The effect of immunosuppressive drug cyclosporine A on myeloid-derived suppressor cells in transplanted mice.

Abstract

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. The subjects of the study include BALB/c skin-grafted C57BL/6 mice and the in vitro MDSCs induction system. Skin-grafted mice were treated with CsA (30mg/kg, i.p.) or control buffer daily. 0.01μg/ml CsA was added during MDSC induction. 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. 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. CsA promotes MDSC induction and immunosuppressive function, which might be of clinical importance in treating graft rejection and autoimmune diseases.