Danger signals and nonself entity of tumor antigen are both required for eliciting effective immune responses against HER-2/neu positive mammary carcinoma: implications for vaccine design
Danger signals and nonself entity of tumor antigen are both required for eliciting effective immune responses against HER-2/neu positive mammary carcinoma: implications for vaccine design
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DOI：
10.1007/s00262-008-0475-8
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发表时间：
2008-09-01
影响因子：
5.8
通讯作者：
Manjili, Masoud H.
中科院分区：
文献类型：
--
作者：
Kmieciak, Maciej;Morales, Johanna K.;Manjili, Masoud H.
使用亲本 FVB 小鼠及其 neu 转基因小鼠 FVBN202，我们首次表明，乳腺上皮细胞的危险增生与对 neu“自身”肿瘤抗原的免疫耐受性的破坏同时发生，尽管这种免疫反应未能阻止 FVBN202 小鼠中自发性 neu 过度表达乳腺癌（MMC）的形成或排斥移植的 MMC。另一方面，neu 特异性免疫反应似乎对亲代 FVB 小鼠中的 MMC 有效，因为大鼠 neu 蛋白在这些动物中被视为“非自身”抗原，并且该蛋白在 MMC 中危险地过度表达。有趣的是，肿瘤中neu“非自身”蛋白的低/中度表达诱导了免疫反应，但这种免疫反应未能排斥FVB小鼠中的肿瘤。我们的结果表明，肿瘤抗原或危险信号的自非自（SNS）实体虽然同样可以诱导抗原特异性免疫反应，但不能保证针对肿瘤的免疫反应的有效性。另一方面，危险条件下的抗原实体，即 neu 非自身蛋白的异常/危险过度表达，将保证 FVB 小鼠中有效的抗肿瘤免疫反应。这种统一的“危险-SNS”模型建议重点关注自然加工的隐秘或突变表位的识别，这些表位被宿主免疫系统视为半非自身，以及疫苗设计中的新型危险佐剂。
Using parental FVB mice and their neu transgenic counterparts, FVBN202, we showed for the first time that dangerous hyperplasia of mammary epithelial cells coincided with breaking immunological tolerance to the neu "self" tumor antigen, though such immune responses failed to prevent formation of spontaneous neu-overexpressing mammary carcinoma (MMC) or reject transplanted MMC in FVBN202 mice. On the other hand, neu-specific immune responses appeared to be effective against MMC in parental FVB mice because of the fact that rat neu protein was seen as "nonself" antigen in these animals and the protein was dangerously overexpressed in MMC. Interestingly, low/intermediate expression of the neu "nonself" protein in tumors induced immune responses but such immune responses failed to reject the tumor in FVB mice. Our results showed that self-nonself (SNS) entity of a tumor antigen or danger signal alone, while may equally induce an antigen-specific immune response, will not warrant the efficacy of immune responses against tumors. On the other hand, entity of antigen in the context of dangerous conditions, i.e. abnormal/dangerous overexpression of the neu nonself protein, will warrant effective anti-tumor immune responses in FVB mice. This unified "danger-SNS" model suggests focusing on identification of naturally processed cryptic or mutated epitopes, which are considered semi-nonself by the host immune system, along with novel dangerous adjuvant in vaccine design.