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

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

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 pot...

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Main Authors: 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
Format: Article
Language:English
Published: Nature Publishing Group 2020-08-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-020-71289-z
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spelling doaj-de36c318422d4c6c994a080dce4925be2021-08-29T11:21:51ZengNature Publishing GroupScientific Reports2045-23222020-08-0110111310.1038/s41598-020-71289-zDonor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivoSongjie Cai0John Y. Choi1Thiago J. Borges2Hengcheng Zhang3Ji Miao4Takaharu Ichimura5Xiaofei Li6Simiao Xu7Philip Chu8Siawosh K. Eskandari9Hazim Allos10Juliano B. Alhaddad11Saif A. Muhsin12Karim Yatim13Leonardo V. Riella14Peter T. Sage15Anil K. Chandraker16Jamil R. Azzi17Renal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolDivision of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolDivision of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolRenal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolAbstract 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.https://doi.org/10.1038/s41598-020-71289-z
collection DOAJ
language English
format Article
sources DOAJ
author 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
spellingShingle 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
Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo
Scientific Reports
author_facet 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
author_sort Songjie Cai
title Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo
title_short Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo
title_full Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo
title_fullStr Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo
title_full_unstemmed Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo
title_sort donor myeloid derived suppressor cells (mdscs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo
publisher Nature Publishing Group
series Scientific Reports
issn 2045-2322
publishDate 2020-08-01
description 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.
url https://doi.org/10.1038/s41598-020-71289-z
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