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D. J. Lee, A. W. Taylor; Natural Emergence of Regulatory Immunity in EAU. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2635.
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We have previously shown that TGFβ producing Treg cells emerge in the spleen of wild-type mice, but not in Melanocortin 5 Receptor KO (MC5r(-/-)) mice after resolution of experimental autoimmune uveitis (EAU). What we do not know is when the Treg cells emerge in the spleen during EAU.
EAU was induced in C57BL/6 mice immunized with IRBP peptide1-20 in CFA. A fundus exam was done every 3-4 days. At one-week intervals after the onset of EAU spleens were collected from the EAU mice, depleted of RBC, activated in vitro with IRBP peptide 1-20, and the supernatants were assayed for TGFβ, IFNγ, and IL17 by ELISA.
Spleen cells from EAU wild type mice produced IFN-γ and IL17 throughout the course of the disease, with production of IL-17 at the onset of EAU. The production of TGF-β by the spleen cells gradually increased as disease progressed, and continued to increase as the disease resolved. Corresponding with the resolution of EAU and the increase in TGF-β production was a parallel decline in IFN-γ and IL-17 production. While MC5r(-/-) mice never show a difference in the course and resolution of EAU, post-EAU spleen cells had a significant decrease in TGFβ production and a significant increase in IFNγ production compared with post-EAU wild-type mice.
Our results show the appearance of IRBP-specific Th1 cells and Th17 cells in the spleen of mice immunized for EAU just before maximum uveoretinitis. We found there is a low level of IRBP-specific TGF-β producing T cells that become the dominant response as the disease resolves. The MC5r(-/-) mice that do not have IRBP-specific Treg cells in their spleen at the resolution of EAU also do not switch to a dominant TGF-β producing response at the resolution of EAU. The influence of the ocular microenvironment reimposing regulation results in a parallel, but not required, change in the autoantigen-response in the spleen. IRBP specific Treg cells emerge as the disease progresses and become dominant as the uveitis resolves.
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