Fan Yang1, Yang Li1, Weilong Zou2, Yanan Xu1, Hao Wang3, Wei Wang4, Yong Zhao5,6. 1. Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China. 2. Surgery of Transplant and Hepatopancrobiliary, The General Hospital of Chinese People's Armed Police Forces, Beijing, China. 3. Department of Radiation Oncology, Peking University Third Hospital, Beijing, China. 4. Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Beijing, 100020, China. zico73@medmail.com.cn. 5. Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China. zhaoy@ioz.ac.cn. 6. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. zhaoy@ioz.ac.cn.
Abstract
AIM AND OBJECTIVE: Efficient production of monocytic myeloid-derived suppressor cells (M-MDSCs) with stable immunosuppressive function is crucial for immunomodulatory cell therapy for many diseases such as transplant rejection, graft-versus-host disease and autoimmune diseases. METHODS: We used M-CSF as growth factor for myeloid progenitor cell differentiation and activated them with IFN-γ during early stage in vitro to produce M-MDSCs. The cell phenotypes were determined using flow cytometry, the immunosuppressive function and mechanisms were determined by skin grafted mouse models and genetic modified mice. RESULTS: IFN-γ treatment endows these cell strong immunosuppressive function by inhibition of T cell proliferation and cytokine productions. The phenotype of these cells also changed towards M-MDSCs. IFN-γ significantly upregulated iNOS expression in these M-MDSCs and inhibition of this molecule significantly reversed their immune regulatory function. The functional stability of induced M-MDSCs by IFN-γ was tested in vivo by transferring them to alloskin-grafted mice. Adoptive transfer of these cells significantly prolonged allograft survival and promoted immune tolerance, whereas iNOS deficiency in these cells reversed this effect. CONCLUSIONS: We established one M-MDSCs-inducting protocol with the combination of M-CSF and IFN-γ in vitro. M-CSF+IFN-γ-induced M-MDSCs are promising to prevent graft rejection by immune regulation.
AIM AND OBJECTIVE: Efficient production of monocytic myeloid-derived suppressor cells (M-MDSCs) with stable immunosuppressive function is crucial for immunomodulatory cell therapy for many diseases such as transplant rejection, graft-versus-host disease and autoimmune diseases. METHODS: We used M-CSF as growth factor for myeloid progenitor cell differentiation and activated them with IFN-γ during early stage in vitro to produce M-MDSCs. The cell phenotypes were determined using flow cytometry, the immunosuppressive function and mechanisms were determined by skin grafted mouse models and genetic modified mice. RESULTS: IFN-γ treatment endows these cell strong immunosuppressive function by inhibition of T cell proliferation and cytokine productions. The phenotype of these cells also changed towards M-MDSCs. IFN-γ significantly upregulated iNOS expression in these M-MDSCs and inhibition of this molecule significantly reversed their immune regulatory function. The functional stability of induced M-MDSCs by IFN-γ was tested in vivo by transferring them to alloskin-grafted mice. Adoptive transfer of these cells significantly prolonged allograft survival and promoted immune tolerance, whereas iNOS deficiency in these cells reversed this effect. CONCLUSIONS: We established one M-MDSCs-inducting protocol with the combination of M-CSF and IFN-γ in vitro. M-CSF+IFN-γ-induced M-MDSCs are promising to prevent graft rejection by immune regulation.
Authors: Meghan A Koch; Glady's Tucker-Heard; Nikole R Perdue; Justin R Killebrew; Kevin B Urdahl; Daniel J Campbell Journal: Nat Immunol Date: 2009-05-03 Impact factor: 25.606