DEVELOPMENT AND COMPETENCE OF NEONATAL MUCOSAL IMMUNITY

新生儿粘膜免疫的发育和能力

基本信息

批准号：
6510567
负责人：
JOHN J CEBRA
金额：
$ 50.54万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-30 至 2004-06-30
项目状态：
已结题

项目摘要

We propose to continue our program concerned with the development and acquisition of competence of the gut mucosal immune system beginning in neonatal life. Our hypothesis is that gut commensal bacteria and enteric viruses drive the normal development of the gut mucosal immune system- humoral and cellular, specific and 'natural'-during neonatal life and act to maintain its 'physiologically normal' state of activation/inflammation. Despite our present appreciation of the roles and protective efficacy of some highly specific mucosal IgA antibodies and mucosal T cells, we know far less about the possible roles of the voluminous amounts of natural' IgA and the abundant 'naturally activated' T lymphocytes in the various compartments of gut-associated lymphoid tissues. Because germ-free adult mice and conventionally-reared neonatal mice share the characteristic of having a markedly underdeveloped gut mucosal immune system, we intend to compare these under controlled conditions of selective colonization with known gut bacteria of enteric viruses (gnotobiotic conditions). Thus we will rely heavily on the use of our now rather rare facility for breeding and maintaining germ-free and gnotobiotic mice. Adult germ-free mice, deliberately colonized with know microbes, provide a more tractable model for subsequent analyses of the development of the gut mucosal immune system in neonatal mice as they develop normally under either conventional or gnotobiotic conditions. We plan to use selected commensal microbes-Morganella, Ochrobactrum, Arthromitis, Helicobater, and Listeria species or mutants,, both facultative and obligate anerobes and both obligate extracellular and facultative intracellular bacteria-to colonize and perturb the 'specific' and 'natural' elements of the mucosal immune system. We plan to analyze, at a cellular and molecular level, how these organisms may drive the development of the mucosal immune system. The practical extension of these studies, which we will pursue, include: 1) mechanisms for 'colonization resistance'; 2) the cellular rationale for long-term secretory IgA mucosal immunity; 3) the bacteria/host gut epithelial interactions that may activate mucosal immunity; 4) the various mechanisms that may result in dissemination of gut bacteria to distant tissues and result in disease or to systemic immune response; 5) the role of gut bacteria in initiating or exacerbating inflammatory bowel disease; and 6) the potential enteric virus/gut bacterial interaction, via the host's gut mucosal immune system, that may affect the outcome of either the viral or the bacterial infection.

我们建议继续我们的项目，关注从新生儿开始的肠道粘膜免疫系统能力的发展和获得。我们的假设是，肠道共生细菌和肠道病毒在新生儿生命期间驱动肠道粘膜免疫系统（体液和细胞、特异性和“自然”）的正常发育，并维持其“生理正常”激活/炎症状态。尽管我们目前对一些高度特异性的粘膜 IgA 抗体和粘膜 T 细胞的作用和保护功效有所了解，但我们对大量天然 IgA 和丰富的“自然激活”T 淋巴细胞在各种疾病中的可能作用知之甚少。肠道相关淋巴组织的区室。由于无菌成年小鼠和传统饲养的新生小鼠的共同特征是肠道粘膜免疫系统明显发育不全，因此我们打算将它们在选择性定植的受控条件下与已知的肠道病毒肠道细菌（限生条件）进行比较。因此，我们将严重依赖使用现在相当罕见的设施来繁殖和维持无菌和无菌小鼠。成年无菌小鼠被故意植入已知微生物，为随后分析新生小鼠肠道粘膜免疫系统的发育提供了一个更容易处理的模型，因为它们在常规或无菌条件下正常发育。我们计划使用选定的共生微生物——摩根氏菌、苍白杆菌、关节炎、螺杆菌和李斯特氏菌物种或突变体、兼性和专性厌氧菌以及专性细胞外和兼性细胞内细菌——来定植和扰乱“特定”和“自然”元素粘膜免疫系统。我们计划在细胞和分子水平上分析这些生物体如何驱动粘膜免疫系统的发育。我们将追求的这些研究的实际延伸包括：1）“殖民抵抗”机制； 2）长期分泌型IgA粘膜免疫的细胞原理； 3）细菌/宿主肠道上皮相互作用，可能激活粘膜免疫； 4）可能导致肠道细菌传播到远处组织并导致疾病或全身免疫反应的各种机制； 5）肠道细菌在引发或加剧炎症性肠病中的作用； 6）通过宿主的肠道粘膜免疫系统，潜在的肠道病毒/肠道细菌相互作用，可能影响病毒或细菌感染的结果。