HUMAN IMMUNE RESPONSE TO HEPATITIS B VACCINE

这个项目的目标是了解遗传基础和 免疫应答和免疫失败的机制 乙肝病毒的主要表面抗原，即乙肝表面抗原。在多大程度上 这种反应是由基因控制的，将通过免疫来定义 同卵双胞胎和他们的直系亲属 与MHC完全相同的兄弟姐妹的反应相同。通过对这些和 其他家族和对体外反应的研究表明，主要的T细胞 将定义乙肝表面抗原的表位，应答或无应答将为 与特定的主要组织相容性复合体(MHC)等位基因和 固定的、扩展的单倍型。免疫显性九肽的结合作用 树突状细胞、单核细胞和B细胞的表位和其他T细胞表位 将对淋巴细胞和分离的II类分子进行检查和结合 将与免疫反应的存在与否相关。从… 仔细研究，包括第二类基因的序列测定， 罕见的有反应的个体是通常无反应的纯合子 扩展的单倍型或无反应者的MHC完全相同的同胞，我们希望 为了确定核苷酸变化是否会影响肽结合裂解 或第二类分子的其他部分以一定的频率和结果出现 作为回应。T细胞抗原受体(TCR)α与T细胞的关系 以及Vbeta基因和序列的用途以及特定的MHC等位基因和扩展 单倍型将在对乙肝表面抗原有反应者和无反应者中定义。TCR 全乙肝病毒表面抗原刺激T细胞增殖的V基因及序列 以及将个别表位与整体表位进行比较 增强前相同应答者和无应答者的曲目。 这些研究的结果将与项目2的结果进行比较 探讨无反应者的缺陷是否存在于抗原提呈或 T细胞识别。MHC类中可能的序列变化的影响 II类分子与IgA和其他免疫球蛋白缺乏症的易感性 (项目3)也将被审查。

The objective of this project is to understand the genetic basis and mechanisms of the immune response and of the failure of response to the major surface antigen of the hepatitis B virus, HBsAg. The extent to which the response is genetically controlled will be defined by immunizing identical twins and their immediate family members and comparing their response with that of MHC-identical siblings. From the study of these and other families and from studies of the response in vitro, the major T cell epitopes of HBsAg will be defined and the response or nonresponse will be correlated with specific major histocompatibility complex (MHC) alleles and fixed, extended haplotypes. The binding of an immunodominant nonapeptide epitope and other T cell epitopes to dendritic cells, monocytes, and B lymphocytes and to isolated class II molecules will be examined and binding will be correlated with the presence or absence of immune response. From the careful study, including sequence determinations in class II genes, of rare responding individuals who are homozygotes for usually nonresponding extended haplotypes or who are MHC identical sibs of nonresponders, we hope to determine whether nucleotide changes affecting the peptide-binding cleft or other parts of class II molecules occur with some frequency and result in response. The relationship between T cell antigen receptor (TCR) Alpha and Vbeta gene and sequence usage and specific MHC alleles and extended haplotypes will be defined in responders and nonresponders to HBsAg. TCR V genes and sequences on T cells proliferating in response to whole HBsAG as well as to individual epitopes will be compared with the overall repertoire of the same responders before boosting and of nonresponders. The results of these studies will be compared with those of Project 2 which explore whether the defect in nonresponders is in antigen presentation or T cell recognition. The effects of possible sequence changes in MHC class II molecules and susceptibility to IgA and other immunoglobulin deficiency (Project 3) will also be examined.