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We aim to uncover the stromal basis of chronic inflammation and related tissue pathology to target fibroblasts across a range of immune-mediated inflammatory diseases.

Stromal Cell Biology Group, Christopher Buckley

A characteristic feature of chronic inflammation is its persistence and predilection for certain anatomical sites. We have demonstrated that tissue-resident stromal cells (fibroblasts) determine both the switch to persistence as well as the site at which inflammation occurs. Furthermore we have shown that fibroblast-mediated inflammation and tissue damage can be uncoupled and is driven by different subsets of fibroblasts, located in distinct anatomical niches in tissue.  A clear understanding of the biology and clinical significance of fibroblast heterogeneity is therefore essential to provide a coherent rationale for their therapeutic targeting in the treatment of inflammatory diseases such as rheumatoid arthritis (RA).

We aim to bring our understanding of fibroblasts and their biology to the same level that has been achieved for leucocyte subsets in the immunology community and to deliver proof-of-concept experimental medicine studies that validate the utility of targeting fibroblast subsets in inflammation

Key questions 

  1. Explore how fibroblast subsets change during the development of inflammation, including at the switch from resolving to persistent disease, in relation to tissue damage, and repair. 
  2. Determine the developmental origins and interrelationships between synovial fibroblast subsets in the different layers of the synovium and how their selective modulation or deletion alters the balance between persistent inflammation and tissue damage.
  3. Deliver clinical trials targeting fibroblasts in patients with Immune Mediated Inflammatory Disease (IMIDs) using current experimental medicine infrastructures within the Arthritis Therapy Acceleration Programme and Oxford Biomedical Research Centre. 

Area of focus include 

Synovial fibroblast biology

Synovial fibroblast biology 

Synovial fibroblasts comprise a key cell type in the synovium and form the bulk of the hyperplastic pannus that invades and destroys cartilage and bone. Fibroblasts also contribute to inflammation and are directly stimulated by inflammatory cytokines present in the inflammatory tissue environment. Despite their biological importance, little is known about how fibroblast numbers and subsets change during inflammation in human arthritis and between rheumatoid and osteoarthritis. Difficulties in accessing patients with very early disease, sampling the tissue involved and the lack of good fibroblast markers have all proved obstacles to such work. We have focused on the fibroblasts subsets that drive synovial inflammation and tissue damage, In the future we will explore how the identification of fibroblast subsets across tissues will allow us to selectively target their different functions in heath and disease.

Inflammation across tissues 

IMIDs are a common, growing problem. Traditional models of research and delivery silo their management within specific specialities and between children and adults. However, patients with disease in one organ system often have co-morbid involvement of another organ and are treated in similar ways with similar drugs. We aim to unravel the common biological pathways underpinning the genetic, molecular, and cellular basis of inflammation across distinct yet clinically related IMIDs such as psoriatic arthritis, psoriasis, Inflammatory Bowel Disease and Spondyloarthropathies. Our objective is to provide a mechanistic link between gene-environment interactions and clinical outcomes via tissue biology. We aim to break down the clinical and operational boundaries that prevent an integrated programme of experimental medicine research in IMIDs.  This work is performed in collaboration with Prof Holm Uhlig (Translational Gastroenterology Unit) and other researchers across Oxford’s Medical Science Division and as part of the NIHR Oxford BRC.

Arthritis Therapy Acceleration Programme (A-TAP) 

Arthritis Therapy Acceleration Programme (A-TAP)

Precision medicine focused on the right drug for the right patient in a particular type of disease has revolutionised the way in which new drugs are being developed. However, precision medicine does not help to identify the right disease indication for an asset early in drug development. To help identify the right drug at the right dose (precision pharmacology) for the right disease (precision pathology) we have developed A-TAP, the first cross-disease, cross-tissue, cross-institute consortium that uses cell-based outcome measures, innovative basket-strategy, Bayesian-driven trial design and statistical approaches to match the right group of diseases to the best treatment option based on the profile of cell types involved in inflammation.

Current methods for drug target identification targeting causative pathways, often with strong genetic links, often fail to take into account the pathogenic cell types involved. By focussing on human tissues obtained from minimally invasive biopsy, A-TAP aims to construct a map of the different cell types involved in inflammatory diseases utilizing concepts drawn for the Human Cell Atlas (HCA). Over the next three years, and with ongoing support from the Kennedy Trust and Industry Partners, A-TAP aims to provide a “medical periodic table” to ultimately match the right drug to the right cellular target in disease. Combined with real, as opposed to imputed, measurements of PK and PD in tissue, our approach aims to accelerate drug development by providing access to high-definition cell-based maps of human tissue in health and disease as opposed to the current low-level histological maps used to define and stratify human pathology. 

PRINCIPAL INVESTIGATOR

Selected publications

Related research themes