The role of innate immune cells in ocular ageing and pathological neovascularisation.
Doctoral thesis, UCL (University College London).
Age-related macular degeneration (AMD) is the major cause of vision loss in the developed world. AMD is a chronic progressive disorder of the outer retina leading to vision loss from atrophy (geographic atrophy) and/or the development of choroidal neovascularisation (CNV). Mounting evidence indicates the importance of innate immunity in its pathogenesis. This thesis describes a programme of work conducted with the aim of further understanding the role of innate immune cells in AMD. Analysis of mouse cell suspensions by flow cytometry demonstrated significantly greater densities of innate immune cell populations in the RPE-choroid than in the neurosensory retina. Dendritic cells accumulated in both tissues with increasing age, and this process was accelerated in mice deficient in a chemokine upregulated in the aged choroid - CCL2. Innate immune cells were recruited to CNV lesions in mouse models of laser-induced and spontaneous CNV. Increasing age was found to correlate with the extent of laser CNV lesion size but not with recruitment of innate immune cells. Impaired recruitment of innate immune cells in CCL2-deficient mice was associated with a smaller laser-CNV lesion size, which nonetheless increased with age. Attenuation of CNV lesion size by targeting key angiogenic pathways using the small molecule pazopanib or by direct targeting of innate immune cells by induction of alternative activation using a CD200R agonist was associated with subtle increases in the recruitment of innate immune cell subpopulations to CNV lesions. Findings did not support the hypothesis that age-related vulnerability to laser CNV is a consequence of age-related changes in innate immune cell populations. However, the results indicated that CCL2 controls dendritic cell migration in the ageing retina and the recruitment of innate immune cells to CNV lesions. Further investigation of these pathways may lead to better treatments in the prevention and management of AMD.
|Title:||The role of innate immune cells in ocular ageing and pathological neovascularisation|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Copyright restricted material on pages 49, 51, 52, 63, 64, 67, 81, 83, 87, 226 has been removed from the e-thesis|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology > Institute of Ophthalmology - Genetics|
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