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: 5200916
• 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/5200916
• 关键词: AIDS vaccines; HIV envelope protein gp160; MHC class I antigen; cervix neoplasms; clinical trials; cytokine; cytotoxic T lymphocyte; disease /disorder model; gene mutation; human immunodeficiency virus 1; human papillomavirus; human subject; human therapy evaluation; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neutralizing antibody; synthetic vaccines; AIDS vaccines; HIV envelope protein gp160; MHC class I antigen; cervix neoplasms; clinical trials; cytokine; cytotoxic T lymphocyte; disease /disorder model; gene mutation; human immunodeficiency virus 1; human papillomavirus; human subject; human therapy evaluation; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neutralizing antibody; synthetic vaccines

We studied mechanisms by which T cells recognize antigens presented by major histocompatibility complex (MHC)-encoded molecules on cell surfaces, and the applications to the design of synthetic vaccines for AIDS and cancer. We developed synthetic vaccines for HIV using broadly reactive HIV helper apitopes combined with CTL and neutralizing antibody epitopes, and showed the importance of covalent linkage of helper and CTL epitopes for induction of CTL, never before demonstrated. We found an adjuvant allowing induction of CTL, TH1 help, and neutralizing antibodies with the same immunication, and just commenced a human phase I immunotherapy trial with these vaccine constructs. We found in murine studies that peptide vaccines for HIV can be made more potent or broadly effective by selective introduction of mutations that improve binding to MHC to T-cell receptors ("epitope enhancement"). To apply this approach to human vaccines we studied the binding of HIV envelope peptides to human HLA molecules, and raised HIV peptide-specific human CTL from blood of an uninfected individual. We made second generation vaccine constructs to show the feasibility of enhancing immunogenicity in mice. We developed a murine tumor model expressing HIV gp160 to test vaccine efficacy, and showed protection against HIV-envelope-expressing tumor challenge. We showed suppression of CTL activity and viral clearance in an animal model, and identified CD3+4-8- cells suppressing the CTL response. We studied the mechanism by which free peptide inhibits CTL, and developed a method to induce high affinity CTL. We developed a new vaccine construct using a portion of anthrax toxin to introduce recombinant protein into the class I mHC processing pathway. We found HIV-peptide- reactive T cells in 75% of seronegative health-care workers exposed to HIV+ blood. We identified several CTL epitopes in proteins of the hepatitis C virus, that causes liver cancer, and demonstrated the predictive value of HLA-transgenic mice in identifying these peitopes. We showed a correlation between IL-2 response to human papillomavirus peptides and stage of cervical neoplastic disease. We developed peptide cancer vaccines inducing CTL immunity to mutant p53 expressed in cancer cells, and also induced murine CTL against fusion proteins from chromosomal translocations in pediatric tumors. Sixteen cancer patients have been treated in a phase I/II clinical trial of mutant p53 or ras peptide vaccine and results are pending. We found that the spacing of hydrophobic pockets in the MHC groove enforces an amphipathic periodicity on the peptides bound.

我们研究了T细胞识别由 细胞上的主要组织相容性复合物（MHC）编码分子 表面，以及用于设计合成疫苗的应用 艾滋病和癌症。 我们开发了使用的合成疫苗用于HIV使用 与CTL和 中和抗体表位，并显示了共价的重要性 助手和CTL表位的连接，用于诱导CTL，从来没有 证明。 我们发现辅助允许诱导CTL，Th1 帮助并用相同的免疫中和抗体中和 这些疫苗开始了人类I期免疫疗法试验 构造。 我们在鼠研究中发现肽疫苗的HIV 通过选择性介绍可以使更有效或广泛有效 改善与MHC与T细胞受体结合的突变（“表位） 增强”）。要将这种方法应用于我们研究的人类疫苗 HIV包膜肽与人HLA分子的结合，并 未感染的血液中提出的HIV肽特异性人CTL 个人。 我们制作了第二代疫苗构造以显示 提高小鼠免疫原性的可行性。 我们开发了一个 表达HIV GP160以测试疫苗功效的鼠肿瘤模型，并 显示了针对表达HIV-Envelope的肿瘤挑战的保护。 我们 显示动物中CTL活性和病毒清除率的抑制 模型，并鉴定出抑制CTL响应的CD3+4-8个细胞。 我们 研究了游离肽抑制CTL的机制，并 开发了一种诱导高亲和力CTL的方法。 我们开发了一个新的 使用一部分炭疽毒素引入疫苗构建 重组蛋白进入I类MHC处理途径。 我们发现 在75％的血清神经卫生保健中，HIV肽反应性T细胞 工人暴露于艾滋病毒+血液。 我们在 肝炎病毒的蛋白质，会导致肝癌，并 证明了HLA转基因小鼠在 识别这些卵子。 我们显示了IL-2之间的相关性 对人乳头瘤病毒肽的反应和宫颈阶段 肿瘤疾病。 我们开发了诱导CTL的肽癌疫苗 对在癌细胞中表达的突变体p53的免疫力，也诱导 来自染色体易位融合蛋白的鼠CTL在染色体易位 小儿肿瘤。 16例癌症患者已在 突变体P53或RAS肽疫苗的I/II期临床试验和 结果正在等待。 我们发现疏水口袋的间距 在MHC凹槽中，在肽上执行两亲周期性 边界。