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

Ahnood D
(2017)
Punctate inner choroidopathy: A review.
in Survey of ophthalmology

Amissah-Arthur KN
(2010)
Reply to wertheim et al. The minim technique for diagnostic anterior chamber paracentesis.
in Eye (London, England)

Aralikatti AK
(2010)
Is ethnicity a risk factor for severe retinopathy of prematurity?
in Archives of disease in childhood. Fetal and neonatal edition

Barry RJ
(2015)
Controversies in the Pharmacological Treatment of Uveitis.
in Current pharmaceutical design

Barry RJ
(2018)
Characteristic optical coherence tomography findings in patients with primary vitreoretinal lymphoma: a novel aid to early diagnosis.
in The British journal of ophthalmology

Blair J
(2017)
A Comprehensive Review of mTOR-Inhibiting Pharmacotherapy for the Treatment of Non-Infectious Uveitis.
in Current pharmaceutical design

Chen P
(2015)
Increased CD1c+ mDC1 with mature phenotype regulated by TNFa-p38 MAPK in autoimmune ocular inflammatory disease.
in Clinical immunology (Orlando, Fla.)

Chu CJ
(2017)
Cataract surgery in uveitis: a multicentre database study.
in The British journal of ophthalmology

Curnow SJ
(2010)
Distinct types of fibrocyte can differentiate from mononuclear cells in the presence and absence of serum.
in PloS one

Dean S
(2017)
"The patient is speaking": discovering the patient voice in ophthalmology.
in The British journal of ophthalmology
Description | Benchside Spectrum of Translational Research in Ophthalmology |
Geographic Reach | National |
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 | Charity/Non Profit |
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 | Academic/University |
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 | Imaging in Uveitis Partnership |
Organisation | Moorfields Eye Hospital NHS Foundation Trust |
Department | Uveitis |
Country | United Kingdom |
Sector | Hospitals |
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 |