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计划，涉及从新生儿生活开始的肠粘膜免疫系统的发展和获得。我们的假设是，肠道共生细菌和肠道病毒推动了肠粘膜免疫系统 - 体液和细胞，特异性和“自然和自然的新生儿生活”的正常发育，并作用于维持其“生理上正常”的激活/炎症状态。尽管我们目前对某些高度特异性的粘膜IgA抗体和粘膜T细胞的作用和保护性有效性表示赞赏，但我们对天然“ Iga和丰富的自然激活” T淋巴细胞的大量作用的了解远不止于此。由于无菌成年小鼠和常规饲养的新生小鼠具有明显发育不足的肠粘膜免疫系统的特征，因此我们打算在选择性定植的受控条件下与已知的肠道病毒肠道细菌（Gnotobiotic条件）进行比较。因此，我们将在很大程度上依靠我们现在相当罕见的设施来繁殖和维持无菌和gnotobiotic小鼠。成年的无菌小鼠，故意用知识微生物定居，为新生儿小鼠的肠粘膜免疫系统的发展提供了更可探讨的模型，因为它们在常规或gnotobiotic条件下正常发育。我们计划使用选定的Microbes-Morganella，ochrobactrum，关节炎，Helicobater和Listeria物种或突变体，均具有辅助性和强制性厌食症，并且均具有细胞外和辅助细胞内细菌的质感，从而可以与“特定的”和“自然”元素进行重生和伴随。我们计划在细胞和分子水平上分析这些生物如何推动粘膜免疫系统的发展。我们将追求的这些研究的实际扩展包括：1）“殖民化抗性”的机制； 2）长期分泌IgA粘膜免疫的细胞理由； 3）可能激活粘膜免疫的细菌/宿主肠道上皮相互作用； 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）肠道细菌在发起或加剧炎症性肠病中的作用； 6）潜在的肠道病毒/肠道细菌通过宿主的肠粘膜免疫系统，可能影响病毒或细菌感染的结果。