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科学家找到免疫排斥自身来源iPSC的原因
作者:小柯机器人 发布时间:2019/8/20 14:53:28

美国加州大学旧金山分校Sonja Schrepfer课题组的最新研究,揭示了诱导型多潜能干细胞线粒体DNA中的从头突变,在小鼠和人中产生免疫原性新表位。这一研究成果于2019年8月19日在线发表在《自然—生物技术》上。

研究人员猜想线粒体DNA(mtDNA)从头突变的修复机制远不如染色体DNA,可能产生能够引发免疫识别和排斥的新抗原。研究人员在小鼠和人类中找到证据,并证明mtDNA非同义突变能够在重编程iPSC、长期培养和分化为目的细胞的阶段出现并富集。这些mtDNA突变编码能够产生新抗原,其引发高度特异性且依赖于宿主主要组织相容性复合物基因型的免疫应答。这些研究结果表明,自体iPSC及其衍生物对自体移植本质上不具有免疫惰性,并且表明需要筛选iPSC衍生物的mtDNA突变。

研究人员表示,自体诱导的多潜能干细胞(iPSC)疗法用于组织再生的效用取决于产生免疫沉默的、具有功能的iPSC分化产物。然而,已有排斥自体iPSC衍生细胞的情况被报道,尽管排斥反应的机制在很大程度上未知。

附:英文原文

Title: De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans

Author: Tobias Deuse, Xiaomeng Hu, Sean Agbor-Enoh, Martina Koch, Matthew H. Spitzer, Alessia Gravina, Malik Alawi, Argit Marishta, Bjoern Peters, Zeynep Kosaloglu-Yalcin, Yanqin Yang, Raja Rajalingam, Dong Wang, Bjoern Nashan, Rainer Kiefmann, Hermann Reichenspurner, Hannah Valantine, Irving L. Weissman, Sonja Schrepfer 

Issue&Volume: 19 August 2019

Abstract: The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.

DOI: https://doi.org/10.1038/s41587-019-0227-7

Source: https://www.nature.com/articles/s41587-019-0227-7

期刊信息

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:31.864
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex