(图片来源:Proceedings of the National Academy of Sciences)
近日一篇发表在美国国家科学院院刊(Proceedings of the National Academy of Sciences)的文章称,研究者通过基因工程技术研制出了可产生特异性抗肿瘤人类T淋巴细胞的小鼠模型,该模型或可成为人类肿瘤研究的重要方法。
有研究证明经基因修饰的T细胞受体(TCR)可识别并攻击特定的肿瘤细胞,但其过程较为复杂且无法产生稳定并具有自我更新能力的T细胞。因此本文的研究者制造出了可在其体内产生特异性抗黑素瘤的人类T淋巴细胞的小鼠模型,该T细胞由经过基因修饰的人类造血干细胞发展而来。
此前有人制造了可产生HIV特异性T细胞模型,但由于该模型无法完全重建人类细胞而导致其结果无法在体内进行检测。研究者于是对该模型进行了改进,他们通过将一个有功能的人类胸腺和经黑素瘤特异性TCR转导的人类造血祖细胞结合在一起修复了该缺陷。
随后研究者以黑素瘤为检测对象进行检测,结果发现大多数小鼠体内的肿瘤都得到了清除,或者体积缩小。而且,这些转导的人类细胞在移植4个月后仍可以检测到,表明该干细胞的重建一旦启动便可长期存在。
该研究表明,将人类造血祖细胞使用基因工程的方法进行修饰,或许可以成为人类对抗慢性疾病如肿瘤的新武器。(生物谷bioon.com)
doi:10.1073/pnas.1115050108
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Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells
Dimitrios N. Vatakis, Richard C. Koya, Christopher C. Nixon,Liu Wei, Sohn G. Kim, Patricia Avancena, Gregory Bristol,David Baltimore, Donald B. Kohn , Antoni Ribas,Caius G. Radu, Zoran Galic, and Jerome A. Zack.
The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves the use of high-affinity cancer-specific T-cell receptors in gene-therapy protocols. Here, we present the generation of functional tumor-specific human T cells in vivo from genetically modified human hematopoietic stem cells (hHSC) using a human/mouse chimera model. Transduced hHSC expressing an HLA-A*0201-restricted melanoma-specific T-cell receptor were introduced into humanized mice, resulting in the generation of a sizeable melanoma-specific na?ve CD8+ T-cell population. Following tumor challenge, these transgenic CD8+ T cells, in the absence of additional manipulation, limited and cleared human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non-HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the transduced hHSC established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.