immune privileged status, with some patients suffering severe sight-threatening disease. The aim of our research is to identify the way in which the immune response is altered in uveitis. We wish to study the changes that occur in a specific immune cell, the dendritic cell, which acts as a co-ordinator of immune responses. By identifying the changes that occur in these cells in patients with uveitis we aim to identify new therapeutic options for this potentially blinding disease.

Technical Summary

Uveitis (intraocular inflammation) is a group of diseases characterised by inflammation of the uveal tract. Although many cases resolve rapidly, a number will develop persistent severe sight-threatening inflammation. There is clear evidence that activated T cells are involved in the pathogenesis of uveitis (intraocular inflammation) in both humans and animal models of the disease. This suggests that mature dendritic cells (DC) are generated within the inflamed ocular microenvironment, in contrast to the immunosuppressive conditions reported to maintain immune privilege in this tissue. We propose to determine whether the ocular microenvironment (aqueous humour; AqH) in uveitis can deviate DC towards a pro-inflammatory phenotype. We will determine whether the resting non-inflammatory ocular environment (AqH) induces regulatory DC, and if this can be overcome by additional inflammatory/pathogen-derived signals. This will be compared to the capacity of AqH to regulate DC function altered during episodes of uveitis. In addition, we will use AqH from patients receiving glucocorticoid treatment at the time of sampling, allowing us to study the effects of this treatment on DC function. DC will be generated from peripheral blood monocytes by culture with IL-4 and GM-CSF. AqH will be added to immature DC alone and in combination with a number of pro-inflammatory stimuli (cytokines, Toll-like receptor ligands). The phenotype of the resulting DC will be studied, in particular the expression of a number of molecules involved in the stimulation of T cells and the secretion of key cytokines. DC will be cultured with CD4+ allogeneic T cells to determine their ability to stimulate T cell proliferation and effector function. We ultimately aim to identify the signals that regulate changes in DC maturation, and consequently the activation of T cells in uveitis, ultimately providing new therapeutic targets for this group of diseases.

Publications

10 25 50
 
Description Benchside Spectrum of Translational Research in Ophthalmology
Geographic Reach UK 
Policy Influence Type Influenced training of practitioners or researchers
Impact Invited talk to a Royal College of Ophthalmologists Symposium to present the value of our studies based on sampling ocular fluids as a means of investigating pathogenesis and providing biomarkers to patietns with ophthalmic disease.
 
Description AMS Wellcome Clinical Lecturer Starter Grant
Amount £28,000 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description ARVO International Travel Grant
Amount £700 (GBP)
Organisation Association for Research in Vision and Ophthalmology 
Sector Charity/Non Profit
Country United States
Start 05/2008 
End 06/2008
 
Description British Society of Immunology Travel Award
Amount £800 (GBP)
Organisation British Society For Immunology 
Sector Learned Society
Country United Kingdom
Start 05/2009 
End 06/2009
 
Description Equipment Funding
Amount £219,000 (GBP)
Organisation Queen Elizabeth Hospital Birmingham Charity (QEHB) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
 
Description Fight for Sight/Olivia's Vision Small Grant
Amount £14,800 (GBP)
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 10/2013
 
Description Wellcome Trust Health Innovation Challenge
Amount £560,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2016 
End 05/2019
 
Description Imaging in Uveitis Partnership 
Organisation Moorfields Eye Hospital NHS Foundation Trust
Department Retinal Imaging
Country United Kingdom 
Sector Public 
PI Contribution Design of studies
Collaborator Contribution Data analysis and technical design
Impact Keane PA, Allie M, Turne SJ, Southwort HS, Sadda SR, Murray PI, Denniston AK.Characterization of Birdshot Chorioretinopathy using Extramacular Enhanced Depth Optical Coherence Tomography. JAMA Ophthalmol 2012 (EPub ahead of print)
Start Year 2012
 
Description UK Eye Network 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution This is still in its early phase, but I have brought a new PhD student whom I will jointly supervise.
Collaborator Contribution They are the host institution. They are also funding the fellowship, which my PhD student was successful in obtaining.
Impact Pending
Start Year 2017
 
Description 'A Sight for Sore Eyes' Exhibition at the British Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact A half-day series of talks covering Ocular Infection and Immunity and how our research impacts on this; audience 20-30 of public, some of whom had ocular disease. Also we put on an interactive exhibit run by 'Sherlock Holmes' where the public could diagnose ocular infections for themselves and work out the culprit organism. This was targeted at secondary school children upwards and ran over three days as part of The Body in Health and Disease exhibition at the BSF. The stand had a 'footfall' of around 1000 people.

Up to 45mins of questions at the end of the talks series. Many people attending the exhibit took literature away, and expressed that they had 'really learnt something'.
Year(s) Of Engagement Activity 2010
 
Description Birdshot Uveitis Society Day 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Presentation to 200 patients and their supporters;
Youtube video of the talk;

Ongoing involvement with the group
Year(s) Of Engagement Activity 2012
 
Description Education Video on the Eye Clinic 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Educational video on the embedding of ophthalmic examination within the multidisciplinary clinic for rare diseases
Year(s) Of Engagement Activity 2017
 
Description MRC Max Perutz Prize 2008 (Short-list) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Primary Audience Media (as a channel to the public)
Results and Impact Summary of personal research for lay audience

Short-listed for prize; published as a podcast on the MRC website
Year(s) Of Engagement Activity 2008
 
Description MRC Max Perutz Prize 2009 (Runner-up) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Primary Audience Media (as a channel to the public)
Results and Impact Summary of research for lay audience

Published in the On-line Guardian
Year(s) Of Engagement Activity 2009
 
Description The Big Bang 
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 http://www.thebigbangfair.co.uk/home.cfm
From 15 - 17 March 2012, the Big Bang welcomed over 56,000 visitors to The NEC, Birmingham and "amazed them at just how exciting engineering and science can be". Our stand provided visitors with the oportunity to try out corneal surgery on a tomato and showed videos of real ophthalmic surgery. There was a constant stream of visitors, with numerous questions about what we do.

Opportunities to present both our research and the translational outcome of what we do.
Year(s) Of Engagement Activity 2012