Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.762362
Title: The role of interleukin 22 in human colonic inflammation
Author: Pavlidis, Polychronis
ISNI:       0000 0004 7656 4451
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Abstract:
The role of interleukin 22 (IL22) in chronic intestinal inflammation is controversial, with pre-clinical studies providing conflicting results. Some studies in pre-clinical models of inflammatory bowel disease (IBD) suggest that IL22 has a pathogenic role, in synergy perhaps with other contributing pro-inflammatory mediators, leading to the supposition that inhibition may provide a therapeutic benefit in human disease. Others suggest a protective role and hence advocate for exogenous supplementation of IL22. A clinical study in haematopoietic stem cell transplant recipients (HSCT) associated a higher frequency of circulating, gut homing, IL22 producing, innate lymphoid cells (ILC) with a lower risk of acute gastrointestinal graft versus host disease (aGI-GvHD) – a common and feared complication of HSCT. In this translational study I test the hypotheses that IL22 production is diminished in the colonic mucosa of patients with IBD and aGI-GvHD and that the IL22 protective pathways are lost in the context of human colonic inflammation. By treating human colonic 3D mini-guts (organoids) with IL22 and other relevant cytokines, and exploring the transcriptional programmes instructed, I found that the IL22 shared many pathways with cytokines known to have a pro-inflammatory role in human gut inflammation, like TNFα. By selecting the top 50 most upregulated genes by each cytokine and testing for their enrichment as separate gene sets utilising different datasets of colonic transcriptional profiles of patients with IBD and aGI-GvHD, I found that the IL22 gene set was enriched in the context of active inflammation in both conditions. In addition, colonic IL22 production was higher in active inflammation. Using multiparametric, flow cytometry I show that in the human setting the main cellular compartment producing IL22 in the colonic lamina propria (LP) is the CD3+CD4+ T effector lymphocytes, in both homeostasis and IBD. I found an enrichment of CD3+CD4+IL22+ producing cells in the context of IBD. IL22 producing T-cells are multifunctional, producing other pro-inflammatory cytokines like TNFα, IFNγ and IL17A conforming to a broad definition of Th17 cells (or the so-called ‘Th1/Th17 hybrid’ subset). They are enriched in the periphery of both IBD and aGI-GvHD patients. The gut homing compartment of ILC could not be confidently identified either in the periphery or the LP of HSCT recipients with or without a diagnosis of aGI-GvHD, since the entire ILC compartment was virtually absent in these patients, while an enrichment of gut homing ILC was seen in IBD. I show that the IL22 transcriptional footprint, and an epithelia-specific ER stress gene set, are both enriched in human colonic IBD and correlate with objective markers of disease severity, including endoscopic severity of disease and recognised biomarkers of disease activity (e.g. faecal calprotectin). Ustekinumab, a human monoclonal antibody targeting the p40 shared subunit of IL12 and IL23 cytokines (which is the key upstream cytokine triggering release of IL22), downregulates both these pathways in CD patients treated in the context of a phase 3 clinical trial (UNITI). These results support a pathogenic role for IL22 in human IBD and aGI-GvHD and challenge the wisdom of current strategies looking to administer recombinant IL22 in the context of chronic colonic inflammation.
Supervisor: Powell, Nicholas ; Lombardi, Giovanna Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.762362  DOI: Not available
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