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世界生命科学前沿动态周报（八十四）
科技日报：干细胞技术能够帮助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月第一期分别发表了两篇文献，报告了使用干细胞技术成功再生出了病人的免疫细胞，被大量制造出的这些细胞寿命很长且可以识别特异性靶细胞：艾滋病毒感染细胞和癌细胞。
该结果可能帮助找到对策从而还原（rejuvenate）患者衰竭的免疫系统。
研究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。然后扩增这些iPSCs并使他们重新分化为T细胞。新生成的T细胞被还原（rejuvenate）后生长潜能提高、寿命延长，且仍然具有最初的识别癌症和艾滋病感染靶细胞的能力。这意味着用iPSCs技术调控T细胞可能帮助将来建立更有效的免疫疗法。
其中一个研究使用的T细胞是从艾滋病感染患者体内获得的。再生出的这些重新分化的细胞具有无限的寿命，且其染色体两端的端粒酶（或称“帽”）很长，保持细胞不衰老。这一点很有价值，因为普通的T细胞衰老都会限制其扩增，导致免疫疗效不佳。来自东京大学的资深作者Dr. Hiromitsu Nakauchi说“我们建立的体系能够为抗艾滋病和癌症的免疫疗法‘提供年轻活跃的’T细胞。”
另一个研究团队研究的是恶性黑色素瘤患者体内获得的T细胞。他们制造出的重新分化细胞识别了黑色素瘤普遍表达的蛋白MART-1。来自RIKEN变态反应及免疫学研究中心的资深作者Dr. Hiroshi Kawamoto说 “下一步我们计划检验这些再生的T细胞是否可以选择性杀死肿瘤细胞而不伤害其他健康组织。如果能够生成这类细胞，他们将被直接应用于患者。”“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，两者虽然基因组相同，但形态与功能截然不同。
点评: 用山中申弥使用的方法获得的iPSCs并重新分化的T细胞，尽管是源自病人体内，实质是基因改造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本质差别，因此关于其在选择性杀死肿瘤细胞而不伤害其他健康组织方面的目标难以预测，直接应用于患者的可能性不大。
相关文献：
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.
