基于白介素21的细胞治疗促进乙型肝炎病毒持续性感染清除的机制及应用研究

乙型肝炎病毒(HBV)慢性感染可进展为肝纤维化、肝硬化以至肝癌，现有临床治疗手段难以实现病毒清除、特别是病毒cccDNA的清除。申请人在前期工作中发现白介素21(IL-21)通过诱生、激活特异性CD8+ T细胞反应，有效促进HBV慢性化小鼠清除病毒，特别是清除肝内HBV DNA（包括cccDNA类似物rcccDNA）。更为重要的是，HBV慢性化小鼠脾细胞在体外经IL-21和HBV表面抗原刺激后注射入HBV慢性化小鼠，可促进小鼠清除病毒，显示基于IL-21的细胞治疗方法在小鼠模型中的有效性。本项目在上述工作基础上，深入研究HBV慢性化小鼠模型中基于IL-21的细胞治疗有效性的细胞及分子机制，并根据机制研究结果对于治疗方案进行优化改进；同时，利用慢性乙型肝炎患者来源的外周血单核细胞验证小鼠模型获得的结果，确定基于IL-21的细胞治疗作为人类HBV慢性感染干预手段的潜在应用价值。

Chronic infection by hepatitis B virus (HBV) can progress onto liver fibrosis, cirrhosis and hepatocellular carcinoma. Current treatments for chronic HBV infection do not induce viral clearance efficiently, especially clearance of viral cccDNA. In prior work, we found that interleukin 21 (IL-21), through the induction and/or activation of specific CD8+ T cell responses, efficiently promotes viral clearance in mice harboring persisting HBV replicons, including clearance of intrahepatic HBV DNA like cccDNA-mimic rcccDNA. More importantly, splenocytes from HBV persistence mice treated in vitro with IL-21 and HBV surface antigen were able to induce HBV clearance after infusion into HBV persistence mice, proving the effectiveness of IL-21-based cellular therapy in mouse model. Based on these findings, this project will probe the cellular and molecular mechanisms underlying the effectiveness of IL-21-based cellular therapy in mice, and improve the therapy protocol accordingly. In the meantime, this project will use peripheral blood mononuclear cells to test results obtained in mouse model and establish the potential usefulness of IL-21-based cellular therapy for treating human chronic HBV infecitons.