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  • Project No: #OxKEN-2021/5
  • Intake: OxKEN

Project overview  

Inflammatory bowel diseases (IBDs) are a heterogeneous group of chronic relapsing disorders that manifest in the inflammation of the gastrointestinal tract lining. Current long-term therapy in IBD is now dominated by the use of biologics (e.g., anti-TNF), which target inflammatory mediators with high specificity. The response to these biologics is very heterogeneous, indicating that we are not always targeting the specific tissue inflammatory process with the biologic we prescribe. Biologics fail in more than half of the patients with IBD, and uncontrolled inflammation can lead to the surgical removal of the affected bowel parts, or expedite tissue fibrosis.  

Very recent findings we made demonstrate that the complex multifactorial nature of IBD results in considerable heterogeneity in the cell types and molecular processes that drive inflammation. This is also reflected at the microscopic level, where observed features range from mucosal lymphoid aggregates to epithelial ulceration with granulocyte presence. The diverse inflammatory tissue ecologies in patients with IBD are currently not well described. The molecular and cellular hallmarks of these ecologies could however allow us to select the most efficient biologic therapy for each patient, moving towards personalised medicine in IBD.

By using molecular and histologic phenotyping of IBD patient cohorts, as well as in vitro and in vivo approaches, this project will interrogate the tissue ecologies in IBD that are associated with poor outcome in IBD, in particular the non-response to biologics, fibrosis and surgery. This translational project offers the opportunity to apply cutting edge technologies such as transcriptomics, digital pathology and pre-clinical organoid/experimental mouse models to address the unmet clinical needs in IBD.  

References

  1. Friedrich M *, Pohin M *, Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity 25th Anniversary Edition 2019;50(4):992.
  2. Uhlig H and Powrie F. Translating Immunology into Therapeutic Concepts of Inflammatory Bowel Disease. Annual Reviews Immunology 2018;36:755
  3. West N *, Hegazy A *,  Owens B,  Bullers S,  Linggi B,  Buonocore S,  Coccia M,  Görtz D, This S,  Stockenhuber K, Pott J, Friedrich M,  Ryzhakov G,  Baribaud F,  Brodmerkel C,  Cieluch C,  Rahman N, Müller-Newen G, Owens R,  Kühl A, Maloy K, Plevy S, Keshav S, Travis S, Powrie F. Oncostatin M drives intestinal inflammation in mice and its abundance predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nature Medicine 2017; 23(5):579.