基于组学研究三氧化二砷抑制 T 细胞介导的同种异体器官移植免疫排斥作用机制

The Development of new immunosuppressant for organ transplantation is the main research direction for the past few years. To synthesis any new types of drug require extensively long terms of research and clinical trials. Thus, to utilize already existed and in used clinical substance is the best of choice. The paradox of the Chinese medicine in respect of their mechanism in clinical still remained largely unraveled. One of the well-known market available immunosuppressant that extracted from Chinese Medicine is arsenic trioxide. Arsenic trioxide has been used as anticancer drugs since 19th century. Lately, our preliminary studies have demonstrated that arsenic trioxide can effectively inhibits T-cell-mediated immune rejection, both were found in animal heart transplants and islet allograft transplantation model in mice, as well as a series of in vitro experiments. However, the mechanism in orchestrating such negative immune response after organ transplantation still demanding a broad collection of experimental data. The mission of this research project is to demonstrate and define the mechanism that how did arsenic trioxide has been involved in immune response after organ or tissue transplantation. The experiments will be conducted under both in vivo and in vitro models, which will maximally mimic and present the signaling pathways that arsenic trioxide participated. Samples will be analysed from different perspectives, such as transcriptome, metabolome and proteome. The focus of this project will lies on the effect of arsenic trioxide on the immune responsive cells, particularly on T lymphocyte subsets. Experiments are designed to clarify the role of arsenic trioxide targeted protein and signaling pathways, predict and test the mechanisms of its participation in organ allograft rejection. Our vision in this research is to use arsenic trioxide, as the new immunosuppressant, to develop immune tolerance inducible drug for the clinical application in the soon future. As the leading arsenic trioxide focused research group, we are strived for the protection and promotion of the Chinese medical resources, and provide further theoretical support in respect of the development of new immunosuppressive agents.

开发新型免疫抑制剂对于器官移植具有重要的意义。在前期研究已证实三氧化二砷可抑制T细胞介导的免疫排斥反应基础上，借助同种异体小鼠的心脏移植和胰岛移植模型以及一系列的体外实验，结合转录组、代谢组、蛋白质组等组学方法，系统研究三氧化二砷对T淋巴细胞主要亚群的作用，阐明三氧化二砷发挥作用的靶蛋白和信号通路，明确其参与器官移植免疫排斥的作用机制。在此基础上，结合本课题组在免疫抑制剂方面的研究基础，研发基于三氧化二砷的免疫耐受诱导策略，诱导同种异体心脏移植和胰岛移植免疫耐受。争取促进中医药资源的保护及深度开发，并为新型免疫抑制剂开发提供进一步的理论支持。

开发新型免疫抑制剂对于器官移植具有重要的意义。在前期研究已证实三氧化二砷可抑制T细胞介导的免疫排斥反应基础上，本项目旨在系统研究三氧化二砷对T淋巴细胞免疫抑制作用，明确其参与器官移植免疫排斥的作用机制。通过四年的研究，本课题组借助转录组学、蛋白质组学等组学技术以及同种异体心脏移植和自身免疫病模型，系统研究了三氧化二砷对T淋巴细胞主要亚群的作用机制，并根据三氧化二砷通过诱导凋亡来抑制T淋巴细胞作用的机制，探索了用三氧化二砷和供体脾细胞输注来诱导同种异体器官移植免疫耐受的可行性。截止目前，项目共培养研究生9名，已发表SCI论文10篇、中文核心1篇，此外有2篇文章待发表，相关成果为将三氧化二砷开发为新型的免疫抑制剂提供了进一步的理论支持。