Chenlu Han1,2, Tingting Wu1, Ning Na3, Yang Zhao1, Weiguo Li4, Yong Zhao5. 1. College of Life Science, Henan Normal University, Xinxiang, Henan, China. 2. Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, 100101, Beijing, China. 3. Department of Kidney Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. 4. Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, 100101, Beijing, China. liwg0618@htu.cn. 5. College of Life Science, Henan Normal University, Xinxiang, Henan, China. zhaoy@ioz.ac.cn.
Abstract
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.
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.
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