Identification of T-helper peptide-epitopes against gene product of Epstein-Barr virus and Hunan T-cell leukemia virus type I.

EB病毒和湖南T细胞白血病病毒I型基因产物的T辅助肽表位的鉴定。

基本信息

批准号：
18590360
负责人：
KOBAYASHI Hiroya
金额：
$ 2.57万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590360/
关键词：
EBV STEAP HLA Peptide Epitope Helper T lymphocyte Tumor Immunotherapy HTLV-1 Tax T cell ワクチン

项目摘要

Epstein-Barr virus (EBV)-encoded latent membrane protein l (LMP1) has oncogenic potential and is expressed in many EBV-associated malignancies. Although LMP1 is regarded as a potential tumor associated antigen (TAA) for immunotherapy and several LMP1-specific MHC class I-restricted CTL epitopes have been reported, little is known regarding MHC class II-restricted CD4 helper T lymphocytes (HTL) epitopes for LMP1. The goal of the present studies was to determine whether MHC class II restricted CD4 T cell responses could be induced against the LMP1 antigen and to evaluate the anti-tumor effect of these responses. We have combined the use of a predictive MHC class II binding peptide algorithm with in vitro vaccination of CD4 T cells using candidate peptides to identify naturally processed epitopes derived from LMP1 that elicit immune responses against EBV-expressing tumor cells. Peptide LMP1_<159-175> was effective in inducing HTL responses that were restricted by HLA-DR9, DR53 or DR15, indicating that this peptide behaves as a promiscuous T cell epitope. Moreover, LMP1_<159-175>-reactive HTL clones directly recognized EBV-lymphoblastoid B cells, EBV-infected NK/T lymphoma cells and naturally processed antigen in the form of LMP1+ tumor-cell lysates presented by autologous dendritic cells. Since the newly identified epitope LMP1_<159-175> overlaps with an HLA-A2-restricted CTL epitope (LMP1_<159-175>), this peptide might have ability of inducing simultaneous CTL and HTL responses against LMP1. Overall, our data should be relevant for the design and optimization of T-cell epitope based immunotherapy against various EBV associated malignancies including NK/T cell lymphomas.

爱泼斯坦 - 巴尔病毒（EBV）编码的潜在膜蛋白L（LMP1）具有致癌潜力，并且在许多与EBV相关的恶性肿瘤中表达。尽管LMP1被认为是用于免疫疗法的潜在肿瘤抗原（TAA），并且已经报道了几种LMP1特异性MHC MHC I限制的CTL表位，但对于LMP1而言，对于MHC II限制的CD4辅助CD4辅助CD4助手T淋巴细胞（HTL）表位，MHC II限制的CD4辅助CD4助手T淋巴细胞（HTL）表现鲜为人知。本研究的目的是确定是否可以针对LMP1抗原诱导MHC II限制的CD4 T细胞反应，并评估这些反应的抗肿瘤效应。我们已经将预测性MHC II类结合肽算法与使用候选肽的体外疫苗接种CD4 T细胞的使用结合在一起，以鉴定从LMP1产生的自然处理的表位，从LMP1产生了对EBV表达EBV表达肿瘤细胞的免疫反应。肽LMP1_ <159-175>在诱导受HLA-DR9，DR53或DR15限制的HTL响应有效，表明该肽的表现是滥交T细胞表位。此外，LMP1_ <159-175> - 反应性HTL克隆直接识别EBV - 蛋白母细胞B细胞，EBV感染的NK/T淋巴瘤细胞以及以自体树突状细胞提供的LMP1+肿瘤裂解液形式的自然加工抗原。由于新确定的表位LMP1_ <159-175>与HLA-A2限制的CTL表位（LMP1_ <159-175>）重叠，因此该肽可能具有诱导同时CTL和HTL响应LMP1的CTL和HTL响应。总体而言，我们的数据应与针对各种EBV相关的恶性肿瘤（包括NK/T细胞淋巴瘤）的基于T细胞表位的免疫疗法的设计和优化有关。