肠道CD4+T淋巴细胞在非酒精性脂肪性肝炎致病过程中的作用的研究

The mechanism of nonalcoholic steatohepatitis is still not well charified .Most researches focused on the change of liver immune wheareas few study was about intestine immune.It has been reported the infiltration of intestinal lymphocytes in the liver of PSC patients.Our previous data also showed that the CD4+T lymphocyte increased in the liver and the mesenteric lymphocytes of high-fat diet induced obese mice could selectively migrate into liver and result in the increase of transaminase .Therefore this project aims to clarify the role of intestinal CD4+T lymphocyte migration into liver through(1)the activation and subset of intestinal CD4+ T lymphocyte in NAFLD mice and its mechanism;(2)the role and mechanism of the migration of intestinal CD4+ T lymphocyte in NASH onset and progression.This project aims to find new mechanism of NASH by studying the interaction of liver immune and intestine immune and provide a new possibility in the treatment of NASH.

非酒精性脂肪性肝炎（NASH）的发生机制目前尚未完全阐明。大部分的研究局限于肝脏免疫的变化，而对于肠道免疫的变化研究甚少。既往的研究提示了原发性硬化性胆管炎患者的肝脏中有肠道来源的淋巴细胞，我们的预实验提示了在非酒精性脂肪肝小鼠肝脏中CD4+T淋巴细胞增多，肠道淋巴细胞会向肝脏迁移并导致转氨酶升高。因此本研究拟以CD4+T淋巴细胞为重点进行更深入的探讨，采用非酒精性脂肪肝（NAFLD）小鼠模型，通过以下两方面探讨NAFLD小鼠肠系膜淋巴结（MLN）中CD4+T淋巴细胞向肝脏迁移的机制及对NASH进展的影响：（1）NAFLD小鼠肠系膜淋巴结（MLN）中CD4+T淋巴细胞活性及亚群的变化及机制；（2）NAFLD小鼠MLN中CD4+T淋巴细胞迁移到肝脏后产生肝损伤的机制对NASH进展的影响。本研究通过探讨肠肝免疫对话来探寻NASH发生发展的新机制，也为非酒精性脂肪肝的治疗寻找新的方向。

非酒精性脂肪肝（NAFLD）发病机制至今尚未阐明，肠肝对话可能在其中发挥了重要作用，目前已知在NAFLD背景下存在肠道菌群失调及肠粘膜屏障受损，但它们对肝脏的影响尚不清楚。本研究中我们通过动物实验及细胞培养实验探讨了肠系膜淋巴细胞中CD4+T淋巴细胞在NAFLD发病中的作用及其机制。C57BL小鼠喂以高脂饮食12周构建NAFLD模型，结果显示肠系膜淋巴结及肝脏淋巴细胞中CD4+T细胞的Th1/Th2比例以及Th17/Treg比例失衡，回输试验提示高脂饮食小鼠的肠系膜中CD4+T淋巴细胞较正常小鼠更易向肝脏中迁移，并且会造成肝脏转氨酶升高，肝脏脂肪变加重，炎性因子增加。给与NAFLD小鼠抗生素以及益生菌后能够重建Th1/Th2与Th17/Treg的正常比例，减轻肝脏脂肪变程度，炎性因子减少。上述结果提示了NAFLD小鼠肠系膜淋巴结中CD4+T淋巴细胞各亚群比例失衡，可能在NALFD疾病进展过程中发挥了重要作用。