Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo

Songjie Cai, John Y Choi, Thiago J Borges, Hengcheng Zhang, Ji Miao, Takaharu Ichimura, Xiaofei Li, Simiao Xu, Philip Chu, Siawosh K Eskandari, Hazim Allos, Juliano B Alhaddad, Saif A Muhsin, Karim Yatim, Leonardo V Riella, Peter T Sage, Anil K Chandraker*, Jamil R Azzi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2Kb, I-Ab) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2Kd, I-Ad) or third-party (C3H, H2Kk, I-Ak) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regulated proinflammatory cytokines. Immune phenotyping showed that the donor MDSCs administration suppressed effector T cells in recipients. Interestingly, significant increase in recipient endogenous CD11b+Gr1+ MDSC population was observed in the group treated with donor-derived MDSCs compared to the control groups. Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Furthermore, we observed that the allogeneic mixed lymphocytes reaction was suppressed in the presence of CD11b+Gr1+ MDSCs in a donor-specific manner. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient's endogenous MDSCs.

Original languageEnglish
Article number14249
Number of pages13
JournalScientific Reports
Volume10
DOIs
Publication statusPublished - 28-Aug-2020
Externally publishedYes

Keywords

  • Allografts/immunology
  • Animals
  • Graft Rejection/immunology
  • Graft Survival/immunology
  • Heart Transplantation/methods
  • Hematopoietic Stem Cell Transplantation
  • Immune Tolerance
  • Immunosuppression/methods
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Myeloid Cells/immunology
  • Myeloid-Derived Suppressor Cells/immunology
  • T-Lymphocytes/immunology
  • Tissue Donors
  • Transplantation, Homologous

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