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.
Highlights
Solid organ transplantation is a lifesaving therapy for patients with end-organ disease
Co-culturing naive T cells isolated from C57BL/6 mice (H2Kb, I-Ab) with BALB/c (H2Kd, I-Ad) derived conventional DCs stimulates an alloreactive T cell proliferation
We observed that the addition of BALB/c myeloid-derived suppressor cells (MDSCs) to this Allogeneic mixed lymphocyte reaction (alloMLR) system significantly inhibited the proliferation of CD4+ and CD8+ T cells compared to conventional myeloid derived cells (Fig. 1A,B)
Summary
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. Significant increase in recipient endogenous CD11b+Gr1+ MDSC population was observed in the group treated with donorderived MDSCs compared to the control groups Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient’s endogenous MDSCs. Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Based on the above clinical and preclinical studies, we hypothesized that donor-derived MDSCs may induce donor-specific immune suppression in allogeneic organ transplantation. We demonstrated that the administration of donor-derived MDSCs prolong allogeneic cardiac graft survival in a donor-specific manner through induction of recipients’ endogenous MDSCs
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