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Novel therapeutic targets in uveitis

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Title: Novel therapeutic targets in uveitis
Authors: Tempest-Roe, Shenzhen Makahn
Item Type: Thesis or dissertation
Abstract: Autoimmune posterior uveitis is a potentially blinding ocular disorder characterized by inflammation of the choroid and retina. Etiology is unknown and is assumed to be autoimmune and proposed to involve activation of autoreactive retinal-peptide specific T-cells, blood-retinal barrier breakdown, further leukocyte recruitment and ensuing ocular inflammation. The P2X7 receptor is a transmembrane purinergic receptor activated by high concentrations of ATP. Expression is ubiquitous with highest expression in immune cells. Stimulation results in the production and release of pro-inflammatory cytokines and potentiates leukocyte recruitment. Differences in mechanisms of P2X7 regulation in macrophages, dendritic cells and T cells were explored in vitro. Dendritic cells and macrophages have been proposed to release IL-1β through the NLRP3 inflammasome, requiring TLR4 stimulation followed by P2X7 stimulation. Dendritic cells were found to release IL-1β with TLR4 stimulation only, unlike macrophages which required additional P2X7 stimulus. Potential mechanisms of P2X7 regulation were explored, and it was found that T cells and not macrophages or dendritic cells exhibited significantly potentiated P2X7 mediated dye uptake upon lipid raft disruption. These results suggested a role for lipid rafts in P2X7 regulation in T cells. In vivo experiments utilized animal models of anterior, posterior and pan-uveitis. Mice deficient in P2X7 were protected against developing severe posterior uveitis, and treatment of mice with established EAU with P2X7 specific antagonist A438079 prevented the development of severe panuveitis. Finally, the role of the spleen tyrosine kinase (SYK) was investigated in murine posterior uveitis. Recent research implicates potential crossover of the P2X7 and SYK signalling pathways. SYK inhibition with the specific inhibitor fostamatinib did not prevent the development of uveitis in mice.
Content Version: Open Access
Issue Date: Mar-2017
Date Awarded: Dec-2017
URI: http://hdl.handle.net/10044/1/75500
DOI: https://doi.org/10.25560/75500
Copyright Statement: Creative Commons Attribution Non-Commercial No Derivatives licence.
Supervisor: Taylor, Simon
Tam, Frederick
Sponsor/Funder: Biotechnology and Biological Sciences Research Council (Great Britain)
GlaxoSmithKline
Funder's Grant Number: NN0785_WMIR
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses