DEVELOPMENT AND COMPETENCE OF NEONATAL MUCOSAL IMMUNITY

新生儿粘膜免疫的发育和能力

• 批准号: 2442616
• 负责人: JOHN J CEBRA
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442616
• 关键词: Escherichia coli infections; Listeria infections; Peyer's patches; Reoviridae; SCID mouse; Salmonella typhimurium; cell sorting; developmental immunology; enzyme linked immunosorbent assay; gastric mucosa; gene rearrangement; growth /development; gut associated lymphoid tissue; humoral immunity; immunity; immunocytochemistry; immunoglobulin A; immunoglobulin genes; immunoglobulin isotypes; immunologic memory; immunosuppression; laboratory mouse; mucosal immunity; newborn animals

The humoral and cellular mucosal immune systems likely play a critical role in protecting neonates against many bacterial and viral pathogens that infect or invade via the gastrointestinal or respiratory mucosae. However, our knowledge about the ontogeny and maintenance of these systems starting at birth is very limited. From many studies of germ-free vs. conventionally reared laboratory animals we do know that the development and maintenance of many elements of the mucosal immune system depend on continuous local stimulation of the gut mucosa by environmental antigens. Presumably, these stimuli may begin to act at birth. We aim to analyze each element of the mucosal immune system of developing neonatal mice -- the competence to generate IgA preplasmablasts and memory cells vis a vis germinal center reactions in Peyer's patches, the early contributions of B-1 B cells to IgA plasma cells in lamina propria, the development of 'natural' IgA based on the populating of lamina propria with IgA plasma cells, the maturation and activation state of CD4+ T cells in the gut, the establishment of skewed ratios of TH2>>TH1 cells in gut tissues, and the increase in cellularity, functionality, and diversity of subsets of CD8+ T cells in the intraepithelial leukocyte compartment. By using reciprocally crossed scid/scid x +/+ murine parents, raised conventionally or under germ-free conditions, we plan to compare these processes as they occur in neonates in the presence of or 'insulated' and 'isolated' from passive maternal immune effects and/or environmental microbial stimuli. Our second aim is to investigate mechanisms of immunosuppression/immunopotentiation in neonates mediated by maternal antibodies, pathogens, or environmental antigens, and to evaluate methods to overcome or enhance these processes. We particularly aim to establish a role, if any, for bacterial lipopolysaccharide in mediating the maturation of neonatal B cells and in developing the 'natural' gut IgA response. Further, we would like to devise procedures that would allow neonates to benefit from passively acquired maternal antibodies while overcoming their suppression of active, mucosal immunization -- via mucosal adjuvants, microencapsulated antigens, etc. Model gut mucosal stimuli/infectious agents will include Types 1 and 3 reoviruses, Morganella morganii, Escherichia coli, Salmonella typhimurium Lactobacilli sp., Listeria monocytogenes, and segmented filamentous bacteria (an obligate anaerobe).

体液和细胞粘膜免疫系统可能发挥着关键作用 在保护新生儿免受许多细菌和病毒病原体侵害方面的作用 通过胃肠道或呼吸道粘膜感染或侵入。 然而，我们对这些系统的个体发育和维护的了解 从出生开始就非常有限。 来自许多关于无菌与无菌的研究 我们确实知道传统饲养的实验动物的发展 粘膜免疫系统许多要素的维持取决于 环境抗原对肠粘膜的持续局部刺激。 据推测，这些刺激可能在出生时就开始起作用。 我们的目的是分析 发育中的新生小鼠粘膜免疫系统的每个要素—— 产生 IgA 前质母细胞和记忆细胞的能力 派尔氏集结的生发中心反应，早期贡献 B-1 固有层中 B 细胞向 IgA 浆细胞的发育 基于 IgA 血浆填充固有层的“天然”IgA 细胞，肠道中 CD4+ T 细胞的成熟和激活状态， 建立肠道组织中 TH2>>TH1 细胞的倾斜比例，以及 CD8+ 子集的细胞结构、功能和多样性增加 上皮内白细胞室中的 T 细胞。 通过使用 scid/scid x +/+ 小鼠亲本相互杂交，按常规饲养 或者在无菌条件下，我们计划比较这些过程 发生在新生儿存在或“绝缘”和“隔离”的情况下 母体被动免疫效应和/或环境微生物刺激。 我们的第二个目标是研究机制 母体介导的新生儿免疫抑制/免疫增强 抗体、病原体或环境抗原，并评估方法 克服或增强这些过程。 我们特别致力于建立 如果有的话，细菌脂多糖在介导 新生儿 B 细胞的成熟和“天然”肠道 IgA 的发育 回复。 此外，我们希望制定程序，允许 新生儿受益于被动获得的母体抗体，同时 克服它们对主动粘膜免疫的抑制——通过 粘膜佐剂、微囊化抗原等 肠粘膜模型 刺激物/传染性病原体包括 1 型和 3 型呼肠孤病毒， 摩根氏菌、大肠杆菌、鼠伤寒沙门氏菌、乳酸杆菌 sp.、单核细胞增生李斯特氏菌和分段丝状细菌（一种 专性厌氧菌）。