ONTOGENY OF GENERATION OF NEONATAL ANTIBODY DIVERSITY

新生儿抗体多样性产生的个体发生

• 批准号: 2674152
• 负责人: Richard A. Insel
• 金额: $ 21.32万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2674152
• 关键词: B lymphocyte; antibody formation; clinical research; developmental immunology; enzyme linked immunosorbent assay; gene mutation; human subject; immunoglobulin genes; immunologic memory; newborn human (0-6 weeks); perinatal; polymerase chain reaction; pregnancy immunology; premature infant human; tetanus toxoid; tissue /cell culture; vaccines

DESCRIPTION (Adapted from Applicant's Description): Both premature and full term human neonates generate suboptimal antibody (Ab) responses to vaccines. The overall goal of this proposal is to investigate whether defects in the preimmune Ab repertoire of neonatal B cells and in the diversification of this repertoire after immunization contribute to defective Ab responses and whether immunization during pregnancy is able to alter the immunoglobulin repertoire and B cell memory of the neonate. In Aim 1, the investigators hypothesize that the preimmune repertoire of the neonate is restricted in diversity of the immunoglobulin heavy chain third complementarity determining region (CDR3), which arises from the joining of Ig gene segments and N region addition. To investigate this hypothesis, they will characterize and compare the diversity and structure of the CDR3 regions of preterm and full term neonatal and adult B lymphocytes. They will analyze the potential antigen binding activity of a CDR3 library expressed from each group with a single immunoglobulin heavy chain variable region gene (VH) and light chain gene in a Fab surface phage expression library for binding to self and non-self antigens. In Aim 2, we will investigate the hypothesis that the neonate fails to diversify postimmunization and Ab repertoires with somatic hypermutation of VH by analyzing somatic hypermutation in VH at birth and after immunization of the neonate. To explore the hypothesis that the neonatal B cell repertoire can be altered by maternal immunization during pregnancy with vaccines that induces a high titered clonally restricted IgG Ab response, they will immunize pregnant women in the third trimester of pregnancy with Haemophilus influenzae b vaccines, which generate a high-titered oligoclonal IgG Ab response, and analyze the offspring for evidence of immunologic priming with Ab production and generation of B cell memory. The results of these investigations should provide novel insights into the ontogeny of the neonatal B cell repertoire and in the potential to accelerate of immunity.

描述（改编自申请人的描述）：过早和完整 足月人类新生儿对疫苗产生次优的抗体（Ab）反应。 本提案的总体目标是调查 新生儿B细胞的免疫前抗体库和 免疫后的这一库导致缺陷性Ab应答， 怀孕期间的免疫接种是否能够改变免疫球蛋白 库和B细胞记忆。在目标1中，研究人员 假设新生儿的前免疫库被限制在 免疫球蛋白重链第三互补性的多样性 决定区（CDR 3），其由IG基因片段的连接产生 和N区添加。为了研究这个假设，他们将 表征和比较CDR3区的多样性和结构， 早产和足月新生儿和成人B淋巴细胞。他们将分析 从每一种表达的CDR 3文库的潜在抗原结合活性 具有单个免疫球蛋白重链可变区基因（VH）的组，和 Fab表面噬菌体表达文库中的轻链基因，用于结合 自身和非自身抗原。在目标2中，我们将研究假设 新生儿未能使免疫后和抗体库多样化， 通过分析VH中的体细胞超突变， 出生后和新生儿免疫后。为了探索这个假设， 新生儿B细胞库可通过母体免疫改变 在怀孕期间接种疫苗， 限制性IgG抗体反应，他们将在第三次免疫孕妇 妊娠三个月内接种流感嗜血杆菌B疫苗， 产生高滴度寡克隆IgG Ab应答，并分析 后代，以获得产生Ab的免疫启动证据， 产生B细胞记忆。这些调查的结果应 为新生儿B细胞库的个体发育提供了新的见解 以及免疫力的增强。