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人HER-2/neu蛋白免疫可规避对大鼠neu的耐受性：一种针对“自身”肿瘤抗原的疫苗策略。

Human HER-2/neu protein immunization circumvents tolerance to rat neu: a vaccine strategy for 'self' tumour antigens.

作者信息

Disis M L, Shiota F M, Cheever M A

机构信息

Department of Medicine, University of Washington, Seattle 98195-6527, USA.

出版信息

Immunology. 1998 Feb;93(2):192-9. doi: 10.1046/j.1365-2567.1998.00424.x.

DOI:10.1046/j.1365-2567.1998.00424.x
PMID:9616368
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1364178/
Abstract

Many newly defined tumour antigens are 'self' proteins. Immunizing cancer patients against these antigens may be difficult due to tolerance. The HER-2/neu oncogenic protein is such a 'self' tumour antigen. Rat neu is homologous with human HER-2/neu and provides a model system for studying vaccination strategies. Rats are tolerant to rat neu. Vaccination with this 'self' protein elicits no detectable immune response. The current studies evaluated whether tolerance to rat neu can be circumvented by immunizing with the highly homologous foreign human HER-2/neu protein. Rats were immunized with human HER-2/neu intracellular domain (hICD) protein that is 92% homologous to rat neu ICD. Animals immunized with hICD developed significant antibody and T-cell responses that were specific for both human HER-2/neu and rat neu. Neu-specific antibodies were present in titres of greater than 1:200,000. Analysis of the specificity of the antibody response using synthetic peptides demonstrated substantial reactivity to an epitope with 100% homology between rat and human protein. Significant T-cell responses (stimulation index > 10) to hICD and rat neu protein (stimulation index > 4) were detected. The T cells also responded to both human and rat ICD. The results imply that immunization with foreign proteins, which are highly homologous to 'self' tumour antigens, may be an effective vaccine strategy for 'self' tumour antigens.

摘要

许多新定义的肿瘤抗原是“自身”蛋白。由于免疫耐受，针对这些抗原对癌症患者进行免疫接种可能会很困难。HER-2/neu致癌蛋白就是这样一种“自身”肿瘤抗原。大鼠neu与人HER-2/neu同源，为研究疫苗接种策略提供了一个模型系统。大鼠对大鼠neu具有耐受性。用这种“自身”蛋白进行疫苗接种不会引发可检测到的免疫反应。当前的研究评估了通过用高度同源的外源人HER-2/neu蛋白进行免疫接种是否可以规避对大鼠neu的耐受性。用与人HER-2/neu细胞内结构域（hICD）蛋白免疫大鼠，该蛋白与大鼠neu ICD的同源性为92%。用hICD免疫的动物产生了显著的抗体和T细胞反应，这些反应对人HER-2/neu和大鼠neu均具有特异性。neu特异性抗体的滴度大于1:200,000。使用合成肽分析抗体反应的特异性表明，对大鼠和人蛋白之间具有百分之百同源性的一个表位有大量反应。检测到对hICD和大鼠neu蛋白的显著T细胞反应（刺激指数>10）以及对大鼠neu蛋白的显著T细胞反应（刺激指数>4）。T细胞也对人和大鼠的ICD有反应。结果表明，用与“自身”肿瘤抗原高度同源的外源蛋白进行免疫接种可能是针对“自身”肿瘤抗原的一种有效疫苗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4cb/1364178/42999ab9d4b7/immunology00046-0061-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4cb/1364178/499cfe2c695b/immunology00046-0060-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4cb/1364178/42999ab9d4b7/immunology00046-0061-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4cb/1364178/499cfe2c695b/immunology00046-0060-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4cb/1364178/42999ab9d4b7/immunology00046-0061-a.jpg

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Human HER-2/neu protein immunization circumvents tolerance to rat neu: a vaccine strategy for 'self' tumour antigens.人HER-2/neu蛋白免疫可规避对大鼠neu的耐受性：一种针对“自身”肿瘤抗原的疫苗策略。
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本文引用的文献

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Antibody to ras proteins in patients with colon cancer.结肠癌患者体内的ras蛋白抗体。
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HER-2/neu protein: a target for antigen-specific immunotherapy of human cancer.HER-2/neu蛋白：人类癌症抗原特异性免疫疗法的一个靶点。
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DNA vaccines for cancer too.用于癌症治疗的DNA疫苗也是如此。
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Curr Opin Immunol. 1996 Oct;8(5):637-42. doi: 10.1016/s0952-7915(96)80079-3.
4
Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.每周静脉注射重组人源化抗p185HER2单克隆抗体治疗HER2/neu过表达转移性乳腺癌患者的II期研究。
J Clin Oncol. 1996 Mar;14(3):737-44. doi: 10.1200/JCO.1996.14.3.737.
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Peptide-based, but not whole protein, vaccines elicit immunity to HER-2/neu, oncogenic self-protein.基于肽而非完整蛋白质的疫苗可引发针对致癌自身蛋白HER-2/neu的免疫反应。
J Immunol. 1996 May 1;156(9):3151-8.
6
The inability to process a self-peptide allows autoreactive T cells to escape tolerance.无法处理自身肽会使自身反应性T细胞逃避免疫耐受。
J Exp Med. 1993 Feb 1;177(2):567-71. doi: 10.1084/jem.177.2.567.
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Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes.人类基因MAGE - 3编码一种抗原，该抗原可被自体溶细胞性T淋巴细胞识别，存在于黑色素瘤中。
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Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes.黑色素细胞谱系特异性抗原gp100可被黑色素瘤来源的肿瘤浸润淋巴细胞识别。
J Exp Med. 1994 Mar 1;179(3):1005-9. doi: 10.1084/jem.179.3.1005.
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Cancer antigens: immune recognition of self and altered self.癌症抗原：自身及改变的自身的免疫识别
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Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide.乳腺癌和卵巢癌特异性细胞毒性T淋巴细胞识别相同的HER2/neu衍生肽。
Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):432-6. doi: 10.1073/pnas.92.2.432.