Objective: Myeloid-derived suppressor cells (MDSCs) play important roles in preventing graft rejection. Immunosuppressive drug cyclosporine A (CsA) is widely used in clinics to treat patients with allografts and autoimmune diseases. However, the effect of CsA on CD11b(+)Gr1(+) MDSCs has not been studied.
Subjects: The subjects of the study include BALB/c skin-grafted C57BL/6 mice and the in vitro MDSCs induction system.
Treatment: Skin-grafted mice were treated with CsA (30 mg/kg, i.p.) or control buffer daily. 0.01 μg/ml CsA was added during MDSC induction.
Methods: Flow cytometry was used to check cell phenotypes and proliferation. Real-time PCR was used for gene expressions. Inducible nitric oxide synthase iNOS-knockout mice were used for the role of iNOS in the immunosuppression of MDSCs.
Results: CsA in MDSC-induction system significantly increased the number of CD11b(+)Gr1(+)MDSCs without detectable effects on the expressions of CD31, CD115 and CD274. However, GM-CSF + CsA-induced MDSCs express higher iNOS than control MDSCs. Blocking iNOS activity by inhibitor or gene deletion significantly reversed the inhibitory effects of GM-CSF + CsA-induced MDSCs on T cell proliferation. Importantly, CsA treatment significantly increased the number and the immunosuppressive ability of CD11b(+)Gr1(+)MDSCs in allogeneic skin-grafted mice.
Conclusions: CsA promotes MDSC induction and immunosuppressive function, which might be of clinical importance in treating graft rejection and autoimmune diseases.
Keywords: Graft rejection; Immune tolerance; Innate immunity; Myeloid-derived suppressor cells.