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Immune phenotyping of refractory rheumatoid arthritis disease


Project Description

Treatment of rheumatoid arthritis (RA) has been transformed with the introduction of targeted therapies twenty years ago (comprising biologic disease modifying anti-rheumatic drugs, bDMARDS; and the more recent small molecule JAK inhibitors). Nevertheless, response to these agents is not universal, reflecting the heterogeneity of RA disease. A trial and error approach to drug selection, compounded by the absence of predictive biomarkers has led to cycling of ineffective therapies, and the (re-emergence) of refractory RA (RefRA) disease. The definition of RefRA has generally followed available therapies rather than a biological understanding, and has thus continually evolved (extended) as new treatments become available.

This project hypothesises that RefRA exhibits unique cellular subpopulation(s) and functional phenotype that are yet to be targeted with the currently available therapeutic strategies. This may comprise a a rare disease subgroup that has an intrinsically different biology from the outset +/- emerges with ongoing inflammation (clinical +/- subclinical) and exposure to therapy)

This project aims to establish the immune phenotype of RefRA towards target validation and novel treatment approaches.
The project will include recruitment of patients with RA that are well-phenotyped at the following stages: (i) early, active RA, targeted therapy naïve (ii) established, active RA refractory (inefficacy) to a minimum 2 different classes of bDMARD (iii) established RA refractory (inefficacy) to a minimum 2 different classes of bDMARD + a JAK inhibitor.

Peripheral blood and synovial tissue will be obtained from recruited patients. Mass cytometry will be performed to investigate immune alterations, together with functional and intracellular signalling characterisation. Analysis of the multi-dimensional complex datasets will identify unique immune signatures that emerge with RefRA. These will be validated in an independent patient cohort using flow cytometry.

Training/techniques to be provided:
The student will be trained in clinical science, experimental design and immunology, and become expert in flow cytometry and mass cytometry of blood and tissue. They will acquire an in-depth understanding of deep clinical phenotyping linked to the immunopathological processes of disease. Specific skills in laboratory and biostatistical and computing skills will provide invaluable interdisciplinary skills for future opportunities and career development.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject such as immunology, biological sciences, biomedical science. Candidates with experience in inflammatory diseases and an interest in translational and experimental medicine are encouraged to apply.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

- Zhang F, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019 Jul;20(7):928-942
- Rao DA, et al. Nature. 2017 Feb 1;542(7639):110-114. doi: 10.1038/nature20810. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.
- Mizoguchi F, et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun. 2018 Feb 23;9(1):789. doi: 10.1038/s41467-018-02892-y.
- Croft AP, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 2019; 570, pages246–251 (2019)
- Fonseka CY, Rao DA, Teslovich NC, Korsunsky I, Hannes SK, Slowikowski K, Gurish MF, Donlin LT, Lederer JA, Weinblatt ME, Massarotti EM, Coblyn JS, Helfgott SM, Todd DJ, Bykerk VP, Karlson EW, Ermann J, Lee YC, Brenner MB, Raychaudhuri S. Mixed-effects association of single cells identifies an expanded effector CD4+ T cell subset in rheumatoid arthritis. Sci Transl Med. 2018 Oct 17;10(463).

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