Targeting cytokine variants for improved control of inflammatory disease

PROJECT OVERVIEW 

Cytokines are essential for life, mediating integrated crosstalk between tissue resident cellular and microbial ecosystems and the host immune system.  Designed to maintain tissue homeostasis, whilst providing effective defence against harmful insult, complex regulatory mechanisms have evolved to uphold this immunological balance.  Breakdown of these pathways precipitates dysregulated inflammation that is the hallmark of much of human pathology (1, 2) and cytokine-directed treatments are the mainstay in clinical management of many autoimmune diseases (3).  However, this type of drug is not universally effective within any one disease, for example, large subsets of people with rheumatoid arthritis and inflammatory bowel disease lack any meaningful response to cytokine blockade, and these strategies have not fulfilled early promise across other diseases (4, 5). 

One reason for this may be that most cytokines, including TNF, IL1, IL6 family members and IL10, are surprisingly functionally pleiotrophic, although it is not well understood how these small molecules exert such diverse, context dependent biological roles.  Work in our lab has shown how post-translational modification of cytokines creates distinct variants with different signaling capabilities, and how this process is mis-regulated in people with inflammatory bowel disease.  This project will: 1) systematically assess cytokine modification in healthy intestinal tissue, during injury and repair, and in chronic inflammatory disease, using mass spec analysis of human clinical samples and in vivo models of intestinal inflammation, and 2) dissect the implications of cytokine modification using structure function analysis to characterize altered receptor binding complexes, and cellular models of inflammation to assess changes in downstream signaling pathways.   Candidate cytokines and associated pathways relevant to human disease will be prioritized for further exploration as novel drug targets designed to effect more specific modulation of cytokine pathology. 

KEYWORDS (5 WORDS)

Immunology, inflammatory disease, cytokines, post-translational modification, drug development

TRAINING OPPORTUNITIES

The Kennedy Institute is a world-renowned research centre, located in the heart of the University of Oxford’s Old Road campus, housing fundamental and clinician scientists working on diverse aspects of immunology and inflammation. This project will combine state of the art cellular immunology, proteomics and tissue biology; training will be provided in a range of immunological, bioinformatic, structural and molecular biology techniques. Students will join a vibrant postgraduate community at the Kennedy. The PhD programme includes a core curriculum of lectures in the first term of year 1, students will take part in group meetings from each of the labs of the supervisory team, and have the opportunity to attend seminars from world leading scientists both in the department and across the wider University. Students will present their work at national and international meetings.

KEY PUBLICATIONS (5 MAXIMUM)

1. Cytokines in the balance. Nat Immunol 20, 1557 (2019).
2. Chen YH, et al Inborn errors of IL-6 family cytokine responses. Curr Opin Immunol. 72:135-145 (2021).
3. Bird, L. Targeting cytokines in disease. Nat Immunol 17 (Suppl 1), S17 (2016).
4. Friedrich M, et al.  IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med (11):1970-1981 (2021).
5. Buckley CD et al. Location, location, location: how the tissue microenvironment affects inflammation in rheumatoid arthritis. Nat Rev Rheumatol. 17(4):195-212 (2021).

THEMES (4 KEY THEMES)

Tissue Biology

Cytokine Biology

Immunology

Translational Medicine

CONTACT INFORMATION OF ALL SUPERVISORS

kim.midwood@kennedy.ox.ac.uk

fiona.powrie@kennedy.ox.ac.uk

holm.uhlig@ndm.ox.ac.uk

anna.hoyle@kennedy.ox.ac.uk