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调节炎症。在G-I粘膜，它们的显性表型是Treg细胞。粘膜佐剂，通过覆盖粘膜Treg细胞的耐受性影响，是解剖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/ tgfb非依赖性途径诱导Th17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，并探索其在体内的潜在炎症影响，我们提出在SA-1中评估口服CT给药是否增强Th17-促DC和负调控treg -促DC。我们将探索cAMP和维甲酸在这一过程中的作用，并将测量和表征不同MLN DC亚群引发的后续th细胞反应。在SA-2中，我们将探索由CT激活的DC产生的CGRPb在粘膜Th17反应中的作用，并将在体外和体内使用各种ko小鼠和wt动物的药理学方法解剖CT诱导的Th17细胞分化，我们将评估这些操纵小鼠对口服OVA/CT免疫产生粘膜免疫反应的能力。剖析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。通过分析CT诱导的粘膜Th17细胞的谱系稳定性，它们的效应功能，谱系承诺，运输及其与其他Th细胞的相互作用，我们将增加我们对粘膜部位炎症与免疫调节的理解。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设计新型粘膜佐剂和/或粘膜炎症调节剂（乳糜泻和IBD）提供新的基础，并可能确定比CT更安全的佐剂用于未来的临床应用。在提出的研究中，我们将探索霍乱毒素介导其粘膜佐剂的细胞和分子途径。

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.