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Maren Hennig, Dirk Bauer, Martin Busch, Susanne Wasmuth, Karoline Walscheid, Solon Thanos, Arnd Heiligenhaus; Effective Treatment Of Experimental Autoimmune Uveitis With Everolimus Is Associated With The Support Of Regulatory T-cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2276.
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To study the efficacy and the action mechanism of everolimus for the treatment of experimental autoimmune uveitis (EAU).
EAU was induced in B10.RIII mice by immunization with interphotoreceptor retinoid-binding protein peptide 161-180 (IRBP). Mice were daily treated therapeutically (day 14-21 post immunization, n=19) with everolimus (5mg/kg in 5% glucose) by oral administration. Control mice received equivalent volumes of 5% glucose without drug (n=20). The eyes were analyzed histopathologically. Lymphocyte proliferation ([3H]-thymidine test) and delayed type hypersensitivity (DTH) were measured. IL-2, IL-6 and IL-17 levels were studied intraocularly (Bead-Array) and in cell-culture supernatants from splenocytes (ELISA). Additionally the presence of IRBP-specific serum-antibodies was tested (ELISA). Regulatory T-cells were studied in peripheral blood, lymph nodes, and spleen by flow-cytometry. The suppressive efficiency of splenic CD4+CD25+ T-cells of everolimus treated and untreated mice were analyzed in a suppression assay.
The EAU incidence and severity, and the DTH of everolimus treated immunized mice were significantly reduced. Splenocytes of everolimus treated mice had decreased proliferative response. Moreover IL-2, IL-6 and IL-17 secretion in the eyes and spleen, and IRBP-specific serum-antibody content were reduced. Everolimus treated mice had increased CD4+CD25+Foxp3+ cell numbers in the spleen. In contrast to CD4+CD25+ splenocytes of untreated mice, the cells from the everolimus treated mice suppressed the antigen specific proliferation of CD4+CD25- effector T-cells.
Uveitis improvement with everolimus was associated with a reduced IRBP-specific effector-cell-response, and an increased frequency of CD4+CD25+Foxp3+ T-cells with an enhanced suppressive efficiency on IRBP-specific effector-T-cells.
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