Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model

Hidenori Kasahara, Taisuke Kondo, Hiroko Nakatsukasa, Shunsuke Chikuma, Minako Ito, Makoto Ando, Yutaka Kurebayashi, Takashi Sekiya, Taketo Yamada, Shinichiro Okamoto, Akihiko Yoshimura

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15 Citations (Scopus)

Abstract

Antigen-specific regulatory T cells (Tregs) possess the potential to reduce excess immune responses in autoimmune diseases, allergy, rejection after organ transplantation and graft-versushost disease (GVHD) following hematopoietic stem cell transplantation. Although in vitro-expanded antigen-specific induced Tregs (iTregs) have been considered to be a promising therapeutic agent against such excessive immune reactions, the instability of iTregs after transfer is a fundamental problem in their clinical application. In this study, we searched for the optimal way to generate stable iTregs for the prevention of the murine GVHD model, in which conventional iTregs are reported to be inefficient. Allo-antigen-specific iTregs were generated by co-culturing naive T cells with allogenic dendritic cells in the presence of TGF-β and retinoic acid. By examining various agents and genes, we found that vitamin C stabilized Foxp3 expression most effectively in adoptively transferred iTregs under a GVHD environment. Vitamin C treatment caused active DNA demethylation specifically on the conserved non-coding sequence 2 (CNS2) enhancer of the Foxp3 gene locus in allo-antigenspecific iTregs and reduced iTreg conversion into pathogenic exFoxp3 cells. Vitamin C-treated iTregs suppressed GVHD symptoms more efficiently than untreated iTregs. Vitamin C also facilitated induction of a FOXP3high iTreg population from human naive T cells, which was very stable even in the presence of IL-6 in vitro. The treatment of vitamin C for iTreg promises innovative clinical application for adoptive Treg immunotherapy.

Original languageEnglish
Pages (from-to)457-469
Number of pages13
JournalInternational immunology
Volume29
Issue number10
DOIs
Publication statusPublished - Oct 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Kasahara, H., Kondo, T., Nakatsukasa, H., Chikuma, S., Ito, M., Ando, M., Kurebayashi, Y., Sekiya, T., Yamada, T., Okamoto, S., & Yoshimura, A. (2017). Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model. International immunology, 29(10), 457-469. https://doi.org/10.1093/intimm/dxx060