Adoptive transfer of IFN--induced M-MDSCs promotes immune tolerance to allografts through iNOS pathway
Adoptive transfer of IFN--induced M-MDSCs promotes immune tolerance to allografts through iNOS pathway
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IFN诱导的M-MDSCs的过继转移通过iNOS途径促进对同种异体移植物的免疫耐受
DOI：
10.1007/s00011-019-01237-9
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发表时间：
2019
影响因子：
6.7
通讯作者：
Zhao Yong
中科院分区：
文献类型：
--
作者：
Yang Fan;Li Yang;Zou Weilong;Xu Yanan;Wang Hao;Wang Wei;Zhao Yong
目的和目的高效产生具有稳定免疫抑制功能的单核骨髓源性抑制细胞（M-MDSCs）对于移植排斥、移植物抗宿主病和自身免疫性疾病等多种疾病的免疫调节细胞治疗至关重要。方法我们使用M-CSF作为骨髓祖细胞分化的生长因子，并在体外早期用IFN-γ激活它们以产生M-MDSCs。采用流式细胞仪测定细胞表型，通过植皮小鼠模型和基因改造小鼠测定其免疫抑制功能和机制。结果IFN-γ处理通过抑制T细胞增殖和细胞因子产生，赋予这些细胞强大的免疫抑制功能。这些细胞的表型也向 M-MDSC 转变。 IFN-γ 显着上调这些 M-MDSC 中 iNOS 的表达，抑制该分子可显着逆转其免疫调节功能。通过将 IFN-γ 诱导的 M-MDSC 转移至同种异体皮移植小鼠体内，测试了其功能稳定性。这些细胞的过继转移显着延长了同种异体移植物的存活率并促进了免疫耐受，而这些细胞中的iNOS缺乏则逆转了这种效应。结论我们在体外建立了一种结合M-CSF和IFN-γ的M-MDSC诱导方案。 M-CSF+IFN-γ诱导的M-MDSC有望通过免疫调节来预防移植排斥。
Aim and objectiveEfficient 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.MethodsWe 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.ResultsIFN-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.ConclusionsWe 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.