HUMAN IMMUNE RESPONSE TO HEPATITIS B VACCINE

乙型肝炎疫苗的人体免疫反应

• 批准号: 6829680
• 负责人: CHESTER Allan ALPER
• 金额: $ 21.59万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829680
• 关键词: MHC class II antigen; active immunization; antigen presentation; clinical research; cytokine; cytotoxic T lymphocyte; family genetics; genetic polymorphism; hepatitis B antigens; hepatitis vaccine; human subject; immune response genes; immunogenetics; nucleic acid sequence; pharmacogenetics; structural genes; virus antigen

Healthy young persons incapacitated for response to the vaccine for hepatitis B virus (nonresponders) fail to make detectable antibody to the major virus envelope protein, HbsAg, and comprise 4% of subjects. Previous work has shown nonresponse to be associated with a lack of HbsAg-specific T cell proliferation, to be recessively inherited, to be MHC-linked and associated with specific extended MHC haplotypes. From mixing experiments, it is clear that the defect in nonresponders in their T cells, not in their antigen presenting cells. We hypothesize that nonresponse is part of a continuum from total nonresponse to both a strong humoral and cellular immune response and that nonresponse is not due to a hole in the T cell repertoire. Additionally, evidence that the class I-restricted CD8+ T cell compartment is or might be functional in response to HB vaccine is extensive. Accordingly, the specific aims of this proposal are: (1) To determine whether the class I-restricted cytotoxic T cell (CTL) compartment is functional in the HbsAg-specific cellular response but defective in nonresponse; (2) To determine whether the relative Th1/Th2 response profile reflects different subclasses of response; (3) To determine whether HbsAg response can be detected soon after the first injection of antigen; and (4) To attempt to predict response and nonresponse in vitro using T cells from subjects naive to HbsAg using dendritic cells for presentation. These experiments should meet our overall objective of understanding the molecular and cellular bases of the human response and nonresponse of HbsAg as a model for the human immune response to vaccination in general.

对乙型肝炎病毒疫苗无反应能力的健康年轻人（无反应者）不能产生可检测到的针对主要病毒包膜蛋白HbsAg的抗体，占受试者的4%。先前的研究表明，无应答与缺乏hbsag特异性T细胞增殖有关，与隐性遗传有关，与MHC相关，并与特定的扩展MHC单倍型相关。从混合实验中可以清楚地看出，无反应的T细胞中存在缺陷，而不是抗原提呈细胞。我们假设无反应是从完全无反应到强烈的体液和细胞免疫反应的连续体的一部分，无反应不是由于T细胞库中的空洞。此外，有大量证据表明，i类限制性CD8+ T细胞区室对乙肝疫苗具有或可能具有应答功能。因此，本提案的具体目的是：(1)确定i类限制性细胞毒性T细胞（CTL）室是否在hbsag特异性细胞应答中起作用，但在无应答中存在缺陷；(2)确定相对Th1/Th2反应曲线是否反映了不同的反应亚类；(3)确定首次注射抗原后能否很快检测到HbsAg反应；(4)利用树突状细胞进行呈递，尝试利用来自初次接触HbsAg的受试者的T细胞，预测其在体外的反应和无反应。这些实验应该满足我们的总体目标，即了解人类对乙肝表面抗原的反应和不反应的分子和细胞基础，作为人类对疫苗接种的一般免疫反应的模型。