PhD Studentship in Immunology - Identifying immune mechanisms and testing new therapeutic targets for inflammatory arthritis and associated comorbidities

Summary

Cytokine-blocking drugs have revolutionised the treatment of inflammatory arthritis. However, ~40% of patients show poor responses to these drugs, continue to display severe disease and also suffer comorbidities (e.g. cardiovascular disease, uveitis). The student will use in vivo arthritis models, imaging, and bioinformatics to test the therapeutic potential of targeting coexisting immune mechanisms active in arthritic joints and tissues affected by comorbidity.

Project description

The incidence of autoimmune and immune-mediated inflammatory diseases (IMIDs) is increasing. These diseases often coexist with chronic conditions that cause disability and mortality. Consequently, multimorbidity is forecast as an upcoming global health challenge. Research into conditions that coexist is nearly always performed separately, hampering the discovery of shared mechanisms that link systemic immune dysregulation with concurrent damage to different tissues. This project aims to increase our understanding of concurrent immune mechanisms active in tissues primarily affected by IMIDs and sites of co-/multi-morbidity. Such insight has the potential to inform the design of improved interventions for patients with IMIDs and complex comorbidities.

Patients with inflammatory arthritis are at higher risk of cardiovascular (CV) disease. Strong evidence points to systemic inflammation in driving this risk. Uveitis and arthritis also coexist in patients with spondyloarthropathies and juvenile idiopathic arthritis. To gain new perspective on tissue events underpinning comorbidities, our studies combine an evaluation of inflamed joints in arthritis, with coexisting immune and functional changes in CV tissues and eyes. Our research reveals that control of CD4 T cells by IL-6 family cytokines critically determines arthritis progression, but also immune cell recruitment to CV tissue and eyes. Combining RNA-sequencing with immunodetection methods, we have identified cytokine networks and T cell effector programmes that coexist across the arthritic joint, CV and ocular tissues. We propose that targeting these pathways has therapeutic application for arthritis-associated CV disease and uveitis. Significantly, drugs against some of these targets show good safety in recent clinical trials (e.g. in cancer) highlighting their potential for repurposing.

The aims of the research are:

Aim 1. Identify coexisting immune mechanisms in CV and ocular tissue during experimental arthritis.

Training in bioinformatics, pathway analysis and data visualisation using our recent RNA-sequencing datasets will enable the student to choose tractable immune targets of interest to them. They will use models of arthritis, in vivo imaging (optical coherence tomography) and immunodetection (immunohistochemistry, Light sheet and fluorescence microscopy, flow cytometry) to validate and spatially localise mechanisms of immune activation in CV tissues and eyes because of arthritis.

Aim 2. Targeting effector functions that determine CD4 T cell pathogenicity.

Human and mouse CD4 T cell cultures will determine how targets from Aim 1 are regulated in T cells and how inhibition (e.g. antibody blockade, small molecule inhibitors, gene knockdown) alters their function and pathogenicity. The student will track effects including proliferation, function (cytokine secretion, activation markers) and cellular metabolism (Agilent Seahorse, with Dr N. Jones, Swansea University).

Aim 3. Testing the impact of target inhibition on arthritis-associated comorbidities.

Arthritis will be induced in mice and the effect of target inhibition on arthritis severity, and co-existing CV and ocular inflammation, will be determined by clinical assessments, imaging, histopathology and measuring vascular function (with Prof A. Williams, Cardiff University).

Collaboration, knowledge transfer and impact

The student will benefit from collaboration with clinical rheumatologists and ophthalmologists (Prof Ramanan and Prof Dick, Bristol Medical School), academics (Dr N. Jones, Swansea University and Prof Williams, Cardiff University) and industry (e.g. GlaxoSmithKline) where the project will inform parallel studies. The student will communicate research through peer-reviewed publications and presentations at internal, GW4, national and international scientific meetings and through public engagement events.

Supervisors:

Dr Gareth Jones, School of Cellular and Molecular Medicine, University of Bristol

Professor Simon Jones, Systems Immunity Research Institute and Division of Infection and Immunity, Cardiff University

Dr Lindsay Nicholson, School of Cellular and Molecular Medicine, University of Bristol

Dr Robert Andrews, Systems Immunity Research Institute and Division of Infection and Immunity, Cardiff University

Eligibility

Residency: The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Please see the GW4 BioMed2Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have all agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD. All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

Academic criteria: Applicants for a studentship must have obtained, or be about to obtain, a UK degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.

How to Apply

You can apply for the project and other projects offered through the programme via our website at gw4biomed.ac.uk. You may apply for up to 2 projects.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’. You may also need to make an application for an 'offer to study' to your chosen institution(s) – further details are on the website.

Please complete the online application form by 5.00pm on Wednesday, 2^nd November 2022. If you are shortlisted for interview, you will be notified by Friday 16^th December 2022. Interviews will be held virtually on 25^th and 26^th January 2023.

Further Information

For informal enquiries, please contact [Email Address Removed]

For project related queries, please contact Dr Gareth Jones ([Email Address Removed]).