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）基因的机制和 抗原介导的T淋巴细胞激活已经探索了该目标 了解免疫反应和学习的调节 操纵它。 我们发现了两个主要或免疫主导抗原位点 在肌红蛋白上，我们的模型蛋白抗原。 每个人都以 不同的II类（或IA）主要的组织兼容性抗原（I-AD或I-ED） 因此，这些IA分子之一的存在导致选择性 特异性的T细胞激活这些位点之一。 合成肽 制成了刺激针对这些站点的T细胞克隆的 用于定义关键氨基酸残基的合成变体。 一个 位点，临界残留物都是亲水性的，在α的一侧 螺旋肽段，但疏水侧也需要 如静脉加工研究所证明的那样暴露。 因此， 两亲性α螺旋结构很重要。 另一个网站也是 两亲α螺旋。 计算机搜索六个序列 具有12个已知T细胞抗原位点的蛋白质表明12个中的10种 地点落入与疏水周期性的区域 两亲性α螺旋螺旋，每个人都有随机发生 P的蛋白质小于0.01。 这种方法可能会导致我们进入生化 对T细胞识别抗原的要求，可能是一个强大的工具 在寻找T细胞位点和合成疫苗的设计中。 开发了几种免疫抑制方法。 发现 IL-2增强了低反应者对高水平的抗体反应 响应者，也许是通过放大T细胞帮助。 另外，针对抗原 通过将抗免疫球蛋白耦合到免疫系统导致增强 B细胞在低浓度下摄取和呈现，结果 刺激T细胞的效力大于10倍以上 抗体的体外和大于10倍的免疫原性 体内生产。 这两种方法都可以开发 弱或稀缺抗原的疫苗，或免疫缺陷的免疫 患者。