Brain:干细胞疗法新突破!植入大脑的干细胞长期存活,无需使用抗排斥药

2019-09-26 顾露露 生物探索

干细胞疗法被认为具有广阔应用前景,如胶质细胞限制性祖细胞(GRP)就已成为治疗多种神经疾病的重要候选目标。但由于免疫屏障的存在,同种异体干细胞移植在临床应用上一直障碍重重。

干细胞疗法被认为具有广阔应用前景,如胶质细胞限制性祖细胞(GRP)就已成为治疗多种神经疾病的重要候选目标。但由于免疫屏障的存在,同种异体干细胞移植在临床应用上一直障碍重重。



9月16日,发表在《Brain》杂志上的一篇研究指出,研究人员找到一种新方法可以选择性地绕过针对外来细胞的免疫反应,让移植的细胞在停止免疫抑制药物后很长一段时间都可以存活、茁壮成长并保护脑组织。

寻找到一种无副作用的、能够阻止过度免疫反应的方法,对于干细胞疗法意义深远。

然而摆在研究人员面前最大的障碍是,如何在替换这些缺陷细胞的同时“绕过”免疫系统。因为我们知道,免疫系统通过快速识别“自身”或“非自身”组织并发动攻击以摧毁非自身或“外来入侵者”而发挥作用。当以细菌或病毒为靶标时,它是有益的,但对移植的器官、组织或细胞来说,这可能是毁灭性的。

传统的抗排斥药物虽然能广谱地和非特异性地降低免疫系统的频率,抵御组织排斥,但易使患者受到感染和其他副作用的影响,且患者需要无限期地使用这些药物。为了在不产生副作用的情况下阻止免疫反应,美国约翰霍普金斯大学医学小组把目标转向了T细胞,因为T细胞是攻击外来入侵者的精英力量。

具体地说,约翰?霍普金斯大学医学院放射与放射科学副教授Piotr Walczak博士和他的团队专注于T细胞开始攻击必须遇到的一系列所谓的“共刺激信号”。“这些信号的存在有助于确保这些免疫系统细胞不会失控,避免攻击人体自身的健康组织,”论文共同作者、约翰霍普金斯大学医学院Gerald Brandacher博士说,这个想法是利用这些共刺激信号的自然趋势,作为训练免疫系统以最终永久接受移植细胞作为“自我”的一种手段。

为此,研究人员使用了两种抗体CTLA4-Ig和抗CD154,它们通过与T细胞表面结合而阻止信号发出,从而阻止T细胞在遇到异物时开始攻击。Walczak说,这种组合以前已成功用于阻断动物体内实体器官移植的排斥反应,但尚未经过细胞移植修复脑髓磷脂的测试。

在一系列关键实验中,Walczak和他的团队向小鼠大脑注射保护性神经胶质细胞。这些细胞能产生围绕神经元的髓鞘,并经过基因工程改造后可以发光,因此研究人员可以随时观察它们。

然后,研究人员将神经胶质细胞移植到三种类型的小鼠中:经过基因工程改造以不形成产生髓鞘的神经胶质细胞的小鼠、正常小鼠和无法产生免疫反应的小鼠。研究人员使用抗体阻断免疫反应,6天后停止治疗。研究人员每天都使用专门的照相机来检测发光细胞并捕获小鼠大脑的图片。

结果发现,移植到未接受抗体处理的对照小鼠中的细胞立即开始死亡,并且到第21天,照相机不再能够检测到它们的发光。接受抗体治疗的小鼠在203天以上的时间内都维持着大量的移植的神经胶质细胞,这表明即使不进行治疗,它们也不会被小鼠的T细胞杀死。

该研究的主要作者,医学博士Shen Li说:“事实上,即使停止治疗后很长时间,细胞仍能存活下来。我们认为这一结果是成功地选择性阻断了免疫系统的T细胞杀死移植细胞。”

下一步是查看移植的神经胶质细胞是否存活得足够好,足以完成神经胶质细胞在大脑中正常发育形成髓鞘。为此,研究人员使用MRI图像寻找神经胶质细胞生长旺盛的小鼠大脑与没有神经胶质细胞的小鼠大脑之间的关键结构差异。在这些图像中,研究人员发现被治疗的动物的细胞确实存在于大脑的适当部位。他们的结果证实,移植的细胞能够茁壮成长,并具有保护大脑神经元的正常功能。

这一成果对于那些出生就患有罕见且具有毁灭性遗传病的儿童来说,是一个福音。以Pelizaeus-Merzbacher病(PMD)为例,它是一种罕见的神经变性疾病,是由中枢神经系统(CNS)髓鞘形成缺陷所致。“由于这些疾病是由引起一种类型细胞功能异常的突变引发的,因此它们非常适用于细胞疗法,”Walczak博士说道。

当然,Walczak强调说,这些结果只是初步的。他们希望将这项发现与大脑细胞传递的方法相结合,以帮助更全面地修复大脑。

原始出处:Shen Li,  Byoung Chol Oh,  Chengyan Chu, et al. Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts. Brain. 16 September 2019

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    2020-01-25 zxxiang
  2. [GetPortalCommentsPageByObjectIdResponse(id=1725011, encodeId=6e711e2501134, content=<a href='/topic/show?id=9ee758586bb' target=_blank style='color:#2F92EE;'>#新突破#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58586, encryptionId=9ee758586bb, topicName=新突破)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=792a33728807, createdName=zxxiang, createdTime=Sat Jan 25 08:02:00 CST 2020, time=2020-01-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=373400, encodeId=0e8a3e340085, content=谢谢了,学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=89, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=30331616752, createdName=txqjm, createdTime=Tue Oct 01 06:20:56 CST 2019, time=2019-10-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1025338, encodeId=557b1025338e7, content=干细胞是热点,但是进入临床仍然需要时间和临床疗效验证哦, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=独孤立克, createdTime=Sun Sep 29 01:02:00 CST 2019, time=2019-09-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1262992, encodeId=3387126299212, content=<a href='/topic/show?id=3c0f56643cd' target=_blank style='color:#2F92EE;'>#排斥#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=56643, encryptionId=3c0f56643cd, topicName=排斥)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=947269, createdName=lvygwyt2781, createdTime=Fri Sep 27 16:02:00 CST 2019, time=2019-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1314488, encodeId=041f13144887c, content=<a href='/topic/show?id=4c6348e80a9' target=_blank style='color:#2F92EE;'>#干细胞疗法#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=48780, encryptionId=4c6348e80a9, topicName=干细胞疗法)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5319428, createdName=jjjiang0199, createdTime=Fri Sep 27 16:02:00 CST 2019, time=2019-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1520620, encodeId=3db0152062079, content=<a href='/topic/show?id=7a736264553' target=_blank style='color:#2F92EE;'>#植入#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=24, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=62645, encryptionId=7a736264553, topicName=植入)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=832411313664, createdName=jiyangfei, createdTime=Fri Sep 27 16:02:00 CST 2019, time=2019-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=373213, encodeId=d8603e321336, content=真的假的啊?, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e5171668917, createdName=坚强007, createdTime=Thu Sep 26 08:43:30 CST 2019, time=2019-09-26, status=1, ipAttribution=)]
    2019-10-01 txqjm

    谢谢了,学习

    0

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    2019-09-29 独孤立克

    干细胞是热点,但是进入临床仍然需要时间和临床疗效验证哦

    0

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    2019-09-27 lvygwyt2781
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    2019-09-27 jiyangfei
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    2019-09-26 坚强007

    真的假的啊?

    0

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