Mucosal adjuvants regulate inflammation and immunity

描述(申请人提供)：淋巴组织中的T辅助细胞采用多种调节炎症的细胞命运。在G-I粘膜，其主要表型为Treg细胞。粘膜佐剂通过推翻粘膜Treg细胞的耐受影响，是解剖黏膜免疫和炎症调节的独特工具。我们的初步数据表明，霍乱毒素(CT)和相关化合物通过cAMP依赖和IL-6/TGFb不依赖的途径诱导Th17细胞分化。为了阐明腺苷环化酶毒素和其他相关的cAMP诱导化合物介导粘膜佐剂作用的机制，并探讨它们在体内的潜在炎症影响，我们在SA-1中建议评估口服CT是否增强Th17促进的DC和负面调节Treg促进的DC。我们将探索cAMP和维甲酸在这一过程中的作用，并将测量和表征随后由不同的mln DC亚群引起的Th细胞反应。在SA-2中，我们将探索CT激活的DC产生的CGRPb在黏膜Th17反应中的作用，并将使用不同的Ko小鼠和wt动物中的药理学方法在体外和体内剖析CT诱导的Th17细胞分化，并评估这些操纵的小鼠在体内对OVA/CT口服免疫的黏膜免疫应答的能力。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Th17细胞的谱系稳定性、其效应器功能、谱系承诺、运输及其与其他Th细胞的相互作用，我们将加深对粘膜部位炎症与免疫调节的理解。这些数据将增加我们关于免疫诱导和粘膜部位炎症调节的知识。我们相信，我们的研究将为设计新型的粘膜佐剂和/或粘膜炎症调节剂(CELAC和IBD)提供新的基础，并可能识别出比CT更安全的佐剂用于未来的临床应用。在拟议的研究中，我们将探索霍乱毒素介导其粘膜佐剂作用的细胞和分子途径。

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.