Tfh细胞-IL21-B细胞轴在慢性乙型肝炎HBeAg血清学转换中的作用及补肾方的干预机制

项目名称： Tfh细胞-IL21-B细胞轴在慢性乙型肝炎HBeAg血清学转换中的作用及补肾方的干预机制

项目编号： No.81473477

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李曼

作者单位： 上海中医药大学

项目金额： 73万元

中文摘要： 乙肝e抗原（eAg）血清转换是慢乙肝（CHB）免疫控制标志。前期RCT研究证实,补肾方（BSR）提高CHB患者eAg阴转率,且eAg血清转换者外周血CXCR5+CD4+Tfh细胞和B细胞频数高于未转换者,提示Tfh是eAg血清转换关键。BCL-6/Blimp-1是Tfh分化的一对相互拮抗的转录因子,高表达BCL-6促进Tfh分化,Tfh表达IL21促进B细胞分泌HBeAb。据此提出假说,BSR通过上调eAg+患者外周血CD4+T细胞BCL-6、下调Blimp-1,促进自身分化为Tfh并表达IL21,活化B细胞分泌HBeAb,提高血清转换率。拟通过临床RCT研究和体外实验探索BSR促进eAg血清转换与BCL-6/Blimp-1平衡和Tfh-IL21-B细胞轴分子表达的内在关系,应用HBV持续感染小鼠模型进一步证实BSR及拆方促进eAg血清转换机制,阐明BSR调节免疫治疗CHB关键靶点。

中文关键词： HBeAg血清学转换；滤泡性辅助性；T细胞；白介素21；B细胞；补肾方

英文摘要： HBeAg seroconversion is the marker of immune control in chronic hepatitis B patients. In previous RCT researches, we found that the HBeAg seroconversion rate was increased after patients were administrated with Bushen Recipe, and the percentages of CXCR5+CD4+Tfh cells and B cells in peripheral blood in patients who achieved HBeAg seroconversion were higher than those in patients who did not achieve HBeAg seroconversion, which suggested that Tfh cell played the key role in HBeAg seroconversion. Bcl-6 and Blimp-1 are a couple of transcription factors of controling the differentiation of Tfh cells, and they are antagonistic to each other.The high expression of Bcl-6 promotes the differentiation of Tfh cells, and IL21 expressed by Tfh cells promotes to the production of HBeAb by B cells. Therefore, the research hepothesis is proposed that when HBeAg positive patients were administrated with Bushen Recipe, the expression of Bcl-6 in CD4+ cells of peripheral blood is upregulated and the expression of Blimp-1 is reduced, which promotes CD4+T cells to defferentiate into Tfh cells, and then IL21 expressed by Tfh cells activates B cells ,and finally HBeAb is secreted. In this study, the relationship between HBeAg seroconversion induced by BSR treatment an the balance of Bcl-6/Blimp-1 and the axis of Tfh cell-IL21-B cell will be explored through the clinial RCT research and in vitro experiments, and the mechanism of HBeAg seroconversion induced by BSR and its herbs treatment will be further confirmed in mouse model of chronic HBV infection,which will illuminate the key targets of immunoregulatory mechanism of Bushen Recipe in chronic hepatitis B patients.

英文关键词： HBeAg seroconversion;follicular helper T cells;IL21;B cell;Bushen Recipe