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MRC DiMeN Doctoral Training Partnership: Biomarkers for assessing the immune state in rheumatoid arthritis and their application in a cellular therapy clinical trial


   MRC DiMeN Doctoral Training Partnership

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  Prof John Isaacs, Prof Catharien Hilkens  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Rheumatoid arthritis (RA) is caused by a loss of immune tolerance to self. Current clinical biomarkers assess inflammation but, as we treat earlier to prevent or cure disease, it will be increasingly important to assess the immune ‘state’, particularly in relation to the establishment of self-tolerance. This is because ‘patients’ may not have symptoms and therefore modulation of the immune state will guide therapeutic success. Similarly, we have developed a novel therapeutic approach with tolerogenic dendritic cells (tolDC) that switch pathogenic self-reactive T-cells into regulatory/anergic T-cells. Our phase I clinical trial showed this therapy to be safe, and our forthcoming trial aims to define the optimal administration route for efficacy. In order to demonstrate appropriate pharmacodynamic effects of tolDC, we will develop assays that assess the immune state, particularly the functional capabilities of autoreactive T-cells. Such surrogate outcome measures are the only way to provide true ‘proof of concept’ for self-tolerance reinstatement by such treatments.

The objective of this studentship project is to validate existing and novel immunomonitoring tools for the characterisation of autoreactive T-cells in clinical samples from RA patients, and to apply these tools to probe changes in autoreactive-T-cells with tolDC treatment. These tools will also be applied to other clinical RA scenarios (for example, RA patients that have achieved remission after treatment with conventional drugs), to broaden our understanding of how autoreactive T cells can be modulated and are involved in maintaining self-tolerance.

The topic of this studentship is timely, as a number of antigen-specific tolerogenic therapies for autoimmune diseases are currently under development for treatment and prevention. These include cell-based (e.g. tolDC) as well as nanoparticle-based strategies. However, suitable pharmacodynamic biomarkers are currently lacking, yet will be essential outcome measures in clinical trials to demonstrate immune modulation.

The student will learn a number of cutting edge techniques to enrich and detect autoreactive T-cells, analysing those cells at single cell level, as well as utilising bioinformatic methodologies and software for data analysis. Techniques learned will include the use of HLA/peptide tetramers to identify and isolate autoreactive cells, single cell RNAseq and spectral flow cytometry. More conventional proliferation and ELIspot assays will also be utilised alongside conventional flow cytometry to identify antigen reactive cells and to measure their functionality via intracellular cytokine production.

The supervisory team consists of two academic rheumatologists and two immunologists, all of whom have longstanding experience in conducting translational immunology studies. They have formed a longstanding and thriving research group of around 20 members, which supports a collaborative environment.

For more information, please visit our websites or Twitter:

https://twitter.com/MRGNewcastle

https://www.ncl.ac.uk/medical-sciences/people/profile/johnisaacs.html

https://www.ncl.ac.uk/medical-sciences/people/profile/catharienhilkens.html

https://www.ncl.ac.uk/medical-sciences/people/profile/amyanderson.html

https://www.ncl.ac.uk/medical-sciences/people/profile/arthurpratt.html

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/how-to-apply


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2023
Good luck!

References

Bell GM, Anderson AE, Diboll J, Reece R, Eltherington O, Harry RA, Fouweather T, MacDonald C, Chadwick T, McColl E, Dunn J, Dickinson AM, Hilkens CM, Isaacs JD. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann Rheum Dis. 2017 Jan;76(1):227-234. doi: 10.1136/annrheumdis-2015-208456.
Anderson AE, Swan DJ, Wong OY, Buck M, Eltherington O, Harry RA, Patterson AM, Pratt AG, Reynolds G, Doran JP, Kirby JA, Isaacs JD, Hilkens CM. Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-β1. Clin Exp Immunol. 2017 Jan;187(1):113-123. doi: 10.1111/cei.12870.
Baker KF, Skelton AJ, Lendrem DW, Scadeng A, Thompson B, Pratt AG, Isaacs JD. Predicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study. J Autoimmun. 2019 Dec;105:102298. doi: 10.1016/j.jaut.2019.06.009.
Spiering R, Jansen MAA, Wood MJ, Fath AA, Eltherington O, Anderson AE, Pratt AG, van Eden W, Isaacs JD, Broere F, Hilkens CMU. Targeting of tolerogenic dendritic cells to heat-shock proteins in inflammatory arthritis. J Transl Med. 2019 Nov 14;17(1):375. doi: 10.1186/s12967-019-2128-4.
Cooles FAH, Tarn J, Lendrem DW, Naamane N, Lin CM, Millar B, Maney NJ, Anderson AE, Thalayasingam N, Diboll J, Bondet V, Duffy D, Barnes MR, Smith GR, Ng S, Watson D, Henkin R, Cope AP, Reynard LN, Pratt AG; RA-MAP Consortium, Isaacs JD. Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming. Ann Rheum Dis. 2022 Jun 9;81(9):1214–23. doi: 10.1136/annrheumdis-2022-222370.
Cooke F, Neal M, Wood MJ, de Vries IJM, Anderson AE, Diboll J, Pratt AG, Stanway J, Nicorescu I, Moyse N, Hiles D, Caulfield D, Dickinson AM, Blamire AM, Thelwall P, Isaacs JD, Hilkens CMU. Fluorine labelling of therapeutic human tolerogenic dendritic cells for 19F-magnetic resonance imaging. Front Immunol. 2022 Oct 3;13:988667. doi: 10.3389/fimmu.2022.988667.
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