DEVELOPMENT AND COMPETENCE OF NEONATAL MUCOSAL IMMUNITY

我们建议继续我们的计划，关注肠道能力的发展和获得。 粘膜免疫系统始于新生儿的生命。我们的假设是肠道共生细菌和肠道病毒 推动肠道粘膜免疫系统的正常发展--体液和细胞的、特异的和自然的 在新生儿的生命过程中，并采取行动，以保持其“生理正常”的激活/炎症状态。尽管我们 某些高度特异的粘膜IgA抗体和粘膜T细胞的作用及保护作用的研究现状 细胞，我们对大量的“天然”免疫球蛋白和大量的天然免疫球蛋白的可能作用知之甚少。 肠道相关淋巴组织不同隔室中活化的T淋巴细胞。因为无菌成人 小鼠和常规饲养的新生小鼠的共同特点是肠道发育明显不足。 黏膜免疫系统，我们打算将这些在受控条件下的选择性定植与已知的 肠道细菌或肠道病毒(灵生条件)。因此，我们将在很大程度上依赖于我们现在相当罕见的 用于培育和维持无菌和生菌小鼠的设施。成年无菌小鼠，被故意殖民 对于已知的微生物，为随后分析肠道粘膜的发育提供了一个更容易处理的模型 无论是在常规条件下还是在诺生菌条件下，新生小鼠的免疫系统都能正常发育。 我们计划使用选定的共生微生物-摩根杆菌、Ochrobactrum、关节炎菌、螺杆菌和李斯特菌 兼性和专性厌氧菌以及专性胞外和兼性胞内的物种或突变体 细菌--侵占和扰乱粘膜免疫系统的“特殊”和“天然”成分。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的发展 系统。 这些研究的实际延伸，我们将继续进行，包括：1)殖民机制 抵抗力1；2)长期分泌型IgA粘膜免疫的细胞基础；3)细菌/宿主肠道上皮 可能激活粘膜免疫的相互作用；4)可能导致肠道播散的各种机制 细菌传播到远处组织并导致疾病或全身免疫反应；5)肠道细菌在启动 或加重炎症性肠道疾病；以及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，这可能会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 or 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 knownmicrobes, 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, Helicobacter, and Listeria species or mutants, both facultative and obligate anaerobes 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 analy2e, at a cellular and molecular level, how these organisms may drive the development of the mucosal immune system. The practical extensions of these studies, which we will pursue, include: 1) mechanisms for 'colonization resistance1; 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.