TDO调节芳烃受体通路对诱导移植肝脏低免疫应答的影响及机制研究

移植肝脏免疫特惠现象机制仍待研究。已知色氨酸（Try）分解代谢与免疫应答密切相关。我们前期研究发现大鼠移植肝Try分解代谢限速酶色氨酸-2,3-双加氧酶（TDO）表达与移植排斥反应程度相关，使肝细胞高表达TDO可抑制细胞毒性T细胞增殖；且加用Try分解代谢产物犬尿氨酸（Kyn）的衍生物可显著减轻大鼠肝移植排斥反应，大幅减少环孢霉素应用剂量。新据Nature报道 Kyn 与芳烃受体（AhR）结合参与肿瘤免疫逃逸。由此推测，作为仅在肝细胞内表达的Try代谢酶，TDO参与移植肝免疫特惠，机制为调节Try代谢和Kyn产生，调控TDO-Kyn-AhR通路，致移植肝免疫低应答或无应答。我们拟采用CRISPR/Cas9技术构建TDO基因敲除大鼠肝移植模型，基因芯片分析Kyn-AhR调控T细胞增殖分化靶点，结合临床病理标本，研究并明确TDO在肝脏免疫特惠中的作用及分子机制，为开发致耐受新药提供理论依据。

The liver is known as an immunologically privileged organ in solid organ transplants. However, its mechanism is to be further understanding. Recently, it shows that the tryptophan metabolism take an important role in the induction of the womb immune tolerance and tumor immune-escape. Our preliminary study found that the expression of the tryptophan catabolism speed limit enzyme, Tryptophan 2,3-dioxygenase (TDO), is effected by reaction degree of the graft rejection in allogenic rat transplant liver tissue. The data also showed that this result was closely related to the inhibition of cell toxicity T lymphocyte proliferation. Moreover, we observed that applying a tryptophan metabolite, kynurenine (Kyn) derivant could alleviate the extent of graft rejection in rat liver transplantation model. A study in 2011 《NATURE》 firstly reported that Kyn is an endogenous ligand of aryl hydrocarbon receptor (AhR). The combination can activate aryl hydrocarbon receptor path to induce tumor immune escape. These indicate the existence of TDO - Kyn - AhR signal pathway. Therefore, we speculate that TDO which only express in hepatocytes participates in graft immune preference. The mechanism might be regulating tryptophan metabolism and kynurenine generation, control of TDO - Kyn - AhR pathway, suppressive of T cell proliferation and induction of Treg cells generation resulted in graft low immune response or immune tolerance. We propose to confirm our speculation by using TDO knockout rat as donor in liver transplantation model combined with human liver sample. This study is going to clarify the effects and its mechanism of TDO in inducing immune tolerance in liver transplantation. The results may help to better understanding of immune preferential phenomenon of liver graft, which probably bring new prospective for inducing clinical immune tolerance.