*Purpose: Myeloid-derived suppressor cells (MDSC) are a naturally occurring, heterogeneous population of highly immunosuppressive CD11b+GR-1+ cells that expand in response to inflammatory conditions. MDSCs develop in the peripheral blood of immunosuppressed solid organ transplant recipients. It is unknown if transplantation alone, in the absence of immunosuppression, leads to MDSC development and how transplant-induced MDSCs might affect graft survival. To this end, we tested the hypothesis that transplant induced MDSC can prolong allograft survival.

*Methods: Heterotopic cardiac transplants were performed between C57BL/6 and BALB/c mice, without immunosuppression. Development of MDSC was assessed by flow cytometry for CD11b⁺Gr-1⁺cells in blood, spleen, and the graft. Co-culture assays were performed to assess the ability of MDSCs to suppress T cell proliferation. Immunohistochemistry was performed to investigate intra-graft and splenic MDSCs. Single cell sorting and adoptive transfer techniques were used to assess the migration to, and activity of, MDSC in the graft.

*Results: In a model of acute rejection (without immunosuppression), allografts were uniformly rejected by day 6. CD11b⁺Gr-1⁺ cells (MDSC) increased more than 3-fold by day 14, and MDSCs were detected in both spleens and grafts of allotransplanted mice. In contrast, MDSCs were not detected in the grafts of syngeneically transplanted mice or in naïve mice. Splenic CD11b⁺Gr-1⁺ MDSC isolated from transplanted mice inhibited anti-CD3-stimulated CD4 T cell proliferation in vitro. To augment the MDSC response post-transplantation, adoptive transfer (ATx) experiments were attempted. ATx of a single dose of syngeneic MDSCs was administered to transplanted animals and increased survival to 9.5 days. To augment autologous MDSCs, GCSF (1mg/Kg weight x 4 doses) was used to expand of recipient-derived MDSCs, and this increased survival to 11 days (p<0.0001). A single dose of anti-CD40L mAb-mediated costimulatory blockade on day 0 significantly prolonged mean graft survival, and this was synergistic with ATx. Median graft survival time was 76 days in recipients under co-stimulation blockade and 115. 5 days in recipients under co-stimulation blockade with MDSC transferring (p<0.0001 among groups). Anti-GR-1 mAb depletion of MDSCs decreased median graft survival to 10 days.

*Conclusions: MDSCs developed in response to solid organ transplantation alone migrated to the graft. MDSCs augmentation and costimulatory blockade were synergistic in graft survival prolongation. Our data suggest that transplant-induced MDSCs may have the capacity to control allogeneic responses after transplantation, and thus may be exploited toward tolerance induction protocols.

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