CN1088310A - 血样的间接荧光鉴定 - Google Patents

血样的间接荧光鉴定 Download PDF

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CN1088310A
CN1088310A CN93119654A CN93119654A CN1088310A CN 1088310 A CN1088310 A CN 1088310A CN 93119654 A CN93119654 A CN 93119654A CN 93119654 A CN93119654 A CN 93119654A CN 1088310 A CN1088310 A CN 1088310A
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罗伯特·A·利费恩
斯蒂芬·C·瓦尔德罗
莱昂·W·M·M·特斯塔彭
迪泽·J·莱克坦沃尔德
托马斯·J·迈尔科林诺
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Abstract

通过对透明试管中的血样进行离心处理来诊断 病人的健康状况。试管中含有一群或多群，诸如每群 有不同密度的脂质体或塑性珠粒的粒子，密度相同的 粒子携带有对可能存在于被测血样内的补体抗原或 抗体有特效的抗原或抗体。向血样中加入一种对所 有结合抗体/抗原偶对有特效的被标记抗体，形成标 记抗体+抗原——抗体复合物(AAAC)。离心后，复 合物粒子依各自的比重落至管内不同区域，各层的标 记辐射程序可定性或定量地分析血样。

Description

本发明涉及一种一次性同时检测结合生物粒子的一种或多种活性偶对中任一方成份的存在或空缺的、并且在需要的时候检测它们在全血、血浆式血清样品中的量值的方法和装置。
对血样中抗体或抗原的存在或缺少进行分析被用于诊断一些疾病，诸如，HIV（人免疫缺陷病毒）感染、肝炎、Lyme病、包括TORCH（即弓形体病（Toxoplasmosis）、风疹（Rubella）、巨细胞病毒（Cytomegalovirus）、疱疹（Herpes）的缩写）检查在内的产前检查，及其它感染性疾病的检查。目前，这类血清诊断常通过标准的间接荧光免疫鉴定来完成。在标准间接荧光免疫鉴定中，抗原作为要检测的抗体的偶对一方首先被固定于固体支持介质中，例如玻璃载片、纸膜等，随后将病人血清样品与被固定的抗原接触下共同培养一段时间，这段时间足以使配对的抗体，如果存在的话，变得与被固定的抗原相结合。然后冲洗支持表面以除去所有未被结合的抗体。将包含一种已标记的人体免疫（抗体）球蛋白抗体的试剂送入与固体支持面相接触，并进行一段时间的培养;这段时间是足以引起已标记材料与可能已与固定抗原相组合的病人之抗体的任何痕迹相键合。再将剩余试剂冲洗掉，对固体支持面进行检验，确定是否有任何标志物存在。对这种制备的样品的检验可以用目测地进行、也可以利用分光光度测定或者X线测量法进行。显然，以上方法需要多个标本操作步骤，包括冲洗、分析技术，所以是相当费时费力。前述过程每次试验只能检查出一种特定抗原的抗体存在与否，若无进一步试验，不能把IgG和IgM区分开来，也不能同时检查出多抗原或抗体。
于1991年10月4日提交的共同待审美国专利申请第07/770，875提出了一种进行不同红血球进行计数的方法和装置，通过使具有不同带比重的微珠粒依比重形成密度分布带，下文将其称为密度标志物（density-markers）。本发明涉及一种用于快速简捷地检测在全血、血清或血浆样品中，结合生物粒子的一种或多种活性偶对的各方成份是否存在的方法和装置。这类可检测的偶对的例子如：促甲状腺激素/抗促甲状腺激素（TSH/Anti    TSH）复合物、T4/抗T4复合物、风疹抗体/抗风疹抗体、HIV抗体/HIV抗原;在此，TSH、T4、风疹抗体和HIV抗体都是目标分析物。本方法只不过需要在一离心管内将试管中的含有几种试剂的血样进行离心，并观察离心步骤的结果而实现的，检测可以在不将血样暴露给医生或技师的情况下进行。
在使包含全血样的试管内被离心之后，红细胞将在试管底部形成连续的密度梯度层，而最稠的红细胞落在红细胞的最底层。当血样在含有以上提到的包含不同比重珠粒或不同比重脂质体群的试管中被离心时，珠粒或脂质体将在红细胞叠层中形成分离的清晰可见的标志物环。离心管中还可以包含一个圆柱形塑料嵌入芯，它可以被固定于试管底部，或者可以在试管中自由活动。如果是自由活动的，它的比重将可以使其沉入离心后血样中的红细胞层。嵌入芯限制了红细胞在试管内可以占居的空间，因此增加了在离心后红细胞层中形成的标志物环之间的距离，并将珠粒或脂质体排至试管周壁，在此可以观察和容易地检测到这些标志物环，而它们的信号不会被红细胞所淹没。
在本发明方法的进行中，珠粒或脂质体将会与一个抗原或抗体相配对，或与另外一种生物活性物质相配对，这种生物活性物质的补体或结合各方（它们可被指定为“目标分析物”）可能存在于病人血液之中。生物活性互补偶对的例子包括：酶及其酶作用物、核甙酸及其互补核甘甙酸、自然出现的蛋白结合物，如：甲状结合球蛋白（TGB）和甲状腺素、“内在内子”和维他命B12、以及一些将选择性地与RNA-DNA杂种相配对的特异性抗体，如Stollar和Rashtchian在他们发表于1987年161.387-394的分析生物化学杂志上的《基因探针鉴定的免疫化学入门》（Immunochemical Approaches to Gene Probe Assays）文章中所描述的。
每个密度标志物群，其中可能仅有一种将与一个偶对粒子相结合，它对一种目标分析物是特效的，这种分析物可能在血样或其它生物样品中存在。将该样品加入试管，以便使密度标志物/偶对粒子群或多群与样品混合，足以引起任何存在于样品中的目标分析物与在密度标志物上他们的补体配偶相配对。
当利用本发明的方法产生了结合偶对时，在配对步骤完成之后，一种被标记或标鉴的“抗-抗原-抗体复合物”抗体（AAAC抗体）对所有在密度标志物上的偶对有特效（这种AAAC抗体可以在样品加入之前就已在试管之中）。这种AAAC抗体可以是干的，覆盖于试管内壁，或者，例如可以以液体形式存在于真空管之中，如在1992年2月11日授予Robert    A.Levine和Stephen    C.Wardlaw的美国专利No.5，086，784中所描述的。
这种类型的一些抗体已由美元加州San    Jose的贝克顿.迪金森公司的免疫血细胞计数系统部（the    Immunocytometry    System    Division    of    Becton    Dickinsin    and    Company，of    San    Jose，California）生产。不同于对所有抗原/抗体复合物偶对有特效，这种已标签AAAC抗体可以仅对免疫球蛋白亚群（IgG和IgM抗原-抗体复合物）有特效。同样，如果待分析物是RNA或DNA，那么试管中应含有一种特效于或将结合于RNA-DNA对的已标记抗体，如Stollar和Rashtchian所描述的那样。
标志物可以是脂质体包围的染色剂或荧光染色剂，或者可以是放射性能量辐射源。标志物必须是可检测到的并且最好是可以计量的。该已标记抗体与所有具有形成于其上的偶对的密度标志物相结合。样品被离心处理，按密度地将密度标志物在试管内分离成间隔的部分带或环。然后检查管内不同的密度标志物带，以确定哪些带（如果有的话）具有可检测的标记量值，并且，如果适当的话，测量标记的量值。而最常用的标记应首推荧光分子，如FITC。
如果需要，不同的密度珠粒可以有不同的固有颜色，这样，每条（如果有一种以上的带的话）不同颜色的带将代表不同的目标分析物。如果采用不同颜色的密度标志物，试管中标记带的颜色将表明哪一些结合的分析物是在样品中;如果置于试管中的密度标志物的带中没有展示出与其有关的任何标记，则说明样品中没有那些分析物。如果没有采用着色的密度标志物，那么标记带在管内的位置将表明哪些分析物是在样品之中而哪些不在。当然，这一信息就可以进行对血样提供者健康情况的诊断。
本发明的目的是提供一种改进的用于对生物样品进行分析的技术，以便确定其中某些目标分析物存在与否。
本发明进一步的目的是提供一种改进的描述特性的技术，其中分析结果可以在透明样品试管中依密度地进行。
本发明进一步的目的是提供一种改进的描述特性的技术，其中分析是利用与抗体和/或抗原相配对的比重不同的珠粒进行的，以便可以在一个试管内一次地进行多项鉴定。
本发明另一个目的是提供一种描述特性的技术，其中分析是通过在样品中形成显著的抗体/抗原配对带而进行的。
本发明其它目的和优点将在以下并于发明的较佳实施例的详细阐述中配合相应附图得到更充分显示。在图中：
图1是用以实现本发明的过程的离心管的侧视图;
图2是其中含有被离心的全血样本的试管，其中红细胞层被放大以特别地显示本发明的特点。
图3是实现本发明中所采用的离心管的第二实施例的轴向剖视图。
现在参见图1和图2。在图1中有一个试管2，它可以是一个玻璃毛细管或其它透明管，它可以含有一根塑料制成的浮漂或嵌入芯4，后者的比重使其在其中装有血样的试管2被离心之后穿过红细胞落入试管2的底部6。比重不同的抗体和/或抗原配对的塑性珠粒亲和群可以被置于试管2内的块5中。一个塑料盖10封闭试管2的底部6。每一珠粒群的比重将大于最轻的红细胞（即最原始的网织红细胞）的比重。
血样被抽入管2之中，在培养了一段时间之后，与嵌入芯4和珠粒5一起被离心。在培养过程中，珠粒块5弥散在血样中，然后在离心步骤中分成不同的带，这些带在红细胞层中形成一些线，如图2所示，同时浮漂4则穿过红细胞R。管2中还含有一些前述的已标记AAAC抗体。
白细胞W在红/白红胞界面I之上的带中分出层。密度标志物珠粒B依密度不同在红细胞层中分层。对带B的检查将显示其中带B中哪些已被标签，因为荧光标记物只能在被加标记的带中被检测到。
图3示出可以用来实现本发明的离心管的另一种替换形式。管12有一个化合物漏斗形孔，带有加大的开口端部分14和受限的封闭端部分16。孔的大小如此设定以便使被离心后血样中红细胞R落入孔的受限部分16，而白细胞和血浆则保留在孔的加大部分14中的大部分中。被标记的密度标志物带B弥散于离心后的红细胞层中。管12由透明玻璃或塑料材料制作。请注意图3所示的实施例中未采用漂浮部件。
从图2和3将可注意到：密度标志物带被分得足够开，使每个带可以不受任何其它带B干扰地地进行荧光鉴定、或其它能量辐射鉴定，并且甚至能够如以下提出的被量值化。当进行血样鉴定时，红细胞的自然属性，即当以排斥血浆的方式被离心时它们相叠的事实，保证了实际上所有在管内的未结合的标记AAAC抗体将结束于血浆层中，并将不影响该过程。
下面举例说明利用本发明对样本中的一种目标分析物定量的一个一般例子。医生可以从文献中预计在已知待验生物液体的体积样品中找到多少一种目标分析物的分子或单位。比如：假设一个遭受Lyne病感染的病人每毫升血液中最多可能含有50Lyme分析物单位（50    Lyme    analyte    units    per    milliter    of    blood）。医生将向每毫升被测血样中至少加入100密度标志物/抗原/抗体配对单位，也将向容器中每毫升样品最少加入100已标记AAAC抗体单位。因为拥有与预计在样品中找到的最大数量的分析物相比超量的结合位点和标记粒子，Lyme珠粒带发出的标记辐射强度将与样本中实际存在的Lyme待分析物的数量成正比。这样，血液中Lyme待分析物的含量就可以通过测量辐射强度而得到估算。定量测定步骤的关键是在血样中提供与预计能在样品中找到的分析物单位的最大数值相比起作用的超量的结合点和标记抗体。只要存在的待分析物的量与最终结合于密度标志物-AAAC抗体偶对上的待分析物之间存在一定数学关系，即使结合的AAAC抗体单位以少于待分析物的摩尔数出现，人们也能够求出分析物的量值。
当一个实验室希望利用血清或血浆样本，或者需要更有价值的密度梯度时，诸如如果需要将很多密度梯度分离开的情形时，则可以用一种稳定材料预先灌注图3所示的试管的狭窄部分，例如灌注具有所需梯度的胶凝Ficoll。这种密度梯度材料，除了可以分离固有带之外，还在离心过程中起到从结合层中冲走未结合的AAAC抗体的作用。
应能理解到，虽然已经结合血液诊断相关描述了本发明，但本发明还可用于诊断其它生物液中所能找到的高度特异性补体偶对的存在与缺少。与象血浆分析一样，当鉴定一种血以外的其它生物液时，离心步骤需要在密度梯度液体中，例如，如上所述的Ficoll凝胶中进行，它将不与生物液的液相相混合，并将使密度梯度液体中的带依密度地分离开，由于同时利用密度标志物的梯度液体冲洗，所以保证了所有未结合标记从带中分离出来。这消除了未结合标记与标记带计量的干扰。当检查全血时，以及当在胶凝的Ficoll中测试一种非细胞液体时（它出现于离心步骤中），将未结合标记从标记细胞中冲走的固有特性，消除了先有技术中所要求的分离冲洗步骤，并且防止了未结合标记影响过程的精度的问题。这种固有冲洗机制对本发明而言是一重要因素。
因为可以在不背离本发明概念的情况下，对本发明所公开的实施例进行很多变化和修改，所以除了由所附权利要求所请求的之外，并不打算对本发明作限制。

Claims (10)

1、一种用检测在一透明管内生物液样品中可疑目标分析物的方法，所述方法包括步骤：
a)向样品中加入一组密度标志物，这些密度标志物具有预定的比重，在所述组中的每种密度标志物与一种结合物质相配对，以形成对该可疑目标分析物特效的密度标志物偶对；
b)向样品中加入被标记的配对结合抗体；
c)培养这种密度标志物/被标记的配对结合抗体样品混合物；
d)依密度将密度标志物聚集到管内的至少一个清晰带中；以及
e)检测是否该带显示出被标记配对结合抗体的存在，进而判定出目标分析物的存在。
2、如权利要求1的方法，其中通过向样品中增加不同组密度标志物，可以检测在透明管中某种生物液样品内一种或多种不同目标分析物，对于样品内每种被怀疑的目标分析物有一组密度标志物，每组密度标志物具有不同于其它组的密度标志物的比重，并且在每组中的每一种密度标志物都与对目标分析物的一种有特效的结合物质相配对，从而每种不同密度标志物/结合物质配对组对可疑目标分析物中一种不同分析物有特效。
3、如权利要求2的方法，进一步包括在依密度进行分离的步骤期间从密度标志物中替换未结合标记配对结合抗体的步骤。
4、如权利要求3的方法，其中液样是全血，并且其中密度标志物的比重大于最轻红细胞的比重。
5、如权利要求4的方法，其中所述替换步骤是通过在全血样内被离心的红细胞所进行的。
6、用于离心地分析一种生物液样中目标分析物的存在或缺少的装置，所述装置包括：
a）一个具有用于容纳液样的孔的透明管;
b）用于在所述管孔内形成一局部缩狭的装置;
c）在所述管内大量的目标分析物特效抗体和/或抗原配对密度标志物;以及
d）在所述管内形成一密度梯度层的装置，在所述管中液样的离心过程中，密度标志物沉入其中。
7、如权利要求6的装置，进一步包括在所述管内的可操作量的被标记抗-抗原-抗体复合物（AAAC）抗体，所述AAAC抗体特效于在所述密度标志物上形成的任何抗体/抗原/分析物偶对，并且可操作以便可检测地突出所述偶对。
8、如权利要求7的装置，其中存在于管内的抗体和/或抗原配对密度标志物和被标记的AAAC抗体的数量超出了预计在液样中可找到的目标分析物单位的数量，大到足以量化液样中目标分析物的程度。
9、如权利要求8的装置，其中抗体和/或抗原配对密度标志物和被标记的AAAC抗体的数量至少是所预计目标分析物量的两倍。
10、用于离心地分析一种生物液样中免疫球蛋白亚群存在或缺少的装置，所述装置包括：
a）一个具有用于容纳液样的孔的透明管;
b）用于在所述管的孔内形成一局部缩狭的装置;
c）在所述管内的大量的免疫球蛋白特效抗体和/或抗原配对密度标志物;
d）在所述管内的可操作量的被标记抗-抗原-抗体混合物（AAAC）抗体，所述AAAC抗体特效于形成于所述密度标志物上的免疫球蛋白抗体-抗原复合物，并且可操作以便可检测地突出所述复合物;以及
e）用于在所述管中形成一密度梯度层的装置，在离心过程中，所述密度标志物将沉入其中。
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US5776710A (en) 1998-07-07
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TW297094B (zh) 1997-02-01
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EP0595641A3 (en) 1995-04-26
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