EBV CTL EPITOPES IN VACCINE DEVELOPMENT

疫苗开发中的 EBV CTL 表位

• 批准号: 2098663
• 负责人: Denis James Moss
• 金额: $ 17.41万
• 依托单位: QUEENSLAND INSTITUTE OF MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-17 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2098663
• 关键词: Burkitt's lymphoma; Epstein Barr virus; clone cells; cytotoxic T lymphocyte; epitope mapping; genetic manipulation; laboratory mouse; synthetic peptide; viral vaccines; virus antigen

Epstein-Barr virus (EBV) is associated with several important human malignancies. It is now well established that cytotoxic T lymphocytes (CTLs) play a critical role in controlling the level of EBV-infected B cells which express a family of latent viral antigens, including EBNAs 1,2,3,4,5 and 6. These latent antigens include CTL epitopes that are presented on the surface of virus-infected cells in conjunction with class I antigens. This proposal is designed to assess, for the first time, the capacity of an EBV CTL peptide epitope (EBNA3 derived/HLA B8 restricted) to activate a primary response in vivo in a cohort of human volunteers. These volunteers will be selected from healthy laboratory and army personnel. If successful, this proposal would establish the potential use of synthetic peptides in the development of a subunit vaccine to EBV and to other human oncogenic viruses where it is unlikely that attenuated strains will ever be accepted as a vaccination procedure. The other major aspect of the proposal relates to the mechanisms whereby EBV-associated tumors escape immune surveillance. Particular attention will be focused on Burkitt's lymphoma (BL) which express only EBNA1. Thus far, no CTL epitopes have been localized on EBNA1. The present proposal seeks to demonstrate unequivocally whether EBNA1 includes CTL epitopes. If CTL epitopes are identified in EBNA1, it will be important to determine whether BL cells process and present these epitopes. These studies are designed to delineate how BL cells escape immunological recognition. The methodology to be used in the proposal includes the following: The activation of an EBV-specific response in vivo will be monitored using a standard EBV regression assay, clonal and polyclonal CTL assays and limiting dilution analysis. The sensitivity of BL cells to CTL lysis will be determined following the treatment of tumor cells with appropriate synthetic peptides, vaccinia constructs and transfected episomal viral mini-gene expression vectors. The presence of CTL epitopes within EBNA1 will be assessed by activating an EBNA1-specific response in human and mouse cells using recombinant EBNA1.

EB 病毒 (EBV) 与多种重要的人类病毒有关 恶性肿瘤。 目前已明确，细胞毒性 T 淋巴细胞 (CTL) 在控制 EBV 感染 B 的水平方面发挥着关键作用 表达潜在病毒抗原家族的细胞，包括 EBNA 1、2、3、4、5 和 6。这些潜在抗原包括 CTL 表位 与类一起呈现在病毒感染的细胞表面 我抗原。 该提案旨在首次评估 EBV CTL 肽表位（EBNA3 衍生/HLA B8 限制）的能力 激活一组人类志愿者体内的初级反应。 这些 志愿者将从健康的实验室和军队人员中选拔。 如果 成功后，该提案将确定合成材料的潜在用途 肽用于开发 EB 病毒和其他人类亚单位疫苗 减毒株不可能存在的致癌病毒 被接受为疫苗接种程序。 该提案的另一个主要方面涉及机制 EBV 相关肿瘤逃避免疫监视。 特别注意 将重点关注仅表达 EBNA1 的伯基特淋巴瘤 (BL)。 因此 到目前为止，EBNA1 上还没有定位 CTL 表位。 目前的建议 试图明确证明 EBNA1 是否包含 CTL 表位。 如果 CTL 表位在 EBNA1 中被鉴定，确定这一点很重要 BL 细胞是否处理并呈递这些表位。 这些研究是 旨在描述 BL 细胞如何逃避免疫识别。 提案中使用的方法包括以下内容： 体内 EBV 特异性反应的激活将使用 标准 EBV 回归测定、克隆和多克隆 CTL 测定以及 有限稀释分析。 BL细胞对CTL裂解的敏感性将 用适当的方法处理肿瘤细胞后确定 合成肽、牛痘构建体和转染的附加型病毒 微型基因表达载体。 EBNA1 中存在 CTL 表位 将通过激活人类中的 EBNA1 特异性反应来进行评估 使用重组 EBNA1 的小鼠细胞。