T细胞受体移植允许病毒学控制乙型肝炎病毒感染

StephenW

T cell receptor grafting allows virological control of hepatitis B virus infection
Karin Wisskirchen,1,2,3 Janine Kah,3,4 Antje Malo,1 Theresa Asen,1 Tassilo Volz,4 Lena Allweiss,4 Jochen M. Wettengel,2 Marc Lütgehetmann,3,5 Stephan Urban,3,6 Tanja Bauer,1,2,3 Maura Dandri,3,4 and Ulrike Protzer1,2,3

First published April 30, 2019 - More info

    Abstract

    T cell therapy is a promising means to treat chronic hepatitis B virus (HBV) infection and HBV-associated hepatocellular carcinoma. T cells engineered to express an HBV-specific T cell receptor (TCR) may cure an HBV infection upon adoptive transfer. We investigated the therapeutic potential and safety of T cells stably expressing high-affinity HBV envelope– or core–specific TCRs recognizing European and Asian HLA-A2 subtypes. Both CD8+ and CD4+ T cells from healthy donors and patients with chronic hepatitis B became polyfunctional effector cells when grafted with HBV-specific TCRs and eliminated HBV from infected HepG2-NTCP cell cultures. A single transfer of TCR-grafted T cells into HBV-infected, humanized mice controlled HBV infection, and virological markers declined by 4 to 5 log or below the detection limit. Engineered T cells specifically cleared infected hepatocytes without damaging noninfected cells when, as in a typical clinical setting, only a minority of hepatocytes were infected. Cell death was compensated by hepatocyte proliferation, and alanine amino transferase levels peaking between days 5 and 7 normalized again thereafter. Cotreatment with the entry inhibitor myrcludex B ensured long-term control of HBV infection. Thus, T cells stably transduced with highly functional TCRs have the potential to mediate clearance of HBV-infected cells, causing limited liver injury.

StephenW

T细胞受体移植允许病毒学控制乙型肝炎病毒感染
Karin Wisskirchen，1,2,3 Janine Kah，3,4 Antje Malo，1 Theresa Asen，1 Tassilo Volz，4 Lena Allweiss，4 Jochen M. Wettengel，2MarcLütgehetmann，3,5 Stephan Urban，3,6 Tanja Bauer ，1,2,3 Maura Dandri，3,4和Ulrike Protzer1,2,3

首次发布于2019年4月30日 - 更多信息

抽象

T细胞疗法是治疗慢性乙型肝炎病毒（HBV）感染和HBV相关肝细胞癌的有希望的手段。经过工程改造以表达HBV特异性T细胞受体（TCR）的T细胞可在过继转移时治愈HBV感染。识别高亲和力HBV包膜或核心特异性TCR识别欧洲和亚洲HLA-A2亚型的T细胞应答的治疗潜力和安全性。当用HBV特异性TCR移植并从感染的HepG2-NTCP细胞培养物中消除HBV时，来自健康供体和慢性乙型肝炎患者的CD8 +和CD4 + T细胞都成为多功能效应细胞。将TCR移植的T细胞单次转移到HBV感染的人源化小鼠中控制HBV感染，并且病毒学标志物下降4至5log或低于检测限。当在典型的临床环境中仅有少数肝细胞被肝细胞增殖补偿时，工程化T细胞特异性地清除受感染的肝细胞而不损害未感染的细胞，并且在第5天和第7天之间达到峰值的丙氨酸氨基转移酶水平再次归一化。用进入抑制剂myrcludex B进行共同治疗可确保长期控制HBV感染。因此，用高功能性TCR转导的T细胞信念具有介导HBV感染细胞清除的潜力，导致有限的肝损伤。

StephenW

https://www.jci.org/articles/vie ... %2C+issue+published