IMMUNOGENIC PROPERTIES OF STRUCTURALLY MODIFIED HUMAN TISSUE PLASMINOGEN ACTIVATORS IN CHIMPANZEES AND MICE
IMMUNOGENIC PROPERTIES OF STRUCTURALLY MODIFIED HUMAN TISSUE PLASMINOGEN ACTIVATORS IN CHIMPANZEES AND MICE
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DOI：
10.1016/0272-0590(92)90094-x
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发表时间：
1992-11-01
期刊：
影响因子：
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通讯作者：
SHIONOYA, H
中科院分区：
文献类型：
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作者：
KATSUTANI, N;YOSHITAKE, S;SHIONOYA, H
第二代人组织纤溶酶原激活剂（tPA）衍生物的免疫原性在黑猩猩和小鼠系统进行了检查。五种修饰的tPAs（mtPAs）（指定为2660、2663、2810、8000和9200）、作为阳性对照的重组天然tPA或牛血清白蛋白（BSA）以合适的间隔皮下注射到黑猩猩中9次，在遗传学上与人类最接近的物种。这些动物通过酶-连接的免疫吸附测定和蛋白质印迹分析。测试的5种mtPA之一的9200和tPA均不具有免疫原性，尽管BSA和其他4种mtPA在这些条件下具有免疫原性。因此，9200上的修饰没有暴露抗原决定物，并且预期这种修饰的tPA在人体中没有免疫原性。在小鼠研究中，用mtPA免疫小鼠。检测这些动物的血清样品中的抗mtPA抗体，这些抗体不能通过对tPA抗体的免疫吸附同时识别天然tPA。当检测9200和除8000外的其他mtPA的血清样品时，改变天然tPA反应性抗体消除的此类抗体的量很少或没有。考虑到黑猩猩研究的结果，可以得出结论，Ag特异性抗体主要产生于小鼠系统中修饰蛋白中存在的未改变的表位，其中天然蛋白具有免疫原性。这些结果表明，黑猩猩模型应该是有用的预测第二代重组蛋白在人的免疫原性，而我们采用的小鼠系统，确定新产生的修饰蛋白的表位，是不够的。
Immunogenic properties of second generation human tissue plasminogen activator (tPA) derivatives were examined in chimpanzee and mouse systems. Five species of modified tPAs (mtPAs) (designated 2660, 2663, 2810, 8000, and 9200), recombinant native tPA or bovine serum albumin (BSA) as a positive control were subcutaneously injected nine times at suitable intervals into chimpanzees, genetically the closest species to man. These animals were tested for antigen(Ag)-specific antibodies to the corresponding proteins by means of enzyme-linked immunosorbent assay and Western blot analysis. Neither 9200, one of the five mtPAs tested, nor tPA was immunogenic, although BSA and the other four mtPAs were immunogenic under these conditions. Thus, an antigenic deter minant was not exposed by the modification on 9200 and this modified tPA is expected not to be immunogenic in humans. In the mouse studies, mice were immunized with mtPAs. Serum sam-pies from these animals were tested for antibodies to the mtPAs which did not concomitantly recognize native tPA by immune ad sorption of the antibodies to tPA. The amount of such antibodies alter the elimination of native tPA-reactive antibodies was little or none when the serum samples from 9200 and from the other mtPAs, except 8000, were tested. Taking into consideration the results of the chimpanzee studies, it can be concluded that Ag-specific antibodies are dominantly produced to unchanged epitopes present in modified proteins in the mouse system, in which the native protein is immunogenic. These results suggest that the chimpanzee model should be useful to predict immunogenicity of second generation recombinant proteins in man, while the mouse system adopted by us, which determines the newly generated epitopes of the modified proteins, is not sufficient.