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M. Takeuchi, T. Hattori, Y. Usui, Y. Okunuki, J. Ma, N. Yamakawa, L. Zhang, T. Kezuka, H. Goto, O. Taguchi; On The Mechanisms by Which Spontaneous Development of Organ-Localized Autoimmune Diseases Induced by Xenogeneic Thymus. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2507.
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© ARVO (1962-2015); The Authors (2016-present)
: Nude mice grafted with embryonic rat thymus beneath the renal capsule (referred to as TG nude mice) induce spontaneously organ-localized autoimmune diseases including dacryadenitis and uveoretinitis. Recently, it has been reported that antigen-presenting cells expressing autoimmune regulator gene (Aire) in the thymus play critical roles to delete T cells reactive to tissue-specific antigens and to develop Foxp3+ regulatory T cells. In this study, we examined origin of Aire-expressing cells in the grafted rat-thymus of TG nude mice, and phenotype of their matured T cells.
To generate TG nude mice, thymi harvested from 15-day-old F344 rat embryos were grafted beneath the renal capsules of 4-week-old female BALB/c nude mice. The grafted rat thymi were extracted one month after grafting, and were stained with anti-mouse or anti-rat MHC class II mAb, and anti-Aire mAb. In addition, T cells obtained from systemic lymph nodes and spleens of normal BALB/c mice or TG nude mice, were analyzed for mRNA expression of IL-17, IFN-g, and Foxp3 by real time PCR, and were measured production of IL-10, IL-17, and IFN-g by FACS when stimulated with interphotoreceptor retinoid-binding protein (IRBP).
In the grafted rat thymus, over 95% of thymocytes were reconstituted by murine cells, however medullary antigen-presenting cells were rat origin, which were only cells expressing autoimmune regulator gene (Aire). T cells from TG nude mice produced IFN-g and IL-17 but not IL-10 by stimulation with IRBP, in which IL-17 production was remarkably more than that of IFN-g. Unexpectedly, Foxp3 mRNA expression was also detected in peripheral T cells of TG nude mice, which was higher than that of naive BALB/c mice, suggesting that Foxp3-positive cells in TG nude mice would not be functional.
In TG nude mice, since thymic medullary antigen-presenting cells expressing Aire remain rat origin, the grafted rat thymus fails to delete T cells reactive to tissue-specific antigens, that develop organ-specific autoimmune diseases by differentiating into Th1 cells and especially into Th17 cells.
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