NKT细胞经由CD1d和TLR调控活化在雷公藤甲素肝毒性中的作用机制研究

雷公藤制剂在自身免疫性疾病的治疗中具有出色疗效，但其肝毒性极大地限制了其临床应用，且毒性作用机制尚未阐明。雷公藤甲素（TP）为雷公藤的主要活性成分和毒性成分，本项目前期研究发现小鼠TP肝毒性模型中，NKT细胞高度活化。NKT细胞连接天然免疫和适应性免疫，在药源性肝损伤中发挥着重要的作用。由此提出假设：NKT细胞通过CD1d的直接活化和Toll样受体（TLR）的间接活化参与了TP诱导肝损伤。本项目应用Crispr/Cas9、CD1d缺陷小鼠和TLR敲除小鼠等寻找TP肝损伤的新靶点，通过NKT细胞特异性活化剂α-GalCer、清除及过继转输NKT细胞等影响TP肝毒性，探索TP肝损伤的免疫治疗新手段。最终为雷公藤制剂肝毒性的临床防治提供实验依据。

Tripterygium wilfordii preparations have excellent efficacy in treatment of autoimmune diseases. However, their hepatotoxicity greatly limits the clinical application and the mechanisms of hepatotoxicity have not been clarified. Triptolide (TP) is the main active ingredient and toxic component of Tripterygium wilfordii. Results of this study showed that NKT cells were highly activated in mouse model of TP-induced hepatotoxicity. NKT cells link the innate and adaptive immunity and plays an important role in drug-induced Liver injury. Therefore, we hypothesized that NKT cells were involved in TP-induced liver injury through direct activation of CD1d and indirect activation of Toll-like receptor (TLR). In order to investigate the novel target of TP-induced liver injury, we used Crispr/Cas9, CD1d-deficient mice and TLR knockout mice. By using NKT cell specific agonist α-GalCer, depletion and adoptive transfer of NKT cells, we explore the innovative immune treatment plan targeting NKT cells. Our studies would provide experimental basis for the clinical prevention and therapy of Tripterygium wilfordii preparation-induced hepatotoxicity.