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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Prevention of alloimmune rejection using XBP1-deleted bone marrow-derived dendritic cells in heart transplantation

  • Author Footnotes
    # Equal contribution as first author.
    Kailun Sun
    Footnotes
    # Equal contribution as first author.
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
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  • Author Footnotes
    # Equal contribution as first author.
    Chanyuan Fan
    Footnotes
    # Equal contribution as first author.
    Affiliations
    Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
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  • Ji Zhang
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
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  • Haiqiang Ni
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
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  • Mengqin Wang
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
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  • Jiasi Zhang
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
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  • Qingwen Li
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
    Search for articles by this author
  • Baicheng Kuang
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
    Search for articles by this author
  • Zhiheng Wang
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
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  • Shuaiheng Hou
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
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  • Nianqiao Gong
    Correspondence
    Reprint requests: Nianqiao Gong, MD, PhD, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, PR China. Telephone: 86-027-83663822. Fax: 86-027-83662892.
    Affiliations
    Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China
    Search for articles by this author
  • Author Footnotes
    # Equal contribution as first author.

      Background

      Genetically modified dendritic cells (DCs) modulate the alloimmunity of T lymphocytes by regulating antigen presentation.

      Methods

      We generated mice with specific deletion of the X-box-binding protein 1 (XBP1) allele in bone marrow cells and cultured bone marrow-derived DCs (Xbp1−/− BMDCs) from these animals. We then tested the phenotype of Xbp1−/− BMDCs, evaluated their capability to activate allogeneic T cells and investigated their mechanistic actions. We developed a mouse model of allogeneic heart transplantation in which recipients received PBS, Xbp1−/− BMDCs, a suboptimal dose of cyclosporine A (CsA), or Xbp1−/− BMDCs combined with a suboptimal dose of CsA to evaluate the effects of Xbp1−/− BMDC transfusion on alloimmunity and on the survival of heart allografts.

      Results

      The deletion of XBP1 in BMDCs exploited the IRE1-dependent decay of TAPBP mRNA to reduce the expression of MHC-I on the cell surface, altered the capability of BMDCs to activate CD8+ T cells, and ultimately suppressed CD8+ T-cell-mediated allogeneic rejection. The adoptive transfer of Xbp1−/− BMDCs inhibited CD8+ T-cell-mediated rejection. In addition, XBP1-deficient BMDCs were weak stimulators of allogeneic CD4+ T cells despite expressing high levels of MHC-II and costimulatory molecules on their cell surface. Moreover, the adoptive transfer of Xbp1−/− BMDCs inhibited the production of circulating donor-specific IgG. The combination of Xbp1−/− BMDCs and CsA treatment significantly prolonged the survival of allografts compared to CsA alone.

      Conclusions

      The deletion of XBP1 induces immunosuppressive BMDCs, and treatment with these immunosuppressive BMDCs prevents alloimmune rejection and improves the outcomes of heart transplantation. This finding provides a promising therapeutic target in combating transplant rejection and expands knowledge of inducing therapeutic DCs.

      Graphical Abstract

      KEYWORDS

      Abbreviations:

      DCs (dendritic cells), XBP1 (X-box binding protein 1), ER (endoplasmic reticulum), BMDCs (bone marrow-derived dendritic cells), HT (heart transplantation), MLR (mixed lymphocyte reaction), IEM (immuno-electron microscopy), TEM (transmission electron microscopy), RIDD (IRE1-dependent decay), POD (post-operative day), DSA (donor specific antibody)
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