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Michel Betancourt, Fernando Cruz-Guilloty, Jose J. Echegaray, Eduardo Viteri, Stephanie Duffort, Asha Ballmick, Ghansham Ramkhellawan, Victor L. Perez; Differential Role of the Immune System versus Retina Microenvironment in a Mouse Model of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):960.
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Our laboratory has developed a murine model of immune-mediated retinal pathology based on human data of age-related macular degeneration (AMD). Carboxyethylpyrrole (CEP) is an oxidative damage-induced modification highly associated with AMD. Mice immunized with CEP-mouse serum albumin (CEP-MSA) develop retinal lesions similar to AMD. In this project, we try to determine the relative contributions of the retina microenvironment or divergent immune responses to CEP by analyzing different mouse strains with different levels of retinal pigmentation and immune system bias.
Three strains of mice (WT BALB/c, WT C57/B6 and Tyr-KO C57/B6) were immunized with CEP-MSA, non-adducted MSA emulsified in complete Freund’s adjuvant (CFA). At day 10 the mice were challenged with incomplete Freund’s adjuvant-CEP-MSA, followed by a second challenge with CEP-MSA at day 40. Eyes were harvested for histology at early (2-3 months), intermediate (4-6 months) and late (8-12 months) time points. Eyes for histology were fixed in 2% Paraformaldehyde and 2.5% Glutaraldehyde in 0.1M PO4 buffer (pH = 7.4) overnight and dehydrated in graded ethanol and propylene oxide. After polymerization in a resin mixture, 0.7µm-thick serial sections were cut from each eye and stained with toluidine blue. Microscopic retinal scoring was divided into "infiltrate cell counts" (cells within the rod outer segment and retina pigment epithelium) or "lesions" (RPE vacuolization, RPE pyknosis, loss of photoreceptor cells).
CEP-MSA immunized WT BALB/c mice attract a higher number of inflammatory cells to the ROS and develop more sub-retinal lesions when compared to age-matched pigmented WT B6 mice. The tempo of infiltrate cell recruitment is faster in the BALB/c mice, in which significant pathology is observed at early time points. Comparing albino B6 mice (Tyr-KO B6) to the age-matched control mice of both WT strains, we found that the kinetics of infiltrate cell recruitment and lesion development followed closely the WT B6 pattern, with lower pathology than BALB/c at the same time points.
The increased number of lesions and infiltrate cells exhibited by WT BALB/c mice is not due simply to light damage susceptibility given that albino C57/B6 mice demonstrate kinetics of infiltrate cell recruitment and sub-retinal lesion development similar to WT B6. Therefore, the differences observed between strains are due to differences in genetic makeup and not to the level of pigmentation.
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