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Title: The role of T cell subsets in steroid refractory intraocular inflammation
Author: Schewitz-Bowers, Lauren Pamela
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Noninfectious intraocular inflammation (uveitis) is a leading cause of blindness in the working age population of developed countries. Corticosteroids remain first-line treatment, however, up to a third of patients fail to achieve disease control at tolerable systemic doses. It is a CD4+ Th17ITh1 mediated disease and steroid refractory (SR) patients have previously been shown to have a SR sub-population of CD4+T cells in their peripheral blood. The aim of this thesis was to characterise these SR T cells and interrogate their potential as a therapeutic target using both human in vitro and murine in vivo experimental models. The data presented refines the SR CD4+ T cell phenotype to the CCR6+ memory subset from which Th17 cells are derived. Subsequent generation of Th17 cells in vitro demonstrated a restricted response to glucocorticoids (GCs) in terms of cytokine protein (IL-17 and IFN-y) and gene expression (RORC, Tbet, IL-17 and IFN-y), in both man and mouse. This was then confirmed in genome wide analyses by microarray. Furthermore, this SR phenotype was not due to altered GR isoform expression or nuclear translocation. Concordant in vivo results were obtained in a murine model of intraocular inflammation (Experimental Autoimmune Uveitis; EAU), in which retina infiltrating Th17 cells escaped GC suppression. Conversely, Th17 cells were shown to be selectively susceptible to inhibition by the calcineurin inhibitor, Cyclosporine A (CsA). Hence it is proposed that Th17 cells have the potential to be exploited as a biomarker for SR disease and targeted with CsA therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available