CN1314939A - 移植物抗宿主病的抑制 - Google Patents
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Abstract
哺乳动物类患者为治疗骨髓源性疾病而进行的细胞移植治疗中产生的移植物抗宿主病,可通过至少将同种异体细胞移植成分中的T-细胞在体外以适当的剂量给予氧化应激而得到预防和减轻,例如用臭氧和氧气的混合气泡通过T-细胞悬液。此方法也包括在应用氧化应激的同时用紫外光照射细胞。氧化应激引起T-细胞内炎症因子生成减少和增殖反应减小。
Description
发明范围
本发明涉及用于医学治疗的细胞成分,其制备方法及其在医学治疗中的用途。更特别地,本发明涉及在哺乳动物类患者,特别是人类患者中,用于减轻称作移植物抗宿主病的同种异体(allogeneic)骨髓移植术后并发症的细胞成分,以及制备这种成分物质的方法。
发明背景
骨髓移植术,BMT,是骨髓遭受破坏后必须进行的治疗。例如,在全身广泛照射或化疗后,骨髓是最先衰竭的靶器官。转移性癌通常给予很大剂量的化疗,这样可杀伤癌细胞,但也有效地破坏了骨髓。这就需要BMT。白血病是骨髓恶性肿瘤,通常在应用化疗和/或放疗根除恶性细胞后用BMT治疗。BMT目前用于治疗危及生命的白血病。一些自身免疫性疾病可能非常严重以至于需要消除其天然免疫系统,这导致了伴随的骨髓破坏,并需要随后的骨髓移植。但,减轻需要用BMT治疗骨髓异常的大多数急性危及生命的疾病,一般来说,被认为非常危险,因为有发生移植物抗宿主病的可能性。
移植物抗宿主病,GVHD,是一种免疫疾病,是限制为治疗无法治愈的血液系统恶性疾病的一些类型,如白血病,所使用的同种异体骨髓或干细胞移植(在此均指allo-BMT)成功和施行的主要因素。GVHD是一个全身性炎症反应,可导致宿主慢性疾病的产生和死亡。目前,同种异体移植总是冒着伴随GVHD的严重危险,即使供体与宿主具有很高的组织相容性。
GVHD由供体T-细胞与全身分布的不相容的宿主抗原相反应所致,引起强烈的炎症。在GVHD中,识别供体与宿主间差异的供体成熟T-细胞全面激活。目前防止和治疗GVHD的方法包括给予药物如环孢菌素-A和皮质激素。这些有严重的副作用,必须长时间给药且对于给药和监控很昂贵。也曾试图应用T细胞消耗以防止GVHD,但这需要复杂和昂贵的设备和专业技术。T-细胞过度消耗导致严重的问题,骨髓干细胞灌输失败、造血重建失败、感染或复发。过多限制的T-细胞消耗残留下的细胞仍能够启动GVHD。其结果,目前治疗GVHD的方法仅在有限的供体和宿主结合中取得成功,以致不能给许多病人提供有效的挽救生命的治疗。
现有技术的简述
Bolton的国际专利申请第PCT/CA97/00564号描述了一种在哺乳动物类患者中减轻自体免疫疾病症状的自体疫苗,由经过处理的部分血液组成,该血液取自同一个患者,在体外用紫外照射处理,在升高的温度(42.5℃)下氧/臭氧气混合气泡流经其中,在经过这些处理后,自体疫苗被重新输给同一患者。
本发明的目的是提供一种减轻接受同种异体-BMT的哺乳动物类患者GVHD并发症形成的方法。
发明概述
根据本发明,正在接受异体-BMT的病人被给予含来自同种异体供体T-细胞的成分,所述的T-细胞已在体外接受氧化应激,以诱导其中的炎症因子产生减少伴随增殖反应减小。看起来,这种氧化应激的同种异体T-细胞在注入哺乳动物类患者体内时,免疫反应和破坏性的抗受者同种异体反应下调,使得造血干细胞的灌输,与或不与应激的T-细胞一起,可以起效,形成GVHD的危险性显著降低。应激的T-细胞群因而看起来能够对哺乳类系统产生充分的保护作用,以防止灌输的失败和感染,同时造血系统至少部分地通过同种异体干细胞的增殖和分化而进行着重建。
相应的,本发明的一个方面提供了一种哺乳动物类患者减轻骨髓性疾病并减轻因此而发生的移植物抗宿主病(GVHD)的治疗方法,它包括给予患者同种异体造血干细胞和同种异体T-细胞,至少部分上述T-细胞在给予患者前体外接受了氧化应激,以诱导其中细胞因子生成状态的改变和增殖反应的减小。
本发明的另一个方面提供了一种哺乳类T-细胞群,特别是不含干细胞,所述的T-细胞在体外接受了氧化应激,在所述细胞内诱导细胞因子生成状态的改变和增殖反应的减小。
本发明进一步提供了一种制备给予患骨髓性疾病病人的同种异体细胞群的方法,它包括在体外使富含在T-细胞内的供体细胞群接受氧化应激,以在所述T-细胞内诱导细胞因子生成状态的改变和增殖反应的减小。
附图的简要说明
图1和2是根据下面的实例3所得到的结果的图解示意。
图3是对下面的实例4所得结果的描述。
优选实例的描述
本发明的方法涉及最初从供体中采集造血干细胞和T-细胞。这种细胞的优选来源是动员的供体外周血干细胞和T-细胞。外周血中的干细胞数量非常少,根据本发明的一个优选的操作方法是浓集供体外周血的干细胞群,然后提取供体的外周血作为干细胞和T细胞的来源,用上述的方法进行治疗,然后注入患者体内。在从供体中提取外周血前,给供体注射一个疗程的适当生长因子,连续几天,如5天,可达到浓集的目的。通过一个已知的程序,白细胞分离置换可从血中收集到合适的细胞部分,提取时,血浆和红细胞在一个密闭的流式系统中回到供体体内。含有干细胞(大约3%)和T细胞(大约40%),以及B细胞,中性粒细胞和其他白细胞的白细胞收集液,可被处理以改变其中T细胞细胞因子的产生状态和减小增殖反应,然后根据本发明,作为细胞(外周血单核细胞)的整体采集注入到宿主体内。然而,供体T-细胞首选地从其它细胞中分离,使得仅有T-细胞接受氧化应激并给予患者,而给患者注入的干细胞与处理的T细胞分开。但是,在实际应用中,外周血单核细胞收集液对应激物的反应是满意的,无需进一步分离以游离T-细胞,这是一个困难而昂贵的步骤。特别优选分别给予干细胞。
如果因某原因需要将整个白细胞收集部分进行氧化应激,以在其中的T-细胞部分内诱导前述的改变,然后将整个部分输给患者,优选的防止干细胞受到氧化应激任何损害效应的方法如下所述。
在一个可供选择,但非优选的方法中,供体的整体骨髓可被用作本发明方法的T-细胞和干细胞来源。在过去,整体骨髓是同种异体骨髓移植方法通常的细胞来源,也确实可用在本发明方法中。然而,这对供体是一个不方便和不适的方法,需要麻醉和较长的抽提过程。原则上,供体的任何T-细胞和干细胞来源均可用,但富含干细胞和T-细胞的外周血在临床上是最方便的。
在本发明方法中T-细胞内诱导的细胞因子生成状态的改变优选炎症细胞因子生成的减少,如干扰素-γ和组织坏死因子-α。
氧化应激可通过将T-细胞置于氧化环境而实施,如添加气态、液态或固态的化学氧化剂(臭氧、分子氧、臭氧/氧混合气、高锰酸盐、高碘酸盐、过氧化物、通过氧化机制作用于生物系统的药物,如阿霉素,以及类似物)。根据本发明的一个优选方法,悬液状态的T-细胞接受气态氧化剂,如臭氧/氧混合气泡通过细胞悬液,可选择与同时对细胞进行适当剂量的紫外照射相结合。
根据本发明的一个方法,对来自供体的同种异体白细胞,包括干细胞和T-细胞,进行氧化应激。这消除了将T-细胞与白细胞组份中的其它细胞成分分开所需要的复杂和费钱的步骤。但是,这种情况下,特别优选的是要防止组份中的干细胞受到应激的有害影响。这可通过在接受应激时,在细胞组份中含有一种或多种干细胞生长因子而实现。氧化应激对干细胞的有害作用可通过生长因子存在而得到防护,因此,在干细胞-T-细胞组分接受氧化应激前,一种或多种干细胞生长因子被加进组分中。用在方法中的干细胞生长因子是在此应激过程中促进干细胞(而非T-细胞)生存的细胞因子。它们是与干细胞上生长受体相作用的细胞因子。它们被确信可激活细胞的MAP-激酶通路,导致erk活化。这种适合的生长因子的实例包括:干细胞特异的生长因子、kit-配体、IL-3、GM-CSF和FLT3配体,它们均是已知的。优选添加精确剂量的提取和纯化的生长因子,或特别是市场上可买到的重组生长因子,或两者结合,适当地溶解或悬浮于适宜的、生物学可接受的液体中。
根据本发明的一个给同种异体T-细胞氧化应激的优选方法包括,将细胞悬液置于医用级的氧气和臭氧中,例如含有臭氧作为较小成分的医用级氧气流沸泡经过细胞悬液。悬浮介质可以是任何通用的生物学可接受的媒介,它保持细胞处于有活力的状态。臭氧气可由本领域内已知的传统来源提供。气流中适合的臭氧含量约为1.0-100μg/ml,优选3-70μg/ml,最优选约为5-50μg/ml。给予液体中的气流速度为每分钟大约0.01-2升,优选每分钟0.05-1.0升,最优选每分钟大约0.06-0.30升(STP)。
另一个给予T-细胞氧化应激使之适合在本发明中使用的方法,是在细胞悬液中加入生物学可接受的剂量的适当的生物学可接受的化学氧化剂。高锰酸盐、高碘酸盐和过氧化物在适量使用时是适合的。为实用的原因,过氧化氢在显示本发明方法的有效性和指导所用氧化剂的合适剂量中是有用的,尽管它不是本发明的首选药物。因此,适合的氧化剂剂量是浓度从1mmol到2mmol的过氧化氢,与含10-6-10-8细胞/ml的细胞悬液10ml接触20分钟,或来自不同氧化剂的相当的氧化应激。最佳的是约1mmol过氧化氢在上述悬液中约20分钟,或计算给予细胞相应氧化应激程度的相当的另一个氧化剂。
要接受氧化应激的细胞悬液的体积通常从大约0.1ml到大约1000ml,优选大约1-500,含有随后给予进行同种异体-BMT病人的适合数量的T-细胞。这些数量通常与以前的方法中同种异体-BMT相关的同种异体T-细胞输入所需的数量相当,为本领域内的工作人员所熟知。
根据本发明的一个特殊方法是,细胞悬液同时接受氧/臭氧气泡经过和紫外照射。这也对T-细胞特性造成适当改变。必须注意不要采用过高剂量的氧/臭氧或UV,以免造成细胞膜破坏,或对大量细胞造成不可逆的损伤。
T-细胞悬液接受氧化应激的温度看起来不严格,只要它保持悬液处于液相,并且不太高以致使细胞膜破坏。温度应当不高于大约45℃。
当紫外照射与氧/臭氧氧化应激因素一起使用时,应当在来自合适的UV射线源处理下,通过照射悬液而合理使用,同时液体保持在前述的温度,并且氧/臭氧混合气同时通过液体。紫外射线可由本领域内已知的任何传统来源提供,例如通过一组低压紫外灯。优选使用标准的紫外照射UV-C源,也就是说UV灯主要在C段波长发射,即短于大约280nm的波长。相对于标准UV-A和UV-B源的紫外照射也可使用。优选应用的是低压紫外灯,其产生的光谱中至少90%的射线波长为大约254nm。与前述温度和氧化应激因素一起使用的这种UV射线的适合剂量,是从输出能量为约5至约25瓦的灯获得的,优选地大约5-约10瓦,在所选的波长下,置于盛有液体的样本容器周围。每个这种灯在1米距离下可提供大约每平方米40-80毫瓦的能量强度。围绕着样本容器的数个灯,在最大强度下工作是可方便地使用的,其在254nm处的结合输出大约为15-40瓦,优选地20-40瓦。在液体的入射表面,3分钟的照射时间内,UV能量可提供约0.25-4.5j/cm2,优选0.9-1.8j/cm2。这种处理可提供一种根据本发明适当修饰,准备注射给病人的悬液。
液体接受应激因素的时间可从数秒到大约60分钟。通常在约0.5-60分钟范围内。这在一定程度上依赖于选择的UV照射强度、温度和应用于液体的氧化剂浓度和速度。一旦其他应激因素水平被设置,对操作人员来讲,进行一些试验以确定最适时间和剂量可能是必要的。在大多数应激因素条件下,优选的时间在大约0.5-10分钟范围内,最优选的为2-5分钟,通常在3分钟左右。
在实施本发明的一个优选方法时,细胞悬液可用氧/臭氧混合气处理,也可选择地用美国专利4,968,483 Mueller中描述的仪器一起进行UV照射。悬液置于一合适的、消毒的、可透射UV-辐射的容器内,然后安装进仪器中。通过应用合适的热源,如一个红外线灯,将液体的温度调整到预先确定的值,如42.5±1℃,在气流用于液体以提供氧化应激之前,打开UV灯一段固定的时间以使UV灯的输出得以稳定。已知组份和控制流速的氧/臭氧混合气以预先确定的0.5-60分钟给予液体,如上所述,优选地1-5分钟,更优选地大约3分钟。以此方式,悬液根据本发明被适当地修饰足以获得所期望的减轻或防止GVHD的作用。
从另一个方面,本发明的优选实例可被看作是通过体外应激T-细胞在给予病人之前处理同种异体T-细胞的方法,它包括给予T-细胞诸如臭氧和臭氧/氧暴露的氧化应激。从本发明方法中得到的经处理的同种异体T-细胞对GVHD的形成和发展具有直接的作用。在注入宿主患者之前,根据本发明方法预先处理的供体T-细胞已被修饰,因而不再具有有害的反应。他们产生炎性细胞因子反应的能力被降低了。例如它们分泌IFN-γ、TNF-α和IL-2的能力,以及对标准分裂素的增殖反应被减小了。因此他们不再对不相容的全身分布的宿主组织相容性抗原产生任何程度的反应而造成炎症。给予病人的同种异体干细胞可继续进行灌输而成功的机会提高。一段时间以后,处理的T-细胞大多恢复其增殖能力和免疫反应功能,但仍对不同的宿主组织相容性抗原相当不反应(耐受)。
为说明起见,本发明在下面的特殊实例中被进一步描述。最佳实例的具体描述
哺乳动物的脾提供了一个方便、易得的细胞来源,特别是T-细胞,也包括小量的干细胞,在为实验目的的动物模型中是特别有用的。
为获得应用本发明方法的指征进行的试验采用SCID小鼠的急性GVHD模型。来源于C57B1/6J(B6)小鼠的T-细胞被静脉注射给接受亚致死量照射的CB-17SCID小鼠。后者先天性淋巴细胞减少,且由于其主要组织相容性位点(MHC)完全不一致而为供体细胞提供了强烈的刺激。在此模型中,宿主小鼠的平均生存时间是14天。GVHD表现为抑制宿主从照射中恢复造血;T-细胞膨胀而用Vβ3链形成其T-细胞受体复合物(TCR’s);供体T-细胞自发分泌干扰素-γ和TNF-α;和供体T-细胞在脾红质中的异常分布。如果供体骨髓与T-细胞共同注射,则形成慢性GVHD。实例1
来自C57B1/6J(B6)小鼠的脾细胞在α-MEM、2ME和10%小牛血清(FCS)中悬浮至密度为107/ml。FCS含有细胞因子和生长因子。细胞悬液在42.5℃接受UV-C灯253.7nm波长的紫外照射,同时14-15mcg/ml臭氧/医用级氧的混合气沸泡通过悬液。处理进行3分钟。
处理后即刻,细胞仅有约10%的活力。实例2
除细胞悬浮在100%FCS中以外,基本重复了实例1的试验。在此情况下,细胞的即刻生存是50-60%,表明FCS中存在的因子对至少部分细胞具有保护作用。实例3
悬浮在100%FCS中的B6鼠脾细胞接受了UV-氧化-热处理。在42.5℃下,细胞悬液接受253.7nm波长的UV-C灯紫外照射,同时14-15mcg/ml臭氧/医用级氧的混合气沸泡通过悬液。处理进行3分钟。不同数量注射入经亚致死量照射的CB-17 SCID小鼠内。它们随后的表现与接受同样数量未经处理的B6脾细胞者相比。
图1是这些实验结果的图解说明,其中每一组中动物的生存%绘制为纵坐标,对应注射处理的和未处理的细胞后的天数。与未处理的细胞相对,当使用经处理的细胞时,在所有的剂量水平生存均有显著的改善,显示本发明的方法减轻GVHD的可能性。
图2是同一实验中,对应于GVHD诱导后天数的每个脾供体细胞数量的绘制图。它显示处理的供体T-细胞在宿主小鼠内生存和数量扩大,尽管同对照、未处理的B6 T-细胞相比程度非常有限。实例4
通过注射供体细胞(处理的和未处理的)在小鼠启动GVHD后6天,供体T-细胞经密度梯度离心法从SCID脾细胞中分离出来。细胞内细胞因子染色根据Ferrick,D.A.等在NATURE373225,257,1995中发表的方法进行。在注射B6脾细胞后第8天对脾细胞悬液进行染色。在存在布雷费的菌素-A的情况下,用植物细胞凝集素和伊屋诺霉素体外刺激后4小时,并选择了CD4+和CD8+后进行细胞因子生成的测定。结果用细胞内流式细胞仪检测并在附图3中描述。记录每个象限内每种细胞的百分数。附图显示,如实例1所描述的被应激的T-细胞同未处理的和对照细胞相比,炎症细胞因子干扰素-γ(INF)和组织坏死因子-α(TNF)水平显著降低,右象限较低。实例5
CD4+对CD8+T-细胞正常比例(通常为大约2∶1)的反转已知是伴随于GVHD的。按Ferrick,D.A.等在NATURE 373225,257,1995中发表的方法进行的细胞内细胞因子染色和采用抗CD4和CD8三色抗体,测定CD4/CD8的比例。未处理的供体脾细胞在注入经亚致死量照射的小鼠后,正常比例的反转得到证实。对未应激的B6和C3H供体T-细胞,在许多动物患了GVHD的第13天,CD4/CD8的最初比例分别从1.3±0.2和2.2±0.3降低到0.33±0.05和0.9±0.1。相反,当供体细胞用如实例1所述的应激因素预先处理时,该比例在所有的时间仍大于1且缺少GVHD的临床表现。实例6
本实例单独采用氧化应激说明本发明的原理,该氧化应激由一有效的化学氧化剂过氧化氢提供,并代表了许多其它的、可能生物学更适合的化学氧化剂。
人外周血单核细胞PBMCs是含约40%T-细胞的血白细胞集合液,通过与不同浓度的过氧化氢水溶液接触20分钟而被应激。测定其即刻的生存和即刻植物血凝素(PHA)反应。然后测定其24小时后的生存,随后测定其7天后的PHA反应(用PHA进行致有丝分裂刺激后的氚化胸苷摄取)和细胞因子状态。结果列于下表。
表
H2O2浓度 | 即刻生存% | 24小时生存% | 即刻PHA反应 | 7天时PHA反应 | 细胞因子状态 |
100μmole/L | 80-90 | 100 | 2000 | + | IFNγ↓ |
300μmole/L | 80-90 | 50 | 2000 | + | IFNγ↓ |
1μmole/L | 80-90 | 40 | 400 | + | IFNγ↓ |
3μmole/L | 80-90 | 40 | 400 | + | IFNγ↓ |
对照 | 95 | 95 | 8575 | + | IFNγ↑ |
这些结果表明单独接受氧化应激的T-细胞发生增殖反应下降和炎症细胞生成减少,适用于本发明。
Claims (21)
1.一种制备同种异体细胞群的方法,所述同种异体细胞群用于给予患有通过骨髓移植术而可能治疗的骨髓疾病的病人,该方法包括体外给予富含T-细胞的供体细胞群以氧化应激,在所述的T-细胞内,诱导改变的细胞因子生成状态和减小增殖反应。
2.根据权利要求1的方法,其中通过提供臭氧/氧气混合气而给与氧化应激。
3.根据权利要求2的方法,其中的臭氧/氧气混合气是以大约每分钟0.01-2升的速率沸泡所述的含有T-细胞的细胞群的水性悬液。
4.根据权利要求2或3的方法,其中臭氧/氧气混合气的臭氧含量大约为1.0-100μg/ml。
5.根据权利要求2的方法,其中臭氧/氧气混合气以大约每分钟0.05-1.0升的速率沸泡所述含有T-细胞的细胞群的水性悬液,混合气的臭氧含量大约为3-70μg/ml。
6.根据前述的任一项权利要求的方法,其中给予含有T-细胞的细胞群额外的UV照射。
7.根据权利要求6的方法,其中含有T-细胞的细胞群同时接受氧化应激和UV照射。
8.根据权利要求7的方法,其中的UV照射是UV-C。
9.根据权利要求7或8的方法,其中同时接受氧化应激和UV照射的时间是0.5-60分钟。
10.根据权利要求9的方法,其中所述的时间是2-5分钟。
11.根据前述的任一项权利要求的方法,其中含有T-细胞的细胞群是通过白细胞分离置换法从人外周血中获得的人白血细胞成分。
12.根据权利要求11的方法,其中含有T-细胞的细胞群是来自人外周血单核细胞成分。
13.根据权利要求1的方法,其中氧化应激是通过在所述的富含T-细胞的供体细胞群悬液中加入一种化学氧化剂而给予的。
14.根据权利要求13的方法,其中富含T-细胞的供体细胞群是来自人血的外周血单核细胞成分。
15.一种治疗哺乳类病人方法,该方法用于减轻通过骨髓移植术而可能治疗的骨髓疾病,并减轻必然发生的移植物抗宿主病,包括给予病人同种异体造血干细胞和同种异体T细胞,在给予病人之前,至少一部分所述的T细胞在体外已接受氧化应激,以诱导其中炎症细胞因子产生的减少和增殖反应的减小。
16.根据权利要求15的方法,其中所述的T细胞与干细胞是分别给予的。
17.根据权利要求16的方法,其中所述的T-细胞基本上由来自人外周血的外周血单核细胞组成。
18.根据权利要求15、16或17的方法,其中所述的T-细胞已通过在其中应用氧/臭氧混合气而受到氧化应激。
19.根据权利要求15、16或17的方法,其中所述的T-细胞已通过在其中应用化学氧化剂而受到氧化应激。
20.根据权利要求18或19的方法,其中所述的T-细胞已在接受氧化应激的同时额外地接受了紫外照射。
21.一种基本上不含干细胞的哺乳类T-细胞群,所述的T细胞已在体外接受了氧化应激以致在所述细胞内诱导炎症细胞因子生成的减少和增殖反应的减小。
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CA2324199A1 (en) * | 2000-10-25 | 2002-04-25 | Vasogen Ireland Limited | Chronic lymphocytic leukemia treatment |
ES2380009T3 (es) * | 2001-07-31 | 2012-05-07 | Genzyme Global S.A.R.L. | Métodos para movilizar las células madre/progenitoras |
US7037900B2 (en) * | 2001-10-12 | 2006-05-02 | Supergen, Inc. | Composition and method for treating graft-versus-host disease |
ES2422193T3 (es) * | 2002-06-28 | 2013-09-09 | Life Technologies Corp | Métodos para restaurar el repertorio inmune en pacientes con defectos inmunológicos relacionados con la autoinmunidad y trasplante de órganos o de células madre hematopoyéticas |
US20040175373A1 (en) * | 2002-06-28 | 2004-09-09 | Xcyte Therapies, Inc. | Compositions and methods for eliminating undesired subpopulations of T cells in patients with immunological defects related to autoimmunity and organ or hematopoietic stem cell transplantation |
US20050084967A1 (en) | 2002-06-28 | 2005-04-21 | Xcyte Therapies, Inc. | Compositions and methods for eliminating undesired subpopulations of T cells in patients with immunological defects related to autoimmunity and organ or hematopoietic stem cell transplantation |
WO2004094463A2 (en) * | 2003-04-18 | 2004-11-04 | University Of Florida Research Foundation, Inc. | Peptide inhibitors of autophosphorylation protein kinases |
WO2007011960A2 (en) * | 2005-07-18 | 2007-01-25 | Advanced Immune Biotechnologies, Inc. | Methods and agents to treat autoimmune diseases |
EP2137297A4 (en) * | 2007-04-11 | 2010-04-14 | Roger Deutsch | METHOD FOR DIAGNOSING BIOLOGICAL SAMPLES WITH STEM CELLS |
US8512696B2 (en) * | 2007-11-30 | 2013-08-20 | Autologous, Llc | Methods of isolating non-senescent cardiac stem cells and uses thereof |
CA2743697A1 (en) * | 2007-11-30 | 2009-06-11 | New York Medical College | Methods of isolating non-senescent cardiac stem cells and uses thereof |
EP3219793A1 (en) * | 2012-01-05 | 2017-09-20 | Taipei Veterans General Hospital | Preparation of cell transplant |
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CN104873540B (zh) * | 2005-11-09 | 2019-11-15 | Abt控股公司 | 多潜能成体祖细胞的免疫调节特性及其用途 |
CN104095878B (zh) * | 2005-11-09 | 2020-01-21 | Abt控股公司 | 多潜能成体祖细胞的免疫调节特性及其用途 |
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