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细胞识别抗原呈现的机制 在与主要组织相容性（MHC）结合的细胞表面上 分子，肽与MHC分子结合的分子基础，而 这些原理在合成疫苗的设计中的应用 用于艾滋病和癌症。 通过研究对应于 抗原表位，但在不同的氨基酸取代 位置，我们确定了对该突变产生更高亲和力的突变 MHC分子或T细胞受体。 艾滋病毒的一种这样的肽 信封更紧密地与II类MHC分子结合，并且有效 作为小鼠的疫苗比天然剂量低10-100倍 引起天然艾滋病毒特异的助手T细胞时的序列 表位。 我们还表明，肽上只有几个残留物 对于正相互作用至关重要，但是其他残留物可能会干扰 不良相互作用，在特异性中起主要作用。 我们发现 细胞毒性T淋巴细胞（CTL）特异于另一种HIV肽 三种菌株的小鼠显示出变质的MHC限制，也使用 有限数量的T细胞受体V-区域基因。 同样的艾滋病毒 I类和II类MHC分子也表明肽 CTL和辅助T细胞分别。 我们比较了氨基酸 每个介绍涉及的残留物，发现一个了不起的 相似性，这可能暗示了结合的相似基础。 我们使用了这些 表位为HIV制造合成肽疫苗。 这 毒理学和临床方案正在为人类阶段编写 我的临床试验。 我们还开发了一种免疫的新方法 使用树突状细胞，没有辅助的肽。 我们应用了这个 为了表明内源性表达的癌症疫苗的发育 肿瘤细胞中突变的p53癌蛋白可以用作靶抗原 CTL，可以通过合成的免疫来引起这种CTL 突变体p53序列的肽。 我们也开始确定 从人乳头瘤病毒（HPV）对肽的助手和CTL反应 癌蛋白E6和E7，用于与HPV相关的宫颈癌。 我们还发现，病毒的CTL活性可以被 与Th1/Th2辅助辅助平衡和转移有关的阴谋体感染和 由我们正在表征的抑制细胞介导。 这个发现 可能是艾滋病毒疾病的更快进展 寄生虫是地方性的。 我们还发现免疫缺陷 在体外T细胞反应中感染HIV的患者可以通过使用来克服 抗IL-10抗体，提出了一种可能的治疗方法。