來(lái)自日本理化研究所過(guò)敏與免疫學(xué)研究中心的研究人員報(bào)道,，他們首次成功地利用誘導(dǎo)性多能干細(xì)胞(induced pluripotent stem cells,， iPS細(xì)胞)構(gòu)建出癌癥特異性的被稱作殺傷性T淋巴細(xì)胞的免疫系統(tǒng)細(xì)胞,。為了構(gòu)建出這些殺傷性細(xì)胞，他們首先不得不將專門(mén)從事于殺死某種類(lèi)型癌癥的T淋巴細(xì)胞重編程為iPS細(xì)胞,，然后這些iPS細(xì)胞產(chǎn)生完全有活性的癌癥特異性的T淋巴細(xì)胞,。這些利用iPS細(xì)胞再生的淋巴細(xì)胞在未來(lái)可能潛在地被用來(lái)治療癌癥。相關(guān)研究結(jié)果于2013年1月3日發(fā)表在Cell Stem Cell期刊上,，論文標(biāo)題為"Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells",。
之前的研究已證實(shí)利用常規(guī)方法在實(shí)驗(yàn)室產(chǎn)生的殺傷性T淋巴細(xì)胞不能有效地殺死癌細(xì)胞，主要原因在于它們的壽命非常短,，這就限制使用它們來(lái)治療癌癥,。
為了克服這些問(wèn)題，在研究員Hiroshi Kawamoto博士的領(lǐng)導(dǎo)下,，日本研究人員將成熟的殺傷性T淋巴細(xì)胞重編程為iPS細(xì)胞,，并研究這些細(xì)胞如何發(fā)生分化。研究人員通過(guò)加入四種轉(zhuǎn)錄因子Oct-3/4,、SOX2,、c-Myc和Klf4而將能夠特異性地殺死某種類(lèi)型皮膚癌的殺傷性T淋巴細(xì)胞重編程為iPS細(xì)胞。這四種轉(zhuǎn)錄因子能夠誘導(dǎo)細(xì)胞返回到一種非特化的多能性狀態(tài),。這些iPS細(xì)胞然后在實(shí)驗(yàn)室培養(yǎng),，經(jīng)誘導(dǎo)后能夠再次分化為殺傷性T淋巴細(xì)胞。他們證實(shí)這些新形成的T淋巴細(xì)胞能夠與原始的淋巴細(xì)胞一樣對(duì)相同類(lèi)型的皮膚癌是特異性的：它們?cè)谒鼈兊谋砻嫔媳磉_(dá)癌癥特異性的受體,。他們還證實(shí)這些新形成的T淋巴細(xì)胞是有活性的,，而且能夠產(chǎn)生抗腫瘤的化合物干擾素γ。
Kawamoto博士解釋道,，"我們通過(guò)產(chǎn)生iPS細(xì)胞并讓它們?cè)俅畏只癁楣δ苄缘腡細(xì)胞而成功地?cái)U(kuò)增抗原特異性的T細(xì)胞,。下一步就是測(cè)試這些T細(xì)胞是否能夠選擇性地殺死腫瘤細(xì)胞而不是體內(nèi)的其他細(xì)胞。如果確實(shí)如此的話,，那么這些細(xì)胞可能直接被注射到病人體內(nèi)來(lái)治療癌癥,。這可能在不太遠(yuǎn)的未來(lái)成為現(xiàn)實(shí)。"(生物谷Bioon.com)
DOI:10.1016/j.stem.2012.12.006
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PMID:
Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells
Raul Vizcardo, Kyoko Masuda, Daisuke Yamada, Tomokatsu Ikawa, Kanako Shimizu, Shin-ichiro Fujii, Haruhiko Koseki, Hiroshi Kawamoto
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.
