Effects of neonatal microbial exposure on anti-polysaccharide B cell development

新生儿微生物暴露对抗多糖 B 细胞发育的影响

• 批准号: 8433271
• 负责人: John Franklin Kearney
• 金额: $ 30.37万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433271
• 关键词: Adult; Affect; Animal Model; Anti-Idiotypic Antibodies; Antibodies; Antibody Formation; Antigens; B cell repertoire; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Antigens; Bacterial Infections; Bacterial Polysaccharides; Biological Assay; Blood; Cells; Characteristics; Childhood; Chronic; Cloaca Chamber; Communicable Diseases; Controlled Study; Country; Development; Employee Strikes; Enteral; Environment; Exposure to; Flow Cytometry; Frequencies; Future; Gene Expression; Genes; Genetic; Goals; Human; Humoral Immunities; Hybridomas; Immune; Immune response; Immune system; Immunoglobulin G; Immunoglobulin Genes; Immunoglobulins; Infant; Infant Health; Infection; Infection prevention; Intervention; Knowledge; Label; Lead; Life; Lymphoid Tissue; Memory; Memory B-Lymphocyte; Modeling; Mus; Nature; Neonatal; Organism; Outcome; Play; Polysaccharides; Predisposition; Production; Property; Public Health; Publishing; Relative (related person); Research; Staging; Streptococcus; Streptococcus Group B; Streptococcus pneumoniae; Streptococcus pyogenes; Structure; Testing; Time; Transgenic Mice; Vaccination; Vaccines; Work; antigen binding; arm; base; clinically relevant; design; fetal; in vivo; man; member; microbial; mouse model; neonatal death; neonatal exposure; novel therapeutics; programs; response; vaccine development; vaccinology

DESCRIPTION (provided by applicant): Gram-negative enteric infections and Gram-positive organisms, including Streptococcus pneumoniae, Group A (GAS) and Group B (GBS) streptococci are leading causes of serious bacterial infections and contribute to neonatal deaths worldwide. In man and mouse the early B cell production of antibodies to these and similar organisms are essential for protection from infection and their blood-borne dissemination. However the adaptive immune system is compromised in early life and human infant protective antibody responses to polysaccharide (PS) take more than two years to develop. Our long range goal is to conduct carefully controlled studies of the neonatal immune response to multiple organisms of clear relevance to infant health. Our immediate goal is to use mouse models to study the interactions of the neonatal immune system with bacterial components that lead to long-lasting protection. The rationale behind our approach is that an understanding of the mechanisms controlling the plasticity of the neonatal repertoire will lead to new therapeutic or vaccination options for the treatment and prevention of infection by these organisms. Because mouse models provide unique opportunities for experimentation that cannot be performed in humans, we anticipate that this knowledge will help understand human infant responses to infection, aid in the development of more effective vaccine strategies, and help understand possible consequences of vaccine interference. These goals will be pursued by three aims: 1) to identify factors affecting the establishment of the B cell clonal repertoire to polysaccharides expressed by S. pneumoniae, S. pyogenes (GAS), S. agalactiae (GBS) and E. cloacae: 2) to identify phenotypic, subset distribution, and functional changes elicited in emerging B cells by exposure to these organisms: and 3) to isolate and determine the characteristics of mAbs derived from neonatally immunized adult mice that provide optimal protection to infection with these organisms. By choosing to study this multi-member panel, we will develop unique models in which we can study B cell clonal competition and other interactions during development. We have also developed a comprehensive panel of anti-idiotype antibodies and labeled antigens which permit us to accurately quantitate B cell clonal frequencies and trace by flow cytometry the development of single antigen-binding B cells in response to vaccination or after infection with our model organisms. In addition, we have constructed immunoglobulin transgenic mice with VH genes from hybridomas responding to the PS expressed by these organisms. Our findings are expected to have impact on the understanding of immune B cell memory development and its persistence throughout life. The likely future introduction of even more childhood vaccines makes it imperative that we better understand vaccine interference that may result from the effects of multiple vaccines, neonatal chronic infections, and co-infection on subsequent immune responses to further vaccination or infection.

描述（由申请方提供）：革兰氏阴性肠道感染和革兰氏阳性微生物，包括肺炎链球菌、A组（GAS）和B组（GBS）链球菌，是严重细菌感染的主要原因，并导致全球新生儿死亡。在人类和小鼠中，早期B细胞产生针对这些和类似生物体的抗体对于保护免受感染及其血液传播是必不可少的。然而，适应性免疫系统在生命早期受到损害，并且人类婴儿对多糖（PS）的保护性抗体应答需要两年多的时间才能形成。我们的长期目标是对新生儿对与婴儿健康明显相关的多种生物体的免疫反应进行仔细控制的研究。我们的近期目标是使用小鼠模型来研究新生儿免疫系统与细菌成分的相互作用，从而产生持久的保护作用。我们的方法背后的基本原理是，了解控制新生儿剧目的可塑性的机制将导致新的治疗或疫苗接种的选择，用于治疗和预防这些生物体的感染。由于小鼠模型为无法在人类中进行的实验提供了独特的机会，我们预计这些知识将有助于了解人类婴儿对感染的反应，有助于开发更有效的疫苗策略，并有助于了解疫苗干扰的可能后果。这些目标将通过三个目标来实现：1）确定影响S.肺炎链球菌（S.化脓链球菌（GAS）、S. agalactiae（GBS）和E.关闭：2）鉴定暴露于这些生物体在新生B细胞中引起的表型、亚群分布和功能变化;和3）分离和确定来自经腹腔免疫的成年小鼠的mAb的特征，所述mAb提供对这些生物体感染的最佳保护。通过选择研究这个多成员小组，我们将开发独特的模型，在其中我们可以研究发育过程中的B细胞克隆竞争和其他相互作用。我们还开发了一组全面的抗独特型抗体和标记抗原，使我们能够准确定量B细胞克隆频率，并通过流式细胞术追踪接种疫苗或感染我们的模型生物体后单个抗原结合B细胞的发展。此外，我们已经构建了免疫球蛋白转基因小鼠与VH基因的杂交瘤响应这些生物体表达的PS。我们的发现有望对理解免疫B细胞记忆的发展及其在整个生命中的持久性产生影响。未来可能会引入更多的儿童疫苗，这使得我们必须更好地了解多种疫苗，新生儿慢性感染和合并感染对后续免疫反应的影响可能导致的疫苗干扰。