The propensity for tissues in our bodies to be affected by inflammation changes as we age. This is particularly true for Hidradenitis Suppurativa (HS), a common IL-23/IL-17 cytokine driven inflammatory disorder with a profound impact on patients’ quality of life. It tends to have its onset in teenage years, become disfiguring and lead to permanent tissue destruction in early life, and generally lessen in terms of inflammatory activity as patients reach middle-age. Developing HS beyond the age of 40 remains rare, yet the reasons for this remain unknown.
There is considerable overlap between HS and psoriatic arthritis/plaque psoriasis pathophysiology. Drugs that are used to treat these diseases are also licenced (anti-TNF adalimumab), or currently being trialled (anti IL-17) for HS. Importantly, the specific roles of distinct leukocyte cell types and stromal cells (such as keratinocytes) in coordinating inflammatory responses in skin remain poorly understood in HS. Furthermore, the effect of IL-17/IL-23 axis blockade on inflammatory networks in HS remains comparatively underexplored, as is the effect of age/ageing on inflammation and response to specific cytokine blockade.
Specific Aims
· Determine the specific roles of leukocytes and stromal cells in coordinating inflammatory responses in HS
· Determine the effect of blocking the IL-17 family members on these pathways in HS, and comparing its effects to sole IL-17A and TNF blockade in patients and in vitro
· Determine and comparing the key drivers of inflammation in different stages of life
The Research Setting
Experimental techniques to be used have previously been established in Dr Shams’, Prof McGonagle’s and Dr McKimmie’s research groups. This includes extensive experience of studying human whole skin explants ex vivo, where we propose to define the inflammatory status of HS derives skin explants, the response to disease-activating TNF-a and treatment with selective IL17A/F inhibitors. Separately, we have developed a novel approach for studying disease-relevant leukocyte-keratinocyte interactions, by functionally sorting leukocytes based on disease-associated chemokine-responsiveness (CCL20 for Th17 cells and CXCL8 for neutrophils) and their subsequent co-culture with keratinocytes in vitro.
The Leeds Centre for Dermatology is one of the largest skin centres in the UK. The centre has a multi-disciplinary tertiary Hidradenitis Suppurativa clinic (and is an NHS England appointed centre for biologics), incorporating dermatology consultants, surgeons and a biologics nurse. With links with clinical immunology, rheumatology, the translational facilities of the University of Leeds and international collaborators (including the EU commission funded ERN-SKIN group, that encompasses Hidradenitis Suppurativa), the HS team lead by Dr Kave Shams and the supervisory team, within one of the World’s most prolific rheumatology research settings, are ideally placed to support the successful candidate through their PhD project.
This project uniquely combines expertise in immunology, dermatology and rheumatology within a World-leading academic setting. The student will have exciting opportunities to make significant advances in the understanding and therapy of a globally important disease. They will be actively supported through the process, and will gain mastery of a range of cutting-edge laboratory and translational medicine techniques.
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: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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