M-CSF and TNF-α Induce Human MDSCs that Attenuate GVHD

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Myeloid-derived suppressor cells (MDSCs) negatively regulate immune response and participate in the induction of prolonged allograft survival in animal models. Human MDSC therapy may be a clinically feasible strategy to repress immune response and prolong allograft survival, so the efficient induction of functional competent human MDSCs is critical for the clinical application. In the study, we tried to establish human MDSC induction system with macrophage colony stimulating factor (M-CSF) and tumor necrosis factor α (TNFα) and investigated the immunosuppressive function of the MDSCs in transplant environment. Human Peripheral blood monocytes were cultured with M-CSF +TNF α for 7 days. Phenotype analysis revealed M-CSF +TNF α-induced MDSCs express CD11b, CD33 and low the MHC class II cell surface receptor HLA-DR. M-CSF +TNFα-induced M-MDSCs showed poor TNFα, IL-12, and IL-6 expressions after lipopolysaccharide(LPS) stimulation compared with M-CSF induced macrophage. M-CSF + TNFα-induced M-MDSCs significantly suppress allogenetic DC stimulating T cell proliferation even in lower doses(1:1/16 between T cells and M-MDSCs) and IFN-γ production by CD8+ T cells and IL-2 production by CD4+ T cells. The MDSCs express high levels of inducingnitric oxide synthase (iNOS) and blocking iNOS activity by a chemical inhibitor significantly reversed the inhibitory effects of the MDSCs on T cells. Adoptive transfer of M-CSF+TNF α-induced MDSCs attenuated GVHD in a mouse model in which human PBMCs engrafted into immunodeficient NOD/SCID IL-2Rγnull (NSG) mice cause GVHD. Thus, M-CSF +TNF α-induced human MDSCs have powerful immunosuppressive activity and may become a clinically strategy to repress immune response and prolong allograft survival.Key Words: MDSCs; TNF-α; GVHD

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