mTOR通路在系统性红斑狼疮发病机制及治疗中的作用研究

Systemic lupus erythematosus (SLE) is a T-cell-mediated autoimmune disease,characterized by a variety of autoantibodies and multiple organs Involvement. It has been demonstrated that the activation of mammalian rapamycin target protein (mTOR) is involved in the regulation of T cell differentiation in peripheral blood T cells of SLE patients. As the mTORC1 inhibitor, Rapamycin plays a therapeutic role by inhibiting Th17 differentiation, DN cell necrosis, IL-4 production, and upregulating Treg. There are still few studies for the effect of the two mTOR pathways’ activation on the T cell differentiation of SLE patients, and the evidence on effect of rapamycin on mTORC2, another important molecule, is also lacking. Here we systematically analyze the expression of pmTOR pathway molecules in different T cell subtypes in SLE patients, and evaluate the effect of different doses of rapamycin on the two mTOR pathways in vitro. In addition, mTORC1 and mTORC2 knockout mice are induced to experimental lupus by pristane, and the role of two mTOR pathways in SLE are explored. The therapeutic effect and the mechanism of different doses of rapamycin on lupus mice are analyzed. In this study, new mechanism of two mTOR pathways in SLE is explored, which provide evidence for mTOR inhibitors in SLE treatment.

系统性红斑狼疮（SLE）是以T 细胞介导的多种自身抗体阳性、累及全身多器官为特征的全身性自身免疫病。已证实患者外周血T细胞哺乳动物雷帕霉素靶蛋白（mTOR）活化参与T细胞分化调控。雷帕霉素作为mTORC1抑制剂，可抑制Th17分化，抑制DN细胞坏死及IL-4产生，上调Treg发挥治疗作用。目前SLE患者不同T细胞亚型中两种mTOR通路活化情况缺乏系统报道，雷帕霉素对另一重要分子mTORC2的作用机制也缺乏证据。本项目系统分析SLE患者外周血不同T细胞亚型的mTOR表达，体外评价不同剂量雷帕霉素对两条mTOR通路的作用，并利用mTORC1和mTORC2基因敲除小鼠构建狼疮鼠模型，进一步证实两种mTOR通路在SLE发病的作用，阐明不同剂量雷帕霉素对狼疮鼠的治疗作用及机制。从分子、细胞、动物和患者等不同方面阐明mTOR通路在SLE发病中的新机制，为mTOR抑制剂用于SLE治疗提供准确科学的数据。

本项目的主要目标是分析mTOR通路在SLE及SS患者T细胞亚型调控中的作用，研究mTORC1抑制剂雷帕霉素对SLE和SS小鼠模型的治疗作用及机制。研究结果证实了雷帕霉素可以抑制SLE小鼠肺泡出血和SS小鼠唾液腺淋巴细胞浸润，改善SS患者疾病活动度评分。在动物实验中证实，雷帕霉素可以上调脾和淋巴结Treg水平，下调Tfh、Th1、Th2和Th17，从而发挥T细胞调控作用。本项目为mTOR抑制剂用于SLE和SS治疗提供了试验依据。但在SS患者外周血中，发现Treg细胞水平下调，而Treg中mTORC1活性也存在下调，雷帕霉素是否通过直接抑制mTORC1发挥Treg调控功能还需进一步研究证实。