Characterisation of the role of IL-18 in neovascular AMD
Citation:
Connolly, Emma, Characterisation of the role of IL-18 in neovascular AMD, Trinity College Dublin.School of Medicine, 2021Download Item:
Abstract:
Age-related macular degeneration is the leading cause of vision loss in the over 50’s in developed countries, accounting for 8.7% of all blindness worldwide. AMD is a progressive disease affecting the macula region of the retina. Late stage ‘wet’ AMD is characterised by the presence of choroidal neovascularisation (CNV) disrupting the retina leading to irreversible vision loss. Treatment options for AMD are limited and to date the only approved treatment available is for wet AMD, which involves frequent intraocular injections of an anti-vascular endothelial growth factor (anti-VEGF) therapy. Recent studies have shown that the inflammatory cytokine interleukin-18 (IL-18) can attenuate CNV formation in mice and non-human primates. The anti-angiogenic function of IL-18 was shown to be most effective when administered in combination with anti-VEGF therapies and therefore presents a novel therapeutic strategy for the treatment of wet AMD. In this study, we report the prevalence of AMD-associated genetic risk variants in the Irish population, we found the prevalence of risk variants in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) are significantly associated with AMD risk and progression comparable with other Caucasian populations. We examine plasma levels of IL-18 and its neutralising protein IL-18 binding protein (IL-18BP) in a subset of this population but found no relationship between plasma IL-18 and AMD status, age, or genotype. However, we did observe change in IL-18 levels in AMD patients over 4-years associating with disease progression. We examine local levels of IL-18 along with 12 other pro-inflammatory cytokines in the aqueous humour of treatment naïve AMD patients receiving anti-VEGF therapy showing intraocular IL-18 increases significantly following VEGF neutralisation. Furthermore, we found increasing IL-18 correlated with improved best corrected visual acuity (BCVA) and reduced central macular thickness (CMT) post treatment. High baseline levels of IFN-α, IFN-γ, TNF-α, IL-12p70 and IL-17A were found to strongly correlate with worse visual outcome post treatment, while high IL-8 levels strongly correlated with increased macular oedema. We evaluate the effect of IL-18 and IL-1α treatment on human retinal endothelial cells (HRMECs) and mouse brain microvascular endothelial cells (pBMVECs), which found IL-1α as a potent inducer of vascular adhesion molecules VCAM-1, ICAM-1 and E-Selectin and endothelial monolayer permeability alone and in combination with VEGF. In direct contrast, IL-18 failed to induce expression of these adhesion molecules or barrier permeability. IL-18 was however shown to induce pro-migratory and pro-angiogenic functions in endothelial cells suggesting that in the context of the eye IL-18 promotes resolution of tissue injury.
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Science Foundation Ireland (SFI)
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:ECONNOL7Description:
APPROVED
Author: Connolly, Emma
Advisor:
Doyle, SarahPublisher:
Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
ThesisCollections
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Full text availableKeywords:
Age-related Macular Degeneration, AMD, Neovascular, IL-18Metadata
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