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J. G. Hollyfield, M. E. Rayborn, M. Yu, K. G. Shadrach, X. Yang, B. A. Bell, N. S. Peachey, R. G. Salomon; Sustained RPE Pathology During Aging of Mice Immunized With CEP-MSA. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6136.
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An acute mouse model for age-related macular degeneration (AMD) generated with three CEP-MSA immunizations shows multiple lesions in the retinal pigment epithelium (RPE) within 3 months of the initial immunization. To understand the persistence of the RPE pathology and the functional consequences of these lesions we performed the following study.
2-3 month old C57Bl/6 mice were immunized with CEP-MSA or MSA controls in complete Freund’s adjuvant (CFA) at day 0, followed by challenge at day 10 in incomplete Freund’s adjuvant (IFA). 3 months following the initial immunization mice were given an additional immunization identical to that applied initially (described in Nature Med. 2009, 14:194). Mice were maintained for an additional 6 months. Dark-and light-adapted ERGs were recorded under anesthesia before sacrifice. Blood was taken for direct ELISA detection of CEP-antibody titer, which was performed in 96-well plates coated with CEP-BSA (100 µl/well) at 1:1000 dilution in PBS and incubated at 37 °C for 1 hr, using 1% BSA solution as a blank control. Eyes were processed for light and electron microscopy.
CEP-antibody titers were higher in the CEP-MSA immunized mice than in any other group. ERG amplitudes were reduced by 20-30 % in the CEP-MSA, and by 10-12 % in the MSA immunized mice when compared to those in non-immunized control animals. Severe focal lesions in the RPE were observed in the fundus of the CEP-MSA immunized mice; involving a few RPE cells to expansive areas over 200 µm in length. The photoreceptor layer was thinner over regions with severe pathology, but appeared normal in areas where the RPE is not affected.
These data demonstrate that changes in the RPE in the acute AMD model are not transitory, but persist long after the completion of the immunization schedule. The focal changes in photoreceptor density over areas with RPE lesions suggest that the reduction in ERG responses is caused by the reduction in photoreceptor density overlying these areas of RPE pathology.
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