载体介导的人MHC-I向肝细胞的递送使得能够在小鼠和猕猴细胞培养物中研究TCR重定向的HBV特异性T细胞。

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Human gene therapy Pub Date : 2023-12-01 Epub Date: 2023-12-05 DOI:10.1089/hum.2023.035
Julia Festag, Marvin M Festag, Theresa Asen, Jochen M Wettengel, Martin A Mück-Häusl, Shaheed Abdulhaqq, Christiane Stahl-Hennig, Jonah B Sacha, Benjamin J Burwitz, Ulrike Protzer, Karin Wisskirchen
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引用次数: 0

摘要

使用天然T细胞受体(TCR)重定向的过继性T细胞治疗是对抗肝脏和其他器官实体癌和病毒感染的一种很有前途的方法。然而,到目前为止,这种TCR+-T细胞的临床疗效是有限的。一个原因是缺乏评估TCR+-T细胞安全性和有效性的同基因临床前模型。因此,我们开发了一种有效的病毒载体策略,介导人MHC-I在肝细胞中的表达,这使得能够评估针对患病肝细胞的TCR-T细胞疗法。我们设计了腺相关病毒(AAV)和腺病毒载体,它们编码人-小鼠嵌合HLA-A*02样分子HHD,或全人类HLA-A*01和人类2微球蛋白(h2m)。在转导小鼠肝细胞后,HLA-A*02构建体在表达水平、内源性加工肽的呈递和移植有HLA-A*02-限制性、乙型肝炎病毒(HBV)特异性TCR的小鼠TCR+-T细胞的活化方面被证明是优越的。在体内,这些T细胞引发效应器功能,控制HBV复制,降低HBV病毒载量和抗原表达,特别是在接受AAV-HBV和AAV-HLA-A*02的小鼠肝脏中。然后,我们通过在猕猴原代T细胞上表达HBV特异性TCRs来证明这种方法的实用性,使其能够在腺病毒转导时识别表达HLA-A*02的HBV感染的猕猴肝细胞。总之,AAV和腺病毒载体适合于递送HLA-A*02和h2m进入小鼠和猕猴肝细胞。当在HLA-A*02转导的小鼠肝脏或猕猴肝细胞上识别HBV时,HLA-A*01受到限制,HBV特异性TCR+-T细胞被激活并发挥抗病毒效应。这种方法适用于其他MHC限制和靶向疾病,为在生理相关的临床前动物模型中进行基于人类TCR的治疗的安全性和有效性研究铺平了道路。
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Vector-Mediated Delivery of Human Major Histocompatibility Complex-I into Hepatocytes Enables Investigation of T Cell Receptor-Redirected Hepatitis B Virus-Specific T Cells in Mice, and in Macaque Cell Cultures.

Adoptive T cell therapy using natural T cell receptor (TCR) redirection is a promising approach to fight solid cancers and viral infections in liver and other organs. However, clinical efficacy of such TCR+-T cells has been limited so far. One reason is that syngeneic preclinical models to evaluate safety and efficacy of TCR+-T cells are missing. We, therefore, developed an efficient viral vector strategy mediating expression of human major histocompatibility complex (MHC)-I in hepatocytes, which allows evaluation of TCR-T cell therapies targeting diseased liver cells. We designed adeno-associated virus (AAV) and adenoviral vectors encoding either the human-mouse chimeric HLA-A*02-like molecule, or fully human HLA-A*02 and human β2 microglobulin (hβ2m). Upon transduction of murine hepatocytes, the HLA-A*02 construct proved superior in terms of expression levels, presentation of endogenously processed peptides and activation of murine TCR+-T cells grafted with HLA-A*02-restricted, hepatitis B virus (HBV)-specific TCRs. In vivo, these T cells elicited effector function, controlled HBV replication, and reduced HBV viral load and antigen expression in livers of those mice that had received AAV-HBV and AAV-HLA-A*02. We then demonstrated the broad utility of this approach by grafting macaque T cells with the HBV-specific TCRs and enabling them to recognize HBV-infected primary macaque hepatocytes expressing HLA-A*02 upon adenoviral transduction. In conclusion, AAV and adenovirus vectors are suitable for delivery of HLA-A*02 and hβ2m into mouse and macaque hepatocytes. When recognizing their cognate antigen in HLA-A*02-transduced mouse livers or on isolated macaque hepatocytes, HLA-A*02-restricted, HBV-specific TCR+-T cells become activated and exert antiviral effector functions. This approach is applicable to any MHC restriction and target disease, paving the way for safety and efficacy studies of human TCR-based therapies in physiologically relevant preclinical animal models.

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来源期刊
Human gene therapy
Human gene therapy 医学-生物工程与应用微生物
CiteScore
6.50
自引率
4.80%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.
期刊最新文献
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