GENETIC CONTROL OF THE IMMUNE RESPONSE TO NATURAL ANTIGENS

对天然抗原免疫反应的基因控制

• 批准号: 4691741
• 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/4691741
• 关键词: B lymphocyte; T lymphocyte; antiantibody; antibody specificity; antigen antibody reaction; autoimmune disorder; cell cell interaction; chromatography; clone cells; enzyme linked immunosorbent assay; genetic regulation; histocompatibility antigens; hybridomas; immune response genes; immunochemistry; immunogenetics; leukocyte activation /transformation; monoclonal antibody; myoglobin; radioimmunoassay; radiotracer; saltwater environment

The mechanisms of antigen-specific immune response (Ir) gene control and of antigen-mediated T-lymphocyte activation have been explored with the goal of understanding the regulation of the immune response and learning to manipulate it. We have found two major or immunodominant antigenic sites on myoglobin, our model protein antigen. Each is recognized with a different class II (or Ia) major histocompatibility antigen (I-Ad or I-Ed) so that the presence of one of these Ia molecules leads to selective activation of T-cells specific for one of these sites. Synthetic peptides were made which stimulate T-cell clones specific for these sites and synthetic variants used to define critical amino acid residues. For one site, critical residues were all hydrophilic and on one side of the alpha helical peptide segment, but the hydrophobic side was also necessary to be exposed, as demonstrated by studies of antign processing. Thus, the amphipathic alpha helical structure was important. The other site was also an amphipathic alpha helix. A computer search of the sequences of six proteins with 12 known T-cell antigenic sites revealed that 10 of the 12 sites fell into regions of hydrophobic periodicity compatible with an amphipathic alpha helix, with a chance of random occurrence for each protein of p less than 0.01. This approach may lead us to the biochemical requirements for T-cell recognition of antigen and may be a powerful tool in the search for T-cell sites and the design of synthetic vaccines. Several methods of immunopotentiation were developed. It was found that IL-2 enhanced antibody responses of low responders to the levels of high responders, perhaps by amplifying T-cell help. Also, targeting the antigen to the immune system by coupling it to anti-immunoglobulin led to enhanced uptake and presentation by B cells at low concentration, with a resultant greater than 10-fold increase in potency for stimulation of T cells in vitro and greater than 10-fold increase in immunogenicity for antibody production in vivo. Both of these approachs may allow development of vaccines for weak or scarce antigens, or immunization of immunodeficient patients.

抗原特异性免疫反应（Ir）基因调控和免疫抑制的机制 抗原介导的T淋巴细胞活化已经被探索， 了解免疫反应的调节并学会 我们发现了两个主要的或免疫显性的抗原位点， 我们的模型蛋白质抗原肌红蛋白。 每一个都是用一个 不同的II类（或Ia类）主要组织相容性抗原（I-Ad或I-Ed） 因此这些Ia分子中的一种的存在导致选择性的 激活对这些位点之一特异的T细胞。 合成肽 刺激特异于这些位点的T细胞克隆， 用于定义关键氨基酸残基的合成变体。 一 位点上，关键残基都是亲水性的，并且在α的一侧， 螺旋肽段，但疏水侧也是必要的 暴露，如antign处理研究所示。 因此 两亲性α螺旋结构是重要的。 另一个网站也是 两亲性α螺旋。 用计算机搜索六个 具有12个已知T细胞抗原位点的蛋白质显示， 网站落入区域的疏水周期兼容的一个 两亲性α螺旋，每个螺旋随机出现的机会 蛋白质含量P <0.01。 这种方法可能会引导我们找到 T细胞识别抗原的要求，可能是一个强大的工具， 寻找T细胞位点和设计合成疫苗。 开发了几种免疫增强方法。 结果发现 IL-2增强了低应答者对高水平IL-2的抗体应答。 反应者，也许是通过放大T细胞的帮助。 同时，针对抗原 通过将其与抗免疫球蛋白偶联， 在低浓度下被B细胞摄取和呈递， 刺激T细胞的效力增加超过10倍， 体外和抗体免疫原性增加10倍以上 体内生产。 这两种方法都可以允许开发 弱抗原或稀缺抗原的疫苗，或免疫缺陷 患者