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: 8376296
• 负责人: Michael Karin
• 金额: $ 25.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8376296
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; CD4 Positive T Lymphocytes; Cells; Development; Diet; Drug Delivery Systems; Effector Cell; Environment; Epigenetic Process; Equilibrium; Food; Generations; Genes; Genetic Transcription; Goals; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunosuppression; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Instruction; Interleukin-17; Intervention; Intestines; Invaded; Knowledge; Lead; Mediating; Medical; Modification; Nuclear Receptors; Pathway interactions; Play; Regulation; Regulatory T-Lymphocyte; Retinoids; Role; Signal Transduction; Stimulus; T cell differentiation; 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， 对无害抗原的耐受性对肠粘膜免疫提出了重大挑战 系统已经鉴定了在不同类型的DC和/或T细胞中起作用的几种机制， 控制免疫耐受和保护性免疫。转化生长因子|特别是3是一个关键的监管机构， 诱导FoxpS+ T细胞，但矛盾的是，在促炎细胞因子存在下， 转化为Th 17效应细胞。这种对比偏差使TGF-β作为亲和 抗炎免疫反应。最近，我们证明了维甲酸和其他类维生素A 作为TGF-β依赖性免疫偏离的关键调节因子，能够抑制 促炎性Thi 7细胞，但促进TGF-β依赖性的抗炎性Thi 7细胞的分化， FoxpS+ lT。我们进一步表明，在没有先天危险信号的情况下， 并由DC释放到它们引发的T细胞。释放的类维生素A然后直接靶向分化 T细胞内的基因表达，以促进抗炎和耐受性免疫。存在下 当DCs感受到危险信号时，类维生素A不再抑制启动的促炎分化。 这表明在先天刺激条件下，类维生素A介导的对T细胞的抑制作用， 细胞被消除和/或在先天刺激存在下类维生素A信号传导可以转向DC 并促进其抗原提呈功能和保护性免疫应答。提议进行的研究 本文旨在阐明类维生素A介导的在T细胞或DC中起作用的机制， 耐受性和保护性免疫之间的平衡。与1、2号机组的合作方法 和3的PPG，将使我们能够扩展这项研究，并评估潜在的串扰之间的 类维生素A途径和其他参与免疫调节的细胞机制，以及 类维生素A介导的控制，在指导免疫反应对特定的病原体，使用各种 感染性动物模型。 相关性（参见说明）： 从这项研究中获得的知识将扩大我们对亲和反调节的理解。 炎性免疫应答，特别是涉及粘膜免疫应答所采用的机制， 控制局部和全身免疫系统。这项研究也有很大的潜力， 新的药物靶点，可能会改善治疗或可能导致新的医疗发展， 预防和/或治疗肠道炎性疾病的干预机会。