Granulocytic myeloid-derived suppressor cells to prevent and treat murine immune-mediated bone marrow failure

Abstract

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which originate in the bone marrow (BM) and have immunoregulatory functions. MDSCs have been implicated in the pathogenesis of several autoimmune diseases but have not been investigated in immune aplastic anemia (AA). We examined the roles of granulocytic-MDSCs (G-MDSCs) in murine models of human AA and bone marrow failure (BMF). As both prophylaxis and therapy, BM-derived G-MDSCs improved pancytopenia and BM cellularity and suppressed BM T cell infiltration in major histocompatibility complex (MHC)-matched C.B10 BMF mice. These effects were not obtained in MHC-mismatched CByB6F1 AA model, likely due to MHC disparity between G-MDSCs and donor T cells. Single cell RNA sequencing demonstrated that G-MDSCs downregulated cell cycle related genes in BM infiltrated T cells, consistent with suppression of T cell proliferation by G-MDSCs through reactive oxygen species pathway. Clearance of G-MDSCs in MHC-mismatched CByB6F1 model using anti-Ly6G antibody facilitated T cell-mediated BM destruction, suggesting an intrinsic immunosuppressive property of G-MDSCs. However, the same anti-Ly6G antibody mildly mitigated marrow failure due to expansion of an intermediate Ly6G population in the BM of MHC-matched C.B10 AA model. Our results demonstrate that G-MDSC eradication and therapeutic efficacy are immune context-dependent.

Influence of Housing Temperature and Genetic Diversity on Allogeneic T Cell-Induced Tissue Damage in Mice

“…We estimated, based upon published frequencies of these cells in the BM and spleen of mice [48,49,53], that these myeloid cells may approximate or exceed the numbers of allogeneic T cells within the BM and spleen. Feng et al have recently reported that PMN-MDSCs potently suppress T cell-mediated BM failure using a mouse model of immune-mediated aplastic anemia [82]. Conceptionally, these data are similar to those of Dong et al who reported that patients with severe immune-mediated aplastic anemia have fewer circulating M-MDSCs that possess impaired immunosuppressive activity [83].…”

Formononetin reverses Treg/Th17 imbalance in immune-mediated bone marrow failure mice by regulating the PI3K/Akt signaling pathway

“…The thymus and lymph nodes were collected from donor C57BL/6J mice, homogenized, centrifuged, and resuspended to obtain the lymphocyte suspension by combining thymocytes and lymph node cells at a ratio of 1:2. Except for the control group, all other groups were established by the total body X-ray radiation, followed by intravenous injection of 0.2 mL of the lymphocyte suspension [ 26 ]. Drug administration started 24 h after modeling.…”

Immunosuppressive Activity of Exosomes from Granulocytic Myeloid-Derived Suppressor Cells in a Murine Model of Immune Bone Marrow Failure

“…new cell therapy and found that G-MDSC therapy is effective in the treatment of murine AA in the minor-H mismatched LN-cell-infusion-induced BMF model [12].…”

“…We used these models to test granulocytic myeloid-derived suppressor cells (G-MDSCs) as a new cell therapy and found that G-MDSC therapy is effective in the treatment of murine AA in the minor-H mismatched LN-cell-infusion-induced BMF model [12].…”