ANTIGEN SPECIFIC T CELL ACTIVATION, APPLICATION TO VACCINES FOR CANCER AND AIDS

抗原特异性 T 细胞激活，在癌症和艾滋病疫苗中的应用

• 批准号: 3796428
• 负责人: J A BERZOFSKY
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3796428
• 关键词: AIDS /HIV test; AIDS vaccines; CD8 molecule; MHC class I antigen; Schistosoma; antigen presentation; cytotoxic T lymphocyte; gene mutation; hepatitis C virus; human immunodeficiency virus 1; human tissue; laboratory mouse; leukocyte activation /transformation; microorganism interaction; neoplasm /cancer vaccine; oncogenes; schistosomiasis; synthetic vaccines; vaccinia virus; virus envelope

We studied mechanisms by which T cells recognize antigens with major histocompatibility complex (MHC)-encoded molecules, and applications to the design of synthetic vaccines for AIDS and cancer. We characterized a peptide fragment of the HIV-1 envelope recognized by CD8+ cytotoxic T lymphocytes (CTL) using a new system we developed in which CTL are stimulated by peptide bound to purified Class I MHC molecules on plastic. A 10-residue HIV peptide is a million times more active than the original 15-residue peptide in the absence of serum, and the longer peptide requires processing by angiotensin converting enzyme (ACE) in serum. We also showed that the Class I molecule plays two roles in CTL activation, one to present the peptide and the other probably to interact with CD8, as it requires only a conserved alpha 3 domain. The MHC molecule binding CD8 does not have to be the same one presenting peptide. We have shown that non-crossreactive CTL distinguish aliphatic from aromatic residues at a single position in this peptide. This finding led us to discover a way to induce broadly crossreactive CTL against multiple variants of HIV by stimulation with a chimeric peptide. CTL fine specificity correlated with specific receptor variable regions used. This CTL site, which also is a target of neutralizing antibodies, has been coupled to sites we identified that stimulate T helper cells in mice and humans of multiple MHC types, and the resulting candidate synthetic vaccine has been found to induce extremely high titers of neutralizing antibodies in mice, as well as specific CTL killing of HIV-1 envelope expressing cells. Also, an early diagnostic test is being developed. We also showed that schistosomiasis resulted in reduced clearance of concurrent vaccinia virus infection and decreased IL-2, interferon and CTL responses. This may account in part for the rapid spread of AIDS in Africa. We are also attempting cancer vaccines to induce CTL to mutant peptides corresponding to oncogene mutations that could kill tumor cells. We succeeded in inducing peptide-specific CTL that will kill tumor targets expressing a mutant p53 gene. Thus such mutant oncogene products, although not expressed on the cell surface, can serve as targets of specific cancer immunotherapy. Also, a CTL determinant of the hepatitis C virus has been found.

我们研究了T细胞识别主要的抗原的机制 组织相容性复合物（MHC）编码的分子，并应用于 用于艾滋病和癌症的合成疫苗的设计。我们描述了一个 CD8+细胞毒性T识别的HIV-1包膜的肽片段 我们使用我们开发的新系统的淋巴细胞（CTL），其中CTL为 被塑料上纯化的I类MHC分子结合的肽刺激。 10个残留的HIV肽比原始的活跃一百万倍 在缺乏血清的情况下，15个残留的肽和较长的肽 需要通过血管紧张素转化血清中的酶（ACE）来加工。 我们 还表明，I类分子在CTL激活中扮演两个角色， 一个呈现肽，另一个可能与CD8相互作用， 因为它仅需要一个保守的alpha 3域。 MHC分子结合 CD8不必是同一呈现肽的同一。 我们已经显示了 这种非反应性CTL将脂肪族与芳族残基区分开 在该肽中的一个位置。 这一发现使我们发现了 诱导多种艾滋病毒变体的广泛交叉反应性CTL的方法 通过用嵌合肽刺激。 CTL的精细特异性相关 使用特定的受体变量区域。 这个CTL网站也 是中和抗体的目标，已与位点耦合到我们 鉴定出刺激小鼠的T辅助细胞和多个的人类 MHC类型以及结果候选合成疫苗已被发现 诱导小鼠中和抗体的极高滴度 以及表达HIV-1包膜的特定CTL杀死。 还， 正在开发早期诊断测试。 我们还表明 血吸虫病导致并发疫苗的清除率降低 病毒感染并减少IL-2，干扰素和CTL反应。 这 可以部分解释非洲艾滋病的迅速传播。 我们也是 尝试将癌症疫苗诱导CTL对相应的突变肽 可能会杀死肿瘤细胞的癌基因突变。 我们成功了 诱导肽特异性CTL，该CTL将杀死表达表达的肿瘤靶标 突变p53基因。 因此，这种突变的致癌基因产品，尽管不是 在细胞表面表达，可以用作特定癌症的靶标 免疫疗法。 此外，丙型肝炎病毒的CTL决定因素一直是 成立。