PD-1在TDO-Kyn-AhR通路诱导肝脏移植免疫耐受中的作用

移植肝脏免疫特惠现象机制仍待研究。前期研究发现：只在肝细胞表达的色氨酸（Try）分解代谢限速酶色氨酸-2,3-双加氧酶（TDO）的激活可造成大鼠移植肝内高犬尿氨酸（Kyn）微环境，Kyn与芳香烃受体（AhR）结合调控T细胞的活性与分化，最终诱导免疫耐受；抑制TDO活性则加重排斥反应。新据 Cancer Cell 报道，肿瘤组织中高Kyn微环境可激活T细胞内AhR，上调PD-1表达，促进CD8+T细胞凋亡，Foxp3+Treg细胞增生，产生免疫逃逸。据此推测：PD-1是Kyn-AhR通路下游调控T细胞活性与分化的关键靶点，在TDO-Kyn-AhR通路诱导的移植肝免疫耐受中发挥重要作用。本研究将采用生物信息学预测、测序、免疫荧光、病毒转染等分子生物学技术，构建免疫排斥和耐受大鼠肝移植模型，结合临床标本，验证上述科学设想，为更深入阐明移植肝脏免疫特惠机制和明确治疗靶点提供理论依据。

The phenomenon of immune preference in liver allograft remains to be studied. Previous studies showed that tryptophan (Try) catabolic rate-limiting enzyme tryptophan -2, 3-dioxygenase (TDO) is only expressed in hepatocytes，of which the activation could induce a high Kyn microenvironment in rat liver allograft，and the combination of Kyn and AhR could regulate the activity and differentiation of T cells and ultimately induce immune tolerance. Inhibition of TDO activity aggravates immune rejection. As reported by Cancer Cell, high Kyn microenvironment in tumor tissues can activate AhR in T cells and then upregulate PD-1 expression, promoting CD8+T apoptosis, Foxp3+Treg proliferation, and thus generating immune escape. We speculate that PD-1 is a key target for the downstream regulation of T cell activity and differentiation and plays an important role in the immune tolerance of liver allograft induced by the TDO-Kyn-AhR signal pathway. In this study, techniques including bioinformatics prediction, ChIP-seq, immunofluorescence, virus transfection will be used to verify the above scientific assumptions, combined with constructing immune rejection and tolerance rat liver transplantation models and collecting clinical samples, so as to provide a theoretical basis for further clarifying the immune preference mechanism of liver allograft, and further developing the therapeutic targets.