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: 3774286
• 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/3774286
• 关键词: AIDS /HIV test; AIDS vaccines; MHC class I antigen; antiantibody; antigen presentation; antigen receptors; cervix neoplasms; cytotoxic T lymphocyte; drug design /synthesis /production; human immunodeficiency virus 1; human papillomavirus; human tissue; laboratory mouse; leukocyte activation /transformation; microorganism interaction; neoplasm /cancer vaccine; oncoproteins; schistosomiasis; synthetic vaccines; virus envelope

We studied the mechanisms by which T cells recognize antigens presented on the surface of cells bound to major histocompatibility (MHC) molecules, the molecular basis of peptide binding to MHC molecules, and the application of these principles to the design of synthetic vaccines for AIDS and cancer. By studying synthetic peptides corresponding to antigenic epitopes, but with amino acid substitutions at different positions, we identified mutations that produced higher affinity for the MHC molecule or for the T-cell receptor. One such peptide from the HIV envelope binds more tightly to a class II MHC molecule and is effective as a vaccine in mice at 10-100-fold lower doses than the natural sequence at eliciting helper T-cells specific for the natural HIV epitope. We also showed that only a few residues on the peptide are critical for positive interaction, but other residues can interfere by adverse interactions, which play a major role in specificity. We found that cytotoxic T lymphocytes (CTL) specific for another HIV peptide from three strains of mice showed degenerate MHC restriction, and also used a limited number of T-cell receptor V-region genes. This same HIV peptide is also presented by both class I and class II MHC molecules to CTL and helper T cells, respectively. We compared the amino acid residues involved in presentation by each, and found a remarkable similarity, that may suggest a similar basis for binding. We used these epitopes to make a synthetic peptide candidate vaccine for HIV. The toxicology and clinical protocols are being written for a human phase I clinical trial. We have also developed a new method of immunizing with peptides without adjuvant, using dendritic cells. We applied this to cancer vaccine development, to show that an endogenously expressed mutant p53 oncoprotein in a tumor cell can serve as a target antigen for CTL, and that such CTL can be elicited by immunization with a synthetic peptide from the mutant p53 sequence. We have also begun determining helper and CTL responses to peptides from human papillomavirus (HPV) oncoproteins E6 and E7, for application to HPV-related cervical cancer. We also found that CTL activity to viruses can be inhibited by Schistosome infection related to a shift in Th1/Th2 helper balance and mediated by a suppressor cell that we are characterizing. This finding may account for the more rapid progression of HIV disease where these parasites are endemic. We have also found that the immune defect in HIV-infected patients in in vitro T-cell response can be overcome by use of anti-IL-10 antibodies, suggesting a possible approach to therapy.

我们研究了T细胞识别抗原的机制， 在与主要组织相容性（MHC）结合的细胞表面 分子，肽与MHC分子结合的分子基础，以及 将这些原则应用于合成疫苗的设计 治疗艾滋病和癌症 通过研究合成肽， 抗原表位，但在不同的氨基酸取代 我们发现了对这些位点产生更高亲和力的突变， MHC分子或T细胞受体。 一种来自艾滋病毒的肽 包膜与II类MHC分子结合更紧密， 作为小鼠的疫苗，剂量比天然疫苗低10-100倍。 在引发对天然HIV特异的辅助性T细胞的序列 表位 我们还表明，只有少数残基的肽是 对于正相互作用至关重要，但其他残基可能会干扰， 不利的相互作用，在特异性中发挥重要作用。 我们发现 细胞毒性T淋巴细胞（CTL）对另一种HIV肽具有特异性， 三种小鼠表现出简并MHC限制，并且也使用了 有限数量的T细胞受体V区基因。 同样的艾滋病毒 肽也由I类和II类MHC分子呈递， CTL和辅助性T细胞。 我们比较了 残基参与介绍了每一个，并发现了一个显着的 相似性，这可能表明约束的相似基础。 我们使用这些 表位来制造艾滋病毒的合成肽候选疫苗。 的 毒理学和临床试验方案正在为人类阶段编写 临床试验。 我们还开发了一种新的免疫方法 使用树突状细胞，用肽无佐剂。 我们采用这种 癌症疫苗的发展，以显示一个内源性表达， 肿瘤细胞中的突变型p53癌蛋白可以作为靶抗原， CTL，并且这样的CTL可以通过用合成的免疫来引发。 突变型p53序列的肽。 我们也开始确定 对人乳头瘤病毒（HPV）多肽的辅助细胞和CTL应答 癌蛋白E6和E7，用于HPV相关的宫颈癌。 我们还发现CTL对病毒的活性可以被抑制， 血吸虫感染与辅助性Th 1/Th 2平衡的改变有关， 由我们所描述的抑制细胞介导。 这一发现 这可能是艾滋病毒疾病进展更快的原因， 寄生虫是地方性的 我们还发现， 艾滋病病毒感染者在体外T细胞反应可以克服使用 的抗IL-10抗体，提示一种可能的治疗方法。