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Aberrant expression of homing markers on dendritic cells drives inflammation in Crohn's disease

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Title: Aberrant expression of homing markers on dendritic cells drives inflammation in Crohn's disease
Authors: Peake, Simon Thomas Charles
Item Type: Thesis or dissertation
Abstract: CD is a chronic transmural inflammatory disease of the gut. The aetiology of CD is unknown, but is likely to result from dysregulated innate immune responses to gut microbiota leading to over activation of the acquired immune system in a genetically susceptible host. Inflammation occurs anywhere from mouth to anus, in addition to extra-intestinal sites. This compartmentalisation of the inflammatory process is linked to tissue-specific innate immune mechanisms and immune cell homing. DCs play a key role in discriminating between gut commensal microbiota and harmful pathogens, directing T-cell polarisation and directing immune cells to specific anatomical locations by expressing and imprinting homing markers. Improved understanding of the immunopathogenic basis of inflammation in CD has led to the development of more efficacious medical therapy, in particular, targeting the pro-inflammatory cytokine TNFα. The precise mechanism of action of TNFα blockade in CD remains unclear. We found homing marker expression on circulating DCs in patients with CD closely correlates with anatomical phenotype of inflammation. When immune cells are cultured with IFX we found homing marker expression on monocytes and T-cells changed from a gut-homing to skin-homing phenotype., perhaps explaining the phenomenon of ‘paradoxical inflammation’ seen in some patients treated with anti-TNFα therapy. Blood-enriched DCs isolated from patients with active CD had higher levels of pro-inflammatory cytokines in culture medium. IFX culture resulted in reduced concentrations of pro-inflammatory cytokines and decreased gut-homing marker expression. Finally, we examined the functional effects of IFX-pre-treated-LDCs on T-cells. There was a dose-dependent reduction in LDC stimulatory capacity with increasing concentrations of IFX, but no changes in T-cell phenotype. The effect of IFX on the immune system goes beyond TNFα blockade alone. This work has identified several mechanisms by which IFX interacts with immune cells in vitro, which may result in changes to CD inflammatory process in vivo.
Content Version: Open Access
Issue Date: Aug-2015
Date Awarded: Mar-2016
URI: http://hdl.handle.net/10044/1/31866
DOI: https://doi.org/10.25560/31866
Supervisor: Knight, Stella
Department: Antigen Presentation Research Group
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Medicine (Research) MD (Res)
Appears in Collections:Medicine PhD theses

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