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细胞识别抗原的机制， 组织相容性复合体（MHC）编码的分子，以及应用于 艾滋病和癌症合成疫苗的设计。我们描述了一个 CD 8+细胞毒性T细胞识别的HIV-1包膜肽片段 使用我们开发的新系统，在该系统中， 通过与塑料上纯化的I类MHC分子结合的肽刺激。 一个10个残基的HIV肽比原来的活性高出一百万倍 15-在不存在血清的情况下， 需要通过血清中的血管紧张素转换酶（ACE）进行处理。 我们 还表明I类分子在CTL活化中起两种作用， 一个呈递肽，另一个可能与CD 8相互作用， 因为它只需要保守的α 3结构域。 MHC分子结合 CD 8不一定是同一个呈递肽。 我们已经表明 非交叉反应性CTL区分脂族和芳族残基 在这个肽中的一个位置上。 这一发现使我们发现了一个 一种诱导广泛交叉反应性CTL对抗多种HIV变体的方法 通过用嵌合肽刺激。 CTL精细特异性相关 使用了特异性受体可变区。 这个CTL网站，也 是中和抗体的靶点， 在小鼠和人类中发现了刺激T辅助细胞的多种 MHC类型，并由此产生的候选合成疫苗已被发现 在小鼠中诱导极高滴度的中和抗体， 以及特异性CTL杀伤HIV-1包膜表达细胞。 还有， 正在开发一种早期诊断测试。 我们还发现， 血吸虫病导致并发的牛痘清除减少 病毒感染和降低的IL-2、干扰素和CTL应答。 这 这可能是艾滋病在非洲迅速蔓延的部分原因。 我们也 试图用癌症疫苗诱导CTL产生相应的突变肽 致癌基因突变可以杀死肿瘤细胞。 我们成功地 诱导肽特异性CTL，其将杀死表达 突变型p53基因。 因此，这种突变的癌基因产物，虽然不是 在细胞表面表达，可以作为特定癌症的靶点 免疫疗法。 此外，丙型肝炎病毒的CTL决定簇已经被发现。 found.