首页> 外文期刊>Journal of molecular medicine: Official organ of the "Gesellschaft Deutscher Naturforscher und Arzte." >Engineered exosomes emerging from muscle cells break immune tolerance to HER2 in transgenic mice and induce antigen-specific CTLs upon challenge by human dendritic cells
【24h】

Engineered exosomes emerging from muscle cells break immune tolerance to HER2 in transgenic mice and induce antigen-specific CTLs upon challenge by human dendritic cells

机译:从肌肉细胞出现的工程外来肌肉在转基因小鼠中断开免疫耐受性,并在人树突细胞攻击时诱导抗原特异性CTL

获取原文
获取原文并翻译 | 示例

摘要

We recently described a novel biotechnological platform for the production of unrestricted cytotoxic T lymphocyte (CTL) vaccines. It relies on in vivo engineering of exosomes, i.e., nanovesicles constitutively released by all cells, with full-length antigens of choice upon fusion with an exosome-anchoring protein referred to as Nef(mut). They are produced upon intramuscular injection of a DNA vector and, when uploaded with a viral tumor antigen, were found to elicit an immune response inhibiting the tumor growth in a model of transplantable tumors. However, for a possible application in cancer immunotherapy, a number of key issues remained unmet. Among these, we investigated: (i) whether the immunogenic stimulus induced by the engineered exosomes can break immune tolerance, and (ii) their effectiveness when applied in human system. As a model of immune tolerance, we considered mice transgenic for the expression of activated rat HER2/neu which spontaneously develop adenocarcinomas in all mammary glands. When these mice were injected with a DNA vector expressing the product of fusion between Nef(mut) and the extracellular domain of HER2/neu, antigen-specific CD8(+) T lymphocytes became readily detectable. This immune response associated with a HER2-directed CTL activity and a significant delay in tumor development. On the other hand, through cross-priming experiments, we demonstrated the effectiveness of the engineered exosomes emerging from transfected human primary muscle cells in inducing antigen-specific CTLs. We propose our CTL vaccine platform as part of new immunotherapy strategies against tumors expressing self-antigens, i.e., products highly expressed in oncologic lesions but tolerated by the immune system.
机译:我们最近描述了一种新型生物技术平台,用于生产不受限制的细胞毒性T淋巴细胞(CTL)疫苗。它依赖于外泌体的体内工程,即所有细胞体组成型纳米粒子,在融合时,通过称为NEF(MUT)的外锚蛋白,具有全长抗原。在肌内注射DNA载体时产生它们,并且当用病毒肿瘤抗原进行时,发现引发免疫应答,抑制可移植肿瘤模型中的肿瘤生长。然而,对于癌症免疫疗法的可能应用,许多关键问题仍然是未满足的。其中,我们研究了:(i)工程外来诱导的免疫原性刺激是否可以破坏免疫耐受性,并在人体系统中施用时的有效性。作为一种免疫耐受的模型,我们考虑了在所有乳腺中自发地发展腺癌的活性大鼠Her2 / neu的表达的小鼠转基因。当将这些小鼠注射用表达NEF(mut)和HER2 / NEU的细胞外结构件的DNA载体注射DNA载体时,抗原特异性CD8(+)T淋巴细胞变得易于检测。这种免疫应答与HER2导向的CTL活性相关,肿瘤发育的显着延迟。另一方面,通过交叉引发实验,我们证明了从转染的人原肌细胞中出现的工程外来肌肉肌肉细胞在诱导抗原特异性CTL中的有效性。我们提出了CTL疫苗平台,作为对表达自我抗原的肿瘤的新免疫疗法策略的一部分,即,在肿瘤病变中高度表达的产品,但受免疫系统耐受的产品。

著录项

相似文献

  • 外文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号