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: 9011989
• 负责人: John Franklin Kearney
• 金额: $ 36.13万
• 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/9011989
• 关键词: Adult; Affect; Animal Model; Anti-Idiotypic Antibodies; Antibodies; Antibody Formation; Antibody Response; 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; Research; Staging; Streptococcus; Streptococcus Group B; Streptococcus pneumoniae; Streptococcus pyogenes; Structure; Testing; Time; Transgenic Mice; Vaccination; Vaccines; Work; antigen binding; arm; base; clinically relevant; co-infection; design; fetal; in vivo; man; member; microbial; mouse model; neonatal death; neonatal exposure; neonatal immune system; 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（由申请人提供）：革兰氏阴性肠道感染和革兰氏阳性生物，包括肺炎链球菌，A组（GAS）和B组（GBS）链球菌（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。在人和小鼠中，早期的B细胞产生了这些和类似生物的抗体，对于免受感染及其传播传播至关重要。但是，自适应免疫系统在早期生命中受到损害，人类婴儿保护性抗体对多糖（PS）的反应需要两年多的时间才能开发。我们的远距离目标是对新生儿免疫反应对多种与婴儿健康相关的生物的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研究新生儿免疫系统与细菌成分的相互作用，从而导致持久保护。我们方法背后的理由是，了解控制新生儿曲目可塑性的机制将导致这些生物体治疗和预防感染的新治疗或疫苗接种选择。因为小鼠模型为人类无法执行的实验提供了独特的机会，所以我们预计这些知识将有助于了解人类对感染的反应，有助于制定更有效的疫苗策略，并帮助了解疫苗干扰的可能后果。 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源自新生儿免疫的成年小鼠的mAb的特征，这些小鼠可为这些生物体感染提供最佳的保护。通过选择研究这个多成员的小组，我们将开发独特的模型，在该模型中，我们可以在开发过程中研究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IDiotype抗体和标记的抗原，使我们能够准确地定量B细胞克隆频率，并通过流式细胞仪进行痕迹，以响应疫苗接种或使用模型生物体感染后，单个抗原结合B细胞的开发。此外，我们已经用来自杂交瘤的VH基因构建了免疫球蛋白转基因小鼠，这些小鼠响应这些生物所表达的PS。我们的发现有望影响对免疫B细胞记忆发展及其持续存在的理解。未来可能的童年疫苗可能会引入更多的疫苗，使我们必须更好地了解疫苗干扰，这可能是由于多种疫苗，新生儿慢性感染的影响以及对随后的免疫反应的影响，对进一步的疫苗接种或感染。