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 potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2K b , I-A b) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2K d , I-A d) or third-party (C3H, H2K k , I-A k) 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 donorderived 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. Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. The Scientific Registry of Transplant Recipients (SRTR) reported that 14,313 kidney 1 , 7,483 liver 2 , 2,465 lung 3 , 432 heart 4 , 80 pancreas 5 , and 109 intestinal 6 transplants were performed in 2017 in the US (Feb 2019 updated). Nevertheless, number of challenges remain for organ recipients after the transplantation, as they suffer from acute and chronic rejection as well as complications of immunosuppression 7-9. One of the more critical issues pertains to the current state of standard immunosuppressive protocols. Calcineurin inhibitor (CNI) based immunosuppressive protocols are not designed to promote antigen-specific tolerance, and may exacerbate chronic allograft injury (i.e. calcineurin toxicity) 10. Therefore, there is an urgent need to establish safer anti-rejection strategies by targeting antigenspecific alloimmunity.

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant injury

“…Previous studies have demonstrated the ability of MDSCs to prolong cardiac graft survival in a murine model, which was significantly reduced when MDSCs were depleted (45,46), and M-MDSCs were shown to promote organ acceptance through recruitment of regulatory T cells in clinical kidney transplantation (47). Furthermore, studies in islet and heart transplantation have demonstrated an association between MerTK function and M-MDSC mediated transplant tolerance, namely through their ability to recruit regulatory T cells (48).…”

“…Depending on the inflammatory microenvironment, these cells are capable of mediating immunosuppression through secretion of anti-inflammatory cytokines, recruitment of regulatory immune cells, exhaustion of pro-inflammatory cells through nutrient sequestering, and facilitating cell polarization to anti-inflammatory phenotypes (14). Previous studies have demonstrated the ability of MDSCs to prolong cardiac graft survival in a murine model, which was significantly reduced when MDSCs were depleted (45, 46), and M-MDSCs were shown to promote organ acceptance through recruitment of regulatory T cells in clinical kidney transplantation (47). Furthermore, studies in islet and heart transplantation have demonstrated an association between MerTK function and M-MDSC mediated transplant tolerance, namely through their ability to recruit regulatory T cells (48).…”

Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease

“…We observed that the presence of donor MDSCs promoted allograft acceptance as all the engrafted patients and all HDMC timepoints had them. Although it could be presumed that the high chimerism status at these time points account for their donor derived origin but a recent murine study revealed that donor MDSCs promote cardiac allograft tolerance via induction of recipient derived MDSCs ( 56 ).…”

Human Myeloid-­Derived Suppressor Cells in Solid Organ Transplantation

“…Ling Zhou, et al found a cardioprotective role of MDSCs in heart failure [73] although the human MDSC response in heart transplantation remains unstudied. In murine models, several studies demonstrated MDSC were required for the induction of transplantation tolerance [47,74,75]. Some authors reported the development of MDSC and induction of tolerance after treating recipients with rapamycin and costimulatory blockade with anti-CD40L mAb [76,77] in contrast to mice treated with either rapamycin or anti-CD40L mAb alone [77].…”