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世界性命科学前沿动态周报（八十四）
科技日报：干细胞技术可能援手利用病人的自身免疫细胞抵抗疾病
内容概述：
《细胞 干细胞》杂志2013年1月第一期别离颁发了两篇文件，汇报了使用干细胞技术成功再生出了病人的免疫细胞，被大量造作出的这些细胞寿命很长且能够鉴别特异性靶细胞：艾滋病毒习染细胞和癌细胞。
该了局可能援手找到对策从而还原（rejuvenate）患者衰竭的免疫系统。
钻研团队使用的技术引用了已知的因子（山中申弥使用的因子）将成熟的免疫T细胞转化为iPSCs。而后扩增这些iPSCs并使他们沉新分化为T细胞。新天生的T细胞被还原（rejuvenate）后成长潜能提高、寿命耽搁，且依然拥有最初的鉴别癌症和艾滋病习染靶细胞的能力。这意味着用iPSCs技术调控T细胞可能援手将来成立更有效的免疫疗法。
其中一个钻研使用的T细胞是从艾滋病习染患者体内获得的。再生出的这些沉新分化的细胞拥有无限的寿命，且其染色体两端的端粒酶（或称“帽”）很长，维持细胞不衰老。这一点很有价值，由于通常的T细胞衰老城市限度其扩增，导致免疫疗效欠安。来自东京大学的资深作者Dr. Hiromitsu Nakauchi说“我们成立的系统可能为抗艾滋病和癌症的免疫疗法‘提供年轻活跃的’T细胞。”
另一个钻研团队钻研的是恶性玄色素瘤患者体内获得的T细胞。他们造作出的沉新分化细胞鉴别了玄色素瘤普遍表白的蛋白MART-1。来自RIKEN畸形反映及免疫学钻研中心的资深作者Dr. Hiroshi Kawamoto说 “下一步我们打算检验这些再生的T细胞是否能够选择性杀死肿瘤细胞而不中伤其他健全组织。若是可能天生这类细胞，他们将被直接利用于患者。”“这在不久的将来可能会被实现。”
图：图中显示的是T-iPSCs分化产生的被还原的（rejuvenated）T细胞，两者固然基因组一样，但状态与职能截然分歧。
点评: 用山中申弥使用的步骤获得的iPSCs并沉新分化的T细胞，只管是源自病人体内，内容是基因刷新产生的新物种癌性细胞，与真正的多能干细胞及其分化的体细胞有性质差距，因而关于其在选择性杀死肿瘤细胞而不中伤其他健全组织方面的指标难以预测，直接利用于患者的可能性不大。
有关文件：
1. Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells
Cell Stem Cell, Volume 12, Issue 1, 31-36, 3 January 2013. 10.1016/j.stem.2012.12.006
Authors
Raul Vizcardo, Kyoko Masuda, Daisuke Yamada, Tomokatsu Ikawa, Kanako Shimizu, Shin-ichiro Fujii, Haruhiko Koseki, Hiroshi Kawamoto
Highlights
► iPSCs generated from T cells specific for the MART-1 melanoma epitope ► Differentiation of iPSCs into T cells with a MART-1 specific T cell receptor ► MART-1-based stimulation of T cells demonstrates retained antigen specificity
Summary
Antigen-specific T cells represent a potential therapeutic avenue for a variety of conditions, but current approaches for generating such cells for therapeutic purposes are limited. In this study, we established iPSCs from mature cytotoxic T cells specific for the melanoma epitope MART-1. When cocultured with OP9/DLL1 cells, these iPSCs efficiently generated TCRβ+CD4+CD8+ double positive (DP) cells expressing a T cell receptor (TCR) specific for the MART-1 epitope. Stimulation of these DP cells with anti-CD3 antibody generated a large number of CD8+ T cells, and more than 90% of the resulting cells were specific for the original MART-1 epitope. Stimulation of the CD8+ T cells with MART-1 antigen-presenting cells led to the secretion of IFN , demonstrating their specific reactivity. The present study therefore illustrates an approach for cloning and expanding functional antigen-specific CD8+ T cells that might be applicable in cell-based therapy of cancer.
2 Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation
Cell Stem Cell, Volume 12, Issue 1, 114-126, 3 January 2013. 10.1016/j.stem.2012.11.002
Authors
Toshinobu Nishimura, Shin Kaneko , Ai Kawana-Tachikawa, Yoko Tajima, Haruo Goto, Dayong Zhu, Kaori Nakayama-Hosoya, Shoichi Iriguchi, Yasushi Uemura, Takafumi Shimizu, Naoya Takayama, Daisuke Yamada, Ken Nishimura, Manami Ohtaka, Nobukazu Watanabe, Satoshi Takahashi, Aikichi Iwamoto, Haruhiko Koseki, Mahito Nakanishi, Koji Eto, Hiromitsu Nakauchi
Highlights
► Reprogramming of antigen-specific T cells to generate iPSCs (T-iPSCs) ► Redifferentiation of CD8+ T cells, with original antigen specificity, from T-iPSCs ► Newly differentiated T cells show high proliferation and elongated telomeres ► T cell antigen-specific cytotoxicity is maintained
Summary
Adoptive immunotherapy with functional T cells is potentially an effective therapeutic strategy for combating many types of cancer and viral infection. However, exhaustion of antigen-specific T cells represents a major challenge to this type of approach. In an effort to overcome this problem, we reprogrammed clonally expanded antigen-specific CD8+ T cells from an HIV-1-infected patient to pluripotency. The T cell-derived induced pluripotent stem cells were then redifferentiated into CD8+ T cells that had a high proliferative capacity and elongated telomeres. These rejuvenated cells possessed antigen-specific killing activity and exhibited T cell receptor gene-rearrangement patterns identical to those of the original T cell clone from the patient. We also found that this method can be effective for generating specific T cells for other pathology-associated antigens. Thus, this type of approach may have broad applications in the field of adoptive immunotherapy.
