Reconstituted complexes of mycobacterial HSP70 and EBV LMP2A-derived peptides elicit peptide-specific cytotoxic T lymphocyte responses and anti-tumor immunity.
Reconstituted complexes of mycobacterial HSP70 and EBV LMP2A-derived peptides elicit peptide-specific cytotoxic T lymphocyte responses and anti-tumor immunity.
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DOI：
10.1016/j.vaccine.2011.07.063
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发表时间：
2011-10
期刊：
影响因子：
5.5
通讯作者：
Genyan Liu;K. Yao;B. Wang;F. Zhou;Yun Chen;Linyun Li;J. Chi;Guangyong Peng
中科院分区：
文献类型：
--
作者：
Genyan Liu;K. Yao;B. Wang;F. Zhou;Yun Chen;Linyun Li;J. Chi;Guangyong Peng
EB病毒潜伏膜蛋白2A（LMP 2A）是EB病毒相关恶性肿瘤如霍奇金病（HD）和鼻咽癌中表达的亚显性抗原。大量的前期研究将LMP 2A描述为EBV相关疾病免疫治疗的理想靶抗原，但在临床试验中取得的成功有限。结核分枝杆菌热休克蛋白70（MtHsp 70）是一种有效的蛋白质或表位疫苗的分子佐剂。在本研究中，我们在体外重建了MtHsp 70和LMP 2A衍生肽（LMP 2A 356 - 364 FLYALALLL和LMP 2A 426 - 434 CLGGLLTMV）的两种伴侣复合物。然后，我们使用EBV感染的健康供体PBMC和HLA-A2.1转基因小鼠模型研究了由MtHsp 70和LMP 2A-肽的重构复合物诱导的LMP 2A特异性免疫应答。我们发现MtHsp 70和LMP 2A-肽的重组复合物在体外和体内显著诱导LMP 2A特异性IFN-γ产生细胞和唤醒细胞毒性T淋巴细胞（CTL）。此外，由MtHsp 70和LMP 2A-肽的重构复合物诱导的LMP 2A特异性免疫应答介导了针对小鼠模型中LMP 2A表达的肿瘤攻击的有效保护活性以及治疗功效。这些研究为开发针对EBV相关恶性肿瘤的新型LMP 2A疫苗提供了新的见解。
Epstein–Barr virus (EBV) latent membrane protein 2A (LMP2A) is a subdominant antigen expressed in EBV-associated malignancies, such as Hodgkin's diseases (HD) and nasopharyngeal carcinoma. A large number of previous studies have described LMP2A as an ideal target antigen in immunotherapy of EBV-related diseases, while limited successes have been achieved in clinical trials. Mycobacterium tuberculosis heat shock protein 70 (MtHsp70) is known as an effective molecular adjuvant for protein- or epitope-based vaccines. In the present study, we reconstituted two chaperone complexes of MtHsp70 and LMP2A-derived peptides (LMP2A356–364FLYALALLL and LMP2A426–434CLGGLLTMV) in vitro. We then investigated LMP2A-specific immune responses induced by reconstituted complexes of MtHsp70 and LMP2A-peptides using both EBV infected healthy donor PBMCs and HLA-A2.1 transgenic mouse models. We found that reconstituted complexes of MtHsp70 and LMP2A-peptides significantly elicit LMP2A-specific IFN-γ-producing cells and rousted cytotoxic T lymphocytes (CTLs) in vitro and in vivo. In addition, LMP2A-specific immune responses induced by the reconstituted complexes of MtHsp70 and LMP2A-peptides mediated potently protective activity as well as therapeutic efficacy against LMP2A-expressed tumor challenge in mouse models. These studies provide new insights for the development of novel LMP2A-based vaccines against EBV-associated malignancies.