Impaired immunosuppressive role of myeloid-derived suppressor cells in acquired aplastic anemia

Abstract

Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous immature myeloid cells and display immunosuppressive function. In this study, MDSCs populations were evaluated in acquired aplastic anemia (AA) (n=65) in which aberrant immune mechanisms contributed to bone marrow destruction. Our data demonstrate that both the proportion and immunosuppressive function of MDSCs are impaired in AA patients. Decreased percentage of MDSCs, especially monocytic-MDSCs, in the blood of AA patients (n=15) is positively correlated with the frequency of T regulatory cells, bone marrow level of WT1 and decreased plasma level of arginase-1. RNA sequence analyses reveal that multiple pathways including DNA damage, interleukin (IL)-4, apoptosis, and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) are upregulated, whereas transcription, IL-6, IL-18, glycolysis, transforming growth factor and reactive oxygen species are downregulated in MDSCs of AA (n=4), compared with that of healthy donors (n=3). These data suggest that AA MDSCs are defective. Administration of rapamycin significantly increases the absolute number of MDSCs and levels of intracellular enzymes, including arginase-1 and inducible nitric-oxide synthase. Moreover, rapamycin inhibits MDSCs from differentiating into mature myeloid cells. These findings reveal that impaired MDSCs are involved in the immunopathogenesis of AA. Pharmacologically targeting of MDSCs by rapamycin might provide a promising therapeutic strategy for AA.

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

“…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].…”

Comprehensive mapping of immune perturbations associated with aplastic anemia

“…S2). Previous research has pointed to a signi cant decrease in MDSC proportions in AA, linked to a noticeable reduction in immunosuppressive capabilities [20]. Employing ow cytometry-based sorting, we isolated MDSCs from both HDs and AA patients for Smart-seq analysis.…”

“…CAA primarily results from genetic mutations, with the diagnosis of congenital bone marrow failure relying mainly on NGS sequencing. In AA, MDSCs exert immunosuppressive effects, leading to a signi cant decrease in their components [20]. We further evaluated the percentage of HLA-DR − CD11b + CD33 + MDSCs in AA and CAA, revealing a marginal decrease in MDSCs in AA compared to the HDs.…”