May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
On The Mechanisms by Which Spontaneous Development of Organ-Localized Autoimmune Diseases Induced by Xenogeneic Thymus
Author Affiliations & Notes
  • M. Takeuchi
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • T. Hattori
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • Y. Usui
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • Y. Okunuki
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • J. Ma
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • N. Yamakawa
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • L. Zhang
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • T. Kezuka
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • H. Goto
    Ophthalmology, Tokyo Medical University, Tokyo, Japan
  • O. Taguchi
    Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan
  • Footnotes
    Commercial Relationships  M. Takeuchi, None; T. Hattori, None; Y. Usui, None; Y. Okunuki, None; J. Ma, None; N. Yamakawa, None; L. Zhang, None; T. Kezuka, None; H. Goto, None; O. Taguchi, None.
  • Footnotes
    Support  Grant-in-Aid 18591935 for Scientific Research from the Japan Society for the Promotion of Science
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2507. doi:https://doi.org/
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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. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : : 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.

Methods: : 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).

Results: : 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.

Conclusions: : 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.

Keywords: autoimmune disease • immunomodulation/immunoregulation • immune tolerance/privilege 
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