DEVELOPMENT AND COMPETENCE OF NEONATAL MUCOSAL IMMUNITY

我们建议继续我们的计划与发展和收购能力的肠道粘膜免疫系统开始在新生儿的生活。我们的假设是，肠道细菌和肠道病毒驱动肠道粘膜免疫系统的正常发育-体液和细胞，特异性和“自然”-在新生儿的生活和行动，以维持其“生理正常”状态的激活/炎症。尽管我们目前认识到一些高度特异性的粘膜伊加抗体和粘膜T细胞的作用和保护功效，但我们对大量天然“伊加”和丰富的“天然活化”T淋巴细胞在肠道相关淋巴组织的各个隔室中的可能作用知之甚少。由于无菌成年小鼠和常规饲养的新生小鼠具有明显不发达的肠道粘膜免疫系统的特征，因此我们打算在选择性定殖的受控条件下与肠道病毒的已知肠道细菌（gnotobiotic条件）进行比较。因此，我们将在很大程度上依赖于使用我们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，故意与已知的微生物定殖，提供了一个更易处理的模型，为后续分析的发展，肠道粘膜免疫系统在新生小鼠，因为他们正常发展的常规或gnotobiotic条件。我们计划使用选定的肠道微生物-摩根氏菌属，苍白杆菌属，Arthromitis，Helicobater，李斯特菌属物种或突变体，既兼性和专性厌氧菌和专性细胞外和兼性细胞内细菌-殖民和干扰的“特定”和“自然”的粘膜免疫系统的元素。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展。这些研究的实际扩展包括：1）“定植抗性”的机制; 2）长期分泌伊加粘膜免疫的细胞原理; 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应答的各种机制; 5）肠道细菌在引发或加重炎性肠病中的作用;和6）潜在的肠道病毒/肠道细菌相互作用，通过宿主的肠道粘膜免疫系统，可能影响病毒或细菌感染的结果。

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.