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Yi hsing Chen, Malihe Eskandarpour, Grazyna Galatowicz, Mahid Chaudhry, Xiaozhe Zhang, Susan Lightman, Virginia Calder; Effects of α4β1 Integrin Inhibitor on Leucocyte Subset Migration in Experimental Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2541.
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α4β1 integrin plays a cardinal role in leukocyte adhesion and trafficking. This study investigated an α4β1 integrin inhibitor (GW559090) on leucocyte migration in mouse CD4+T cell-mediated models of experimental autoimmune uveitis (EAU).
Female B10.RIII or C57/B6 mice (aged 6-8 weeks; n=6-8 mice per group), were immunized with interphotoreceptor retinoid-binding protein and Bordetella pertussis toxin for EAU. Topical GW559090 at 10mg/ml or 30mg/ml was given twice daily at afferent or efferent phase and compared to vehicle or 0.1% dexamethasone eye drops (DEX group) controls. Mice were sacrificed at peak disease for clinical, histological and flow cytometry evaluation. The T cell subsets present within the eye were investigated by immunohistochemistry and 4-colour immunofluorescence staining. The different populations of leucocytes in blood, eye and lymph nodes were analysed with flow cytometry.
There was a significant reduction in clinical and histological scores in the 10mg/ml and 30mg/ml GW559090, and DEX treated groups as compared to vehicle controls given at afferent or efferent phase. There was a decrease in CD45+ leucocytes in the retinal tissues in all treated groups (P < 0.05), but no effects on the retinal structure. The cell number of CD4+ T cells did not differ by flow cytometric analysis. By immunofluorescent and flow cytometric staining, the population of the Th17 cells reduced (each P ≤ 0.001), and the Th1 cells increased (each P ≤ 0.02) in the treated eyes but not systemically. There was a significant increase in the CD11b+CD64+ macrophages in the eye in the 10mg/ml and 30mg/ml treated group (P < 0.001 and P = 0.03), and the CD11b+CD64+ activated monocytes in the blood (P = 0.01) in the 10mg/ml treated group. Furthermore, a decrease in CD11b+ dendritic cells was observed in the eye and the peripheral blood in the 10mg/ml and 30mg/ml treated groups (each P ≤ 0.001). However, there was no such effect on the DEX group.
α4β1 integrin inhibitor may exert a modulatory effect in EAU by selectively blocking Th17 cell migration across the blood-retinal barrier without affecting systemic T cell subsets. α4β1 integrin-directed inhibition could be clinically relevant in Th17-dominant cases of uveitis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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