HUMAN IMMUNE RESPONSE TO HEPATITIS B VACCINE

不能对B型肝炎病毒疫苗产生应答的健康年轻人（无应答者）不能产生可检测的主要病毒包膜蛋白HBsAg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，可重复遗传，与MHC连锁，并与特定的扩展MHC单倍型有关。从混合实验中可以清楚地看出，无应答者的缺陷在于他们的T细胞，而不是他们的抗原呈递细胞。 我们假设无应答是从完全无应答到强烈的体液和细胞免疫应答的连续体的一部分，并且无应答不是由于T细胞库中的孔。 此外，有大量证据表明，I类限制性CD 8 + T细胞区室是或可能是功能性的HB疫苗的反应。 因此，该建议的具体目的是：（1）确定I类限制性细胞毒性T细胞（CTL）区室在HbsAg特异性细胞应答中是否有功能，但在无应答中是否有缺陷;（2）确定相对Th 1/Th 2应答谱是否反映不同的应答亚类;（3）确定在第一次注射抗原后是否可以很快检测到HbsAg应答;和（4）尝试使用树突状细胞呈递，使用来自未接触HBsAg的受试者的T细胞在体外预测应答和无应答。 这些实验应该符合我们的总体目标，即理解作为人类对疫苗接种免疫应答模型的HBsAg的人类应答和非应答的分子和细胞基础。

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.