HUMAN IMMUNE RESPONSE TO HEPATITIS B VACCINE

该项目的目标是了解遗传基础， 免疫反应的机制和免疫反应的失败， B型肝炎病毒的主要表面抗原，HBsAg。 的程度 由基因控制的反应将通过免疫来定义， 同卵双胞胎及其直系亲属，并比较他们的 与MHC相同的兄弟姐妹的反应。 从这些研究和 其他家庭和研究的反应在体外，主要的T细胞 将定义HBsAg的表位，并确定应答或无应答。 与特定的主要组织相容性复合体（MHC）等位基因相关， 固定的扩展单倍型。 免疫显性九肽的结合 表位和其他T细胞表位的树突状细胞，单核细胞，和B 淋巴细胞和分离的II类分子将被检查和结合 将与免疫反应的存在或不存在相关。 从 仔细的研究，包括II类基因的序列测定， 罕见的反应个体是通常无反应的纯合子 扩展的单倍型或无应答者的MHC相同同胞，我们希望 以确定核苷酸变化是否影响肽结合裂缝 或II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α（TCR α） 和Vbeta基因和序列用途以及特异性MHC等位基因， 将在HBsAg应答者和无应答者中定义单倍型。 TCR 响应于全HLAG增殖的T细胞上的V基因和序列 以及单个表位将与总体表位进行比较。 增强前相同应答者和无应答者的库。 这些研究的结果将与项目2的结果进行比较， 探索无应答者的缺陷是否是抗原呈递， T细胞识别。 MHC类中可能的序列变化的影响 II型分子与伊加和其他免疫球蛋白缺乏症易感性 （三）还将审查。

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.