Peptide-based, but not whole protein, vaccines elicit immunity to HER-2/neu, oncogenic self-protein.
Peptide-based, but not whole protein, vaccines elicit immunity to HER-2/neu, oncogenic self-protein.
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DOI：
10.4049/jimmunol.156.9.3151
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发表时间：
1996-05
影响因子：
4.4
通讯作者：
M. Disis;J. Gralow;H. Bernhard;S. Hand;W. D. Rubin;M. Cheever
中科院分区：
文献类型：
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作者：
M. Disis;J. Gralow;H. Bernhard;S. Hand;W. D. Rubin;M. Cheever
HER-2/neu是一种过表达的致癌蛋白，已被提议作为人类癌症疫苗的靶点。然而，HER-2/neu是一种“自身”蛋白，并且尚未建立有效地使患者对“自身”肿瘤Ag免疫的疫苗策略的方法。在人类中定义的许多肿瘤Ag是非突变的自身蛋白，例如，法师，克服耐受性可能是产生有效的抗肿瘤免疫的关键。一种理论认为，对自身蛋白质的耐受性仅针对蛋白质的优势表位，而不是蛋白质的每个部分。因此，耐受性可以通过免疫肽片段而不是整个蛋白质来规避。本文概述的研究表明，大鼠neu特异性免疫可以通过免疫原性大鼠neu肽疫苗接种在大鼠中引起，但不能通过免疫与完整的蛋白。使用大鼠模型，因为大鼠neu蛋白与人HER-2/neu蛋白具有89%的同源性，并且具有相似的组织分布和表达水平。用大鼠neu蛋白胞内域或胞外域氨基酸序列衍生的肽组免疫大鼠，两组均产生对大鼠neu肽和蛋白的CD 4 + T细胞免疫和Ab免疫。以类似方式用完整纯化的大鼠neu蛋白免疫的动物没有对大鼠neu产生Ab或T细胞免疫。此外，发展neu特异性免疫的大鼠没有显示针对表达基础水平大鼠neu蛋白的器官的自身免疫的组织病理学证据。这些研究表明，免疫策略，可能是有效的，在人类癌症疫苗靶向自身肿瘤抗原。
HER-2/neu, an overexpressed oncogenic protein, has been proposed as a human cancer vaccine target. HER-2/neu is a "self" protein, however, and methods of vaccine strategies that would be effective in immunizing patients to a "self" tumor Ag have not been established. Many of the tumor Ags defined in humans are nonmutated self proteins, e.g., MAGE, and overcoming tolerance may be key in the generation of effective anti-tumor immunity. One theory states that tolerance to self proteins is directed only to dominant epitopes of proteins and not to every portion of the protein. Accordingly, tolerance can be circumvented by immunization to peptide fragments, but not whole protein. The studies outlined here demonstrate rat neu-specific immunity could be elicited in rats by vaccination with immunogenic rat neu peptides, but not by immunization with the intact protein. A rat model was used since rat neu protein is 89% homologous to human HER-2/neu protein and has a similar tissue distribution and level of expression. Rats were immunized with groups of peptides derived from the amino acid sequence of the intracellular domain or extracellular domain of rat neu protein and both groups developed CD4+ T cell immunity and Ab immunity to rat neu peptides and protein. Animals immunized in a similar fashion with intact purified rat neu protein did not develop Ab or T cell immunity to rat neu. Furthermore, rats that developed neu-specific immunity showed no histopathologic evidence of autoimmunity directed against organs expressing basal levels of rat neu protein. These studies suggest an immunization strategy that might be effective in human cancer vaccines targeting self tumor Ag.