DEVELOPMENT AND COMPETENCE OF NEONATAL MUCOSAL IMMUNITY

我们建议继续我们的计划，从新生儿开始，发展和获得肠道粘膜免疫系统的能力。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的正常发展-体液和细胞的、特定的和自然的-并保持其激活/炎症的生理正常状态。尽管我们目前对一些高度特异的粘膜IgA抗体和粘膜T细胞的作用和保护效果有所了解，但我们对大量的天然‘IgA’和丰富的‘自然激活’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肠道粘膜免疫系统明显不发达的特征，我们打算将这些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赖于使用我们现在相当稀有的设施来培育和维持无菌和生菌小鼠。成年无菌小鼠故意定居在已知微生物中，为后续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，因为它们在常规条件下或生药条件下正常发育。我们计划使用选定的共生微生物-摩根杆菌、Ochrobactrum、节炎杆菌、Helicobater和李斯特菌物种或突变体，兼性和专性厌氧菌以及专性细胞外和兼性细胞内细菌-来定植和扰乱粘膜免疫系统的“特殊”和“天然”元素。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。这些研究的实际扩展包括：1)耐定植机制；2)长期分泌型IgA粘膜免疫的细胞基础；3)细菌/宿主肠上皮相互作用，可激活粘膜免疫；4)可能导致肠道细菌传播至远处组织并导致疾病或全身免疫反应的各种机制；5)肠道细菌在启动或加重炎症性肠道疾病中的作用；以及6)可能通过宿主肠道粘膜免疫系统影响病毒或细菌感染结果的潜在肠道病毒/肠道细菌相互作用。

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.