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

Research output: Contribution to journalArticle

8 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 - 2017 Oct 1

Fingerprint

Graft vs Host Disease
Ascorbic Acid
Antigens
Transplants
T-Lymphocytes
Adoptive Immunotherapy
Therapeutics
Hematopoietic Stem Cell Transplantation
Organ Transplantation
Regulatory T-Lymphocytes
Tretinoin
Dendritic Cells
Genes
Autoimmune Diseases
Interleukin-6
Hypersensitivity
DNA
Population
In Vitro Techniques

Keywords

  • DNA methylation
  • Foxp3
  • GVHD
  • Immune tolerance
  • Regulatory T cell

ASJC Scopus subject areas

  • Immunology

Cite this

Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model. / Kasahara, Hidenori; Kondo, Taisuke; Nakatsukasa, Hiroko; Chikuma, Shunsuke; Ito, Minako; Ando, Makoto; Kurebayashi, Yutaka; Sekiya, Takashi; Yamada, Taketo; Okamoto, Shinichiro; Yoshimura, Akihiko.

In: International Immunology, Vol. 29, No. 10, 01.10.2017, p. 457-469.

Research output: Contribution to journalArticle

@article{f79d45cdb71d4cc58fa2e238023ccf27,
title = "Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model",
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.",
keywords = "DNA methylation, Foxp3, GVHD, Immune tolerance, Regulatory T cell",
author = "Hidenori Kasahara and Taisuke Kondo and Hiroko Nakatsukasa and Shunsuke Chikuma and Minako Ito and Makoto Ando and Yutaka Kurebayashi and Takashi Sekiya and Taketo Yamada and Shinichiro Okamoto and Akihiko Yoshimura",
year = "2017",
month = "10",
day = "1",
doi = "10.1093/intimm/dxx060",
language = "English",
volume = "29",
pages = "457--469",
journal = "International Immunology",
issn = "0953-8178",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model

AU - Kasahara, Hidenori

AU - Kondo, Taisuke

AU - Nakatsukasa, Hiroko

AU - Chikuma, Shunsuke

AU - Ito, Minako

AU - Ando, Makoto

AU - Kurebayashi, Yutaka

AU - Sekiya, Takashi

AU - Yamada, Taketo

AU - Okamoto, Shinichiro

AU - Yoshimura, Akihiko

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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.

AB - 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.

KW - DNA methylation

KW - Foxp3

KW - GVHD

KW - Immune tolerance

KW - Regulatory T cell

UR - http://www.scopus.com/inward/record.url?scp=85037977204&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85037977204&partnerID=8YFLogxK

U2 - 10.1093/intimm/dxx060

DO - 10.1093/intimm/dxx060

M3 - Article

VL - 29

SP - 457

EP - 469

JO - International Immunology

JF - International Immunology

SN - 0953-8178

IS - 10

ER -