DEVELOPMENT AND COMPETENCE OF NEONATAL MUCOSAL IMMUNITY

新生儿粘膜免疫的发育和能力

• 批准号: 2073721
• 负责人: JOHN J CEBRA
• 金额: $ 18.71万
• 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/2073721
• 关键词: Escherichia coli infections; Listeria infections; Peyer's patches; Reoviridae; SCID mouse; Salmonella typhimurium; cell sorting; 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起关键 保护新生儿免受许多细菌和病毒病原体的作用 通过胃肠道或呼吸道粘膜感染或入侵。 但是，我们对这些系统的本体发育和维护的了解 从出生开始非常有限。 从许多无菌VS的研究中 常规养育的实验室动物，我们确实知道该发展 并维护粘膜免疫系统的许多元素取决于 环境抗原对肠道粘膜的连续局部刺激。 据推测，这些刺激可能在出生时开始起作用。 我们旨在分析 发育新生小鼠的粘膜免疫系统的每个元素 - 生成IgA前肿瘤和记忆细胞的能力 佩耶斑块中的生发中心反应，是 B-1 B细胞至固有层中的IgA浆细胞，发展 基于IgA等离子体的固有椎板的“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 >> Th2细胞的偏度比 CD8+子集的细胞性，功能和多样性的增加 上皮内白细胞室中的T细胞。 通过使用 相互交叉的scid/scid x +/ +鼠父母，常规饲养 或在无菌条件下，我们计划在它们的情况下比较这些过程 在存在或“绝缘”和“隔离”的情况下发生在新生儿中 被动母体免疫作用和/或环境微生物刺激。 我们的第二个目的是研究 由母亲介导的新生儿的免疫抑制/免疫抑制 抗体，病原体或环境抗原，并评估方法 克服或增强这些过程。 我们特别旨在建立 细菌脂多糖在介导的角色（如果有的话） 新生儿B细胞的成熟和开发“天然”肠道IgA 回复。 此外，我们想设计的程序 新生儿可以从被动获得的母体抗体中受益 克服他们抑制活跃的粘膜免疫 - 通过 粘膜佐剂，微囊化抗原等。型肠粘膜 刺激/传染剂将包括1型和3型旋孢子病毒， Morganella Morganii，大肠杆菌，鼠伤寒沙门氏菌乳酸菌 sp。，李斯特菌单核细胞增生和分割的丝状细菌（一个 务实的Anaerobe）。