Effects of Retinoids on the Mucosal Immune System

类维生素A对粘膜免疫系统的影响

• 批准号: 7757206
• 负责人: HILDE MC CHEROUTRE
• 金额: $ 27.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7757206
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Biological Response Modifiers; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Development; Drug Delivery Systems; Effector Cell; Environment; Epigenetic Process; Equilibrium; Food; Generations; Genes; Genetic Transcription; Goals; Immune; Immune Tolerance; Immune response; Immune system; Immunity; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Instruction; Intervention; Intestines; Invaded; Knowledge; Lead; Mediating; Medical; Modification; Nuclear Receptors; Pathway interactions; Play; Regulation; Retinoids; Role; Signal Transduction; Stimulus; T-Lymphocyte; Testing; Tissue-Specific Gene Expression; Transcriptional Regulation; Tretinoin; Vitamin A; cytokine; enteric pathogen; flexibility; improved; in vivo; insight; microbial; microorganism antigen; novel; pathogen; prevent; programs; promoter

instmctions): The simultaneous constraint of highly efficient protective immunity together with the prerequisite for tolerance towards innocuous antigens Imposes a significant challenge for the intesfinal mucosal immune system. Several mechanisms operating in different types of DCs and/or T cells have been identified that control immune tolerance and protective immunity. TGF-|3 in particular is a crucial regulator capable of inducing FoxpS+Tregs, but paradoxically, in the presence of pro-inflammatory cytokines, promoting the conversion to Thi7 effector cells. This contrasting deviation puts TGF-(3 as a principal controller of pro- and anti-inflammatory immune responses. Recently we demonstrated that retinoic acid and other retinoids function as key regulators of the TGF-P-dependent immune deviation, capable of inhibiting the induction of proinflammatory Thi7 cells but promoting the TGF-P-dependent differentiation of anti-inflammatory FoxpS+lTregs. We further showed that in the absence of innate danger signals, retinoids can be absorbed and released by the DCs to the T cells they prime. The released retinoids then directly target differential gene expression within the T cell to promote anti-inflammatory and tolerant immunity. In the presence of danger signals sensed by the DCs, retinoids no longer suppress pro-inflammatory differentiation of primed T cells, suggesting that under innate stimulation conditions, retinoid-mediated suppressive effects on T cells are abolished and/or that retinoid signaling in the presence of innate stimuli can turn towards the DCs and promote their antigen presenting function and protective immune responses. The study proposed here, aims at elucidating retinoid-mediated mechanisms that operate in T cells or DCs and that control the balance between tolerance and protective immunity. The indicated collaborative approaches with Units 1,2 and 3 of this PPG, will allow us to extend this study and evaluate the potential cross talk between the retinoid pathways and other cellular mechanisms involved in immune regulation, as well as the role of retinoid-mediated control in directing immune responses towards specific pathogens, using various infecfious animal models. RELEVANCE (See instructions): The knowledge gained from this study will expand our understanding of regulation of pro- and anti¿ inflammatory immune responses, in particular involving mechanisms employed by the mucosal immune system to control local and systemic immunity. The study has also great potential for the identiflcation of new drug targets that may improve exisfing therapies or may lead to the development of novel medical intervention opportunities to prevent and/or treat intestinal inflammatory diseases.

说明)： 高效保护性免疫的同时约束及其前提条件 对无害抗原的耐受性对最终的粘膜免疫构成了重大挑战。 系统。已确定在不同类型的DC和/或T细胞中工作的几种机制 控制免疫耐受和保护性免疫。尤其是转化生长因子-3是一种关键的调节因子，能够 诱导FoxpS+Tregs，但矛盾的是，在促炎细胞因子的存在下，促进 转化为Thi7效应细胞。这种相反的偏差使转化生长因子-(3)成为PRO-AND的主要控制器 抗炎免疫反应。最近我们证明了维甲酸和其他类维甲酸 作为转化生长因子-β依赖的免疫偏离的关键调节因子，能够抑制诱导 促炎症Thi7细胞可促进转化生长因子-β依赖分化的抗炎作用 FoxpS+lTregs。我们进一步证明，在没有先天危险信号的情况下，类维甲酸可以被吸收 并由DC释放到它们激活的T细胞。然后，释放的维甲酸直接针对差异 T细胞内的基因表达促进抗炎和耐受免疫。在……面前 树突状细胞感知的危险信号，维甲酸不再抑制Primed的促炎分化 T细胞，提示在天然刺激条件下，维甲酸对T细胞的抑制作用 细胞被取消和/或在存在先天刺激的情况下类维甲酸信号可以转向DC 并促进其抗原提呈功能和保护性免疫反应。这项研究建议 在这里，旨在阐明维甲酸介导的机制，它在T细胞或DC中工作，并控制 在耐受性和保护性免疫之间取得平衡。与单元1、2的指定协作方法 和3个PPG，将使我们能够扩展这项研究，并评估 类维甲酸途径和其他参与免疫调节的细胞机制，以及 类维A酸介导的针对特定病原体的免疫反应的控制，使用不同的 感染性动物模型。 相关性(请参阅说明)： 从这项研究中获得的知识将扩大我们对正反两方面调控的理解 炎性免疫反应，特别是涉及粘膜免疫所使用的机制 控制局部和全身免疫的系统。这项研究也有很大的潜力来识别 可能改进现有疗法或可能导致新医学发展的新药物靶点 预防和/或治疗肠道炎症性疾病的干预机会。