Human ErbB-2 (Her-2) transgenic mice: A model system for testing Her-2 based vaccines
Human ErbB-2 (Her-2) transgenic mice: A model system for testing Her-2 based vaccines
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DOI：
10.4049/jimmunol.171.11.5787
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发表时间：
2003-12-01
影响因子：
4.4
通讯作者：
Wei, WZ
中科院分区：
文献类型：
--
作者：
Piechocki, MP;Ho, YS;Wei, WZ
在乳清酸性蛋白启动子下用野生型人c-ErbB-2（Her-2）产生Her-2转基因（Tg）小鼠。它们对Her-2具有耐受性，适合用于测试Her-2疫苗。通过体外转染验证了来自乳清酸性蛋白-Her-2盒的跨膜ErbB-2的表达及其通过胰岛素和氢化可的松的上调。将转基因盒显微注射到来自与B6 C3雄性交配的B6 C3（C3 H X C57 BL/6）雌性的受精卵中。将转基因阳性小鼠与C57 BL/6小鼠回交。人ErbB-2在妊娠期和哺乳期的分泌性乳腺上皮中表达，并在小脑分子层内的Bergman胶质细胞中组成性表达。在检查的任何组织中均未检测到明显的肿瘤转化。对Her-2的耐受性通过具有表达高水平人ErbB-2的同基因肿瘤的BALB/c小鼠证明。肿瘤仅在Her-2 Tg小鼠中生长而不诱导Ab应答，而非转基因同窝小鼠在10个月内保持无肿瘤，并产生了强有力的抗ErbB-2 Ab应答。当分别用编码secErbB-2和GM-CSF的质粒DNA免疫5次时，近似33%的Her-2 Tg小鼠拒绝EL-4/E2肿瘤细胞的致死攻击，而所有免疫的同窝小鼠都拒绝肿瘤。因此，Her-2 Tg小鼠在脑和乳腺中表达人ErbB-2，并表现出对ErbB-2的耐受性，DNA疫苗接种可部分克服这种耐受性。Her-2 Tg小鼠的可破坏耐受性与人类相似，并且这些小鼠特别适合于测试基于人ErbB-2的疫苗。
Her-2 transgenic (Tg) mice were generated with wild-type human c-ErbB-2 (Her-2) under the whey acidic protein promoter. They are tolerant to Her-2 and appropriate for testing Her-2 vaccines. The expression of transmembrane ErbB-2 from the whey acidic protein-Her-2 cassette and its up-regulation by insulin and hydrocortisone was verified by in vitro transfection. The transgene cassette was microinjected into fertilized eggs from B6C3 (C3H x C57BL/6) females mated with B6C3 males. Transgene-positive mice were backcrossed onto C57BL/6 mice. Human ErbB-2 was expressed in the secretory mammary epithelia during pregnancy and lactation and expressed constitutively in the Bergman glia cells within the molecular layer of the cerebellum. Overt, neoplastic transformation was not detected in any tissue examined. Tolerance to Her-2 was demonstrated by inoculating mice with a syngenic tumor expressing high levels of human ErbB-2. Tumors grew exclusively in Her-2 Tg mice without inducing an Ab response, while the nontransgenic littermates remained tumor free for 10 mo and mounted a robust anti-ErbB-2 Ab response. When immunized five times with plasmid DNA encoding secErbB-2 and GM-CSF, respectively, similar to33% of the Her-2 Tg mice rejected a lethal challenge of EL-4/E2 tumor cells, whereas all immunized littermates rejected the tumor. Therefore, Her-2 Tg mice express human ErbB-2 in the brain and mammary gland and demonstrated tolerance to ErbB-2 which was partially overcome by DNA vaccination. The breakable tolerance of Her-2 Tg mice resembles that in human and these mice are particularly suited for testing human ErbB-2 based vaccines.