世界生命科學(xué)前沿動(dòng)態(tài)周報(bào)（八十四）

2013年-01月-03日來(lái)源：mebo

科技日?qǐng)?bào)：干細(xì)胞技術(shù)能夠幫助利用病人的自身免疫細(xì)胞抵抗疾病

內(nèi)容概述：
《細(xì)胞干細(xì)胞》雜志2013年1月第一期分別發(fā)表了兩篇文獻(xiàn)，報(bào)告了使用干細(xì)胞技術(shù)成功再生出了病人的免疫細(xì)胞，被大量制造出的這些細(xì)胞壽命很長(zhǎng)且可以識(shí)別特異性靶細(xì)胞：艾滋病毒感染細(xì)胞和癌細(xì)胞。

該結(jié)果可能幫助找到對(duì)策從而還原（rejuvenate）患者衰竭的免疫系統(tǒng)。

研究團(tuán)隊(duì)使用的技術(shù)引用了已知的因子（山中申彌使用的因子）將成熟的免疫T細(xì)胞轉(zhuǎn)化為iPSCs。然后擴(kuò)增這些iPSCs并使他們重新分化為T(mén)細(xì)胞。新生成的T細(xì)胞被還原（rejuvenate）后生長(zhǎng)潛能提高、壽命延長(zhǎng)，且仍然具有最初的識(shí)別癌癥和艾滋病感染靶細(xì)胞的能力。這意味著用iPSCs技術(shù)調(diào)控T細(xì)胞可能幫助將來(lái)建立更有效的免疫療法。

其中一個(gè)研究使用的T細(xì)胞是從艾滋病感染患者體內(nèi)獲得的。再生出的這些重新分化的細(xì)胞具有無(wú)限的壽命，且其染色體兩端的端粒酶（或稱“帽”）很長(zhǎng)，保持細(xì)胞不衰老。這一點(diǎn)很有價(jià)值，因?yàn)槠胀ǖ腡細(xì)胞衰老都會(huì)限制其擴(kuò)增，導(dǎo)致免疫療效不佳。來(lái)自東京大學(xué)的資深作者Dr. Hiromitsu Nakauchi說(shuō)“我們建立的體系能夠?yàn)榭拱滩『桶┌Y的免疫療法‘提供年輕活躍的’T細(xì)胞。”

另一個(gè)研究團(tuán)隊(duì)研究的是惡性黑色素瘤患者體內(nèi)獲得的T細(xì)胞。他們制造出的重新分化細(xì)胞識(shí)別了黑色素瘤普遍表達(dá)的蛋白MART-1。來(lái)自RIKEN變態(tài)反應(yīng)及免疫學(xué)研究中心的資深作者Dr. Hiroshi Kawamoto說(shuō) “下一步我們計(jì)劃?rùn)z驗(yàn)這些再生的T細(xì)胞是否可以選擇性殺死腫瘤細(xì)胞而不傷害其他健康組織。如果能夠生成這類(lèi)細(xì)胞，他們將被直接應(yīng)用于患者?！薄斑@在不久的將來(lái)可能會(huì)被實(shí)現(xiàn)?！?nbsp;

圖：圖中顯示的是T-iPSCs分化產(chǎn)生的被還原的（rejuvenated）T細(xì)胞，兩者雖然基因組相同，但形態(tài)與功能截然不同。
點(diǎn)評(píng): 用山中申彌使用的方法獲得的iPSCs并重新分化的T細(xì)胞，盡管是源自病人體內(nèi)，實(shí)質(zhì)是基因改造產(chǎn)生的新物種癌性細(xì)胞，與真正的多能干細(xì)胞及其分化的體細(xì)胞有本質(zhì)差別，因此關(guān)于其在選擇性殺死腫瘤細(xì)胞而不傷害其他健康組織方面的目標(biāo)難以預(yù)測(cè)，直接應(yīng)用于患者的可能性不大。

相關(guān)文獻(xiàn)：
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.