Amelioration of acute graft-versus-host disease by adoptive transfer of ex vivo expanded human cord blood CD4+CD25+ forkhead box protein 3+ regulatory T cells is associated with the polarization of Treg/Th17 balance in a mouse model

Authors

  • Jie Yang,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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    • These authors contributed equally to this work.

  • Huahua Fan,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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    • These authors contributed equally to this work.

  • Jun Hao,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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  • Yana Ren,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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  • Liang Chen,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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  • Guiping Li,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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  • Rufeng Xie,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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  • Yiming Yang,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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  • Kaicheng Qian,

    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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  • Mingyao Liu

    Corresponding author
    1. From the Blood Engineering Laboratory, Shanghai Blood Center; the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; and the Shanghai Cord Blood Bank, Shanghai, China.
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  • This study was supported by a grant (09140903000) from the Science and Technology Commission of Shanghai Municipality.

Mingyao Liu, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; e-mail: ibms.ecnu@gmail.com.

Abstract

BACKGROUND: Human cord blood (CB) is a superior source of regulatory T cells (Tregs) compared with peripheral blood. Initial studies have shown that CB-derived Tregs can be effectively expanded ex vivo. However, in vitro suppressor activity of expanded CB-Tregs and their efficacy in the prevention of acute graft-versus-host disease (aGVHD) in vivo are poorly understood.

STUDY DESIGN AND METHODS: In vitro, human CB CD4+CD25+ T cells expanded with anti-CD3/CD28 beads plus interleukin (IL)-2 and the phenotypes, expression of cytokines, and suppression of expanded cells were analyzed after two cycles of stimulation. In vivo, the addition of human CB-Tregs was transferred in the major histocompatibility complex–mismatched aGVHD mouse model. Survival, body weight, GVHD scoring, histopathologic specimens, serum cytokines, and Th subsets were analyzed in CB-Treg–treated mice and untreated controls.

RESULTS: After being expanded ex vivo, human CB-derived Tregs with potent suppressor function could meet clinical demands. Up to 85% of mice with CB-Tregs treatment survived beyond Day 63 after bone marrow transplantation; however, all aGVHD mice died within 18 days. In the serum of the CB-Treg–treated mice, the production of transforming growth factor-β increased continuously, as opposed to IL-17, which decreased quickly. Consistent with the changes of cytokines, the percentage of mouse CD4+ forkhead box protein 3+ Tregs increased while that of Th17 cells decreased.

CONCLUSION: Ex vivo expanded human CB-Tregs significantly prevented allogeneic aGVHD in vivo by modulating various cytokine secretion and polarizing the Treg/Th17 balance toward Treg, which suggests the potential use of expanded CB-Tregs as a therapeutic approach for GVHD.

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