Mucosal adjuvants regulate inflammation and immunity

描述（由申请人提供）：淋巴组织中的T辅助细胞采用多种细胞命运来调节炎症。在G-I粘膜，它们的主要表型是Treg细胞。通过超越粘膜Treg细胞的耐受性影响，粘液佐剂是用于剖析免疫和炎症的粘膜调节的独特工具。我们的初步数据表明，霍乱毒素（CT）和相关化合物通过cAMP依赖性和IL-6/TGF β-非依赖性途径诱导Th 17细胞分化。为了阐明腺苷酸环化酶毒素和其他相关cAMP诱导化合物介导粘膜佐剂性的机制，并探讨其在体内的潜在炎症影响，我们建议在SA-1中评估口服CT给药是否增强Th 17促进DC和负调节Treg促进DC。我们将探讨cAMP和视黄酸在这一过程中的作用，并将测量和表征随后的Th细胞反应引起的不同MLN DC亚群。在SA-2中，我们将探索CT激活的DC产生的CGRPb在粘膜Th 17应答中的作用，并将使用各种KO小鼠和野生型动物中的药理学方法在体外和体内解剖CT诱导的Th 17细胞分化，我们将评估这些操作小鼠体内对口服OVA/CT免疫的粘膜免疫应答的能力。解剖CT和其他cAMP诱导化合物对粘膜DC成熟的影响将丰富我们对粘膜Th反应产生的相关知识。通过解剖CT诱导的粘膜Th 17细胞的谱系稳定性、它们的效应器功能、谱系定型、运输以及它们与其他Th细胞的相互作用，我们将增加我们对粘膜部位的炎症与免疫的调节的理解。这些数据将增加我们对免疫诱导和粘膜部位炎症调节的相关知识。我们相信，我们的研究将为新型粘膜佐剂和/或粘膜炎症（乳糜泻和IBD）调节剂的设计提供新的基础，并可能确定具有比CT更好的安全性特征的佐剂用于未来的临床使用。在本研究中，我们将探讨霍乱毒素介导其粘膜佐剂性的细胞和分子途径。

DESCRIPTION (provided by applicant): T helper cells in lymphoid tissues adopt multiple cell fates that regulate inflammation. At the G-I mucosa, their dominant phenotype is of Treg cells. Mucosal adjuvants, by overriding the tolerant impact of mucosal Treg cells, are unique tools for dissecting mucosal regulation of immunity and inflammation. Our preliminary data indicate that cholera toxin (CT) and related compounds induce Th17 cell differentiation via a cAMP-dependent and an IL-6/TGFb-independent pathway. To elucidate the mechanisms by which adenylyl cyclase toxins and other related cAMP-inducing compounds mediate mucosal adjuvanticity and to explore their potential inflammatory impact in vivo, we propose in SA-1 to evaluate whether oral CT administration enhances Th17- promoting DC and negatively regulates Treg-promoting DC. We will explore the role of cAMP and retinoic acid in this process and will measure and characterize the subsequent Th-cell response provoked by different MLN DC subsets. In SA-2, we will explore the role of CGRPb produced by CT-activated DC in a mucosal Th17 response and will dissect CT-induced differentiation of Th17 cells in vitro and in vivo using various ko mice and pharmacological approaches in wt animals and we will assess the ability of these manipulated mice to mount mucosal immune responses to oral OVA/CT immunization in vivo. Dissecting the impact of CT and other cAMP-inducing compounds on mucosal DC maturation will enrich our knowledge related to the generation of mucosal Th responses. By dissecting the lineage stability of the CT- induced mucosal Th17 cells, their effector function, lineage commitment, trafficking and their interactions with other Th cells, we will increase our understanding of the regulation of inflammation vs. immunity at mucosal sites. These data will increase our knowledge related to the induction of immunity and the regulation of inflammation at mucosal sites. We believe that our studies will provide a new foundation for the design of novel mucosal adjuvants and/or modulators of mucosal inflammation (Celiac and IBD) and may identify adjuvants with a better safety profile than CT for future clinical use. In the proposed studies we will explore the cellular and molecular pathways by which cholera toxin mediates its mucosal adjuvanticity.