Vitamin A Regulates Th1/Th2 Development via RXR Pathway

+描述(由申请人提供)：饮食影响先天免疫功能和适应性免疫功能，因此可能影响对传染病和炎症性疾病的抵抗力和康复。我们的长期目标是确定维生素A如何调节T细胞介导的免疫反应。维生素A缺乏会增加常见儿童感染的死亡率，并损害T辅助2型(Th2)细胞促进的免疫反应。这些反应包括血清IgG1和IgE反应，分泌性IgA反应，以及嗜酸性粒细胞介导的炎症反应，如肠道蠕虫感染和包括哮喘在内的过敏反应。维生素A调节Th2反应的分子机制尚不清楚。我们最近发现，在抗原初始的Th0细胞中，刺激维甲酸X受体(RXR)途径促进Th2记忆细胞的发育(如产生IL-4所示)，而刺激维甲酸受体(RAR)途径不能促进Th2记忆细胞的发育。我们认为RXR介导的特定基因转录是正常Th2发育所必需的。在这项应用中，我们建议使用体外研究来识别这些基因，并确定RXR是单独作用还是与伴侣受体一起作用。RXR或伙伴受体配体调节表达的机制(即，通过与DNA反应元件或转录复合体的其他蛋白质成分相互作用)将被确定。然后，我们将使用受体选择性维甲酸和RXR基因敲除小鼠在体内确定RXR是否调节Th2细胞发育和Th2介导的抗体反应。确定维生素A调节Th2介导的免疫和炎症反应的机制将在几个方面有用。它将有助于评估使用维生素A(也许还有与RXR伙伴受体结合的营养物质，如维生素D和脂肪酸)来评估临床和公共卫生干预措施，以降低贫困人口的发病率和死亡率。了解这些相同的机制也将有助于我们确定美国人群的营养摄入量安全上限，在美国，慢性炎症(由Th2和Th1细胞介导)非常普遍。最后，这项工作可能会提出新的干预策略来调节慢性炎症条件。此外，受体选择性维甲酸目前用于癌症治疗，并正在评估糖尿病的疗效。这项工作将有助于评估这些疗法可能的副作用。

+DESCRIPTION (provided by applicant): Diet affects both innate and adaptive immune function and thus can influence resistance to and recovery from infectious and inflammatory diseases. Our long-term objective is to define how vitamin A regulates T-cell mediated immune responses. Vitamin A deficiency increases mortality from common childhood infections and impairs immune responses promoted by T-helper type 2 (Th2) cells. These responses include the serum IgG1 and IgE responses, the secretory IgA response, and eosinophil-mediated inflammatory responses, such as occur during gut helminth infections and allergic responses, including asthma. The molecular mechanisms by which vitamin A modulates Th2 responses are not known. We have recently found that stimulation of the retinoid X receptor (RXR) pathway in antigen-naive Th0 cells promotes development of Th2 memory cells (as indicated by the production of IL-4), while stimulation of the retinoic acid receptor (RAR) pathway does not. We propose that RXR-mediated transcription from specific genes is required for normal Th2 development. In this application we propose to identify these genes - using in vitro studies - and determine if RXR is acting alone or together with a partner receptor. The mechanism(s) by which RXR or partner receptor ligands regulate expression (i.e., by interacting with DNA response elements or other protein components of the transcription complex) will be identified. We will then use receptor-selective retinoids and RXR-knockout mice to determine, in vivo, if RXR regulates Th2 cell development and Th2-mediated antibody responses. Identifying the mechanisms by which vitamin A modulates Th2-mediated immune and inflammatory responses will be useful in several ways. It will help in evaluating clinical and public health interventions using vitamin A (and, perhaps, nutrients that bind to RXR partner receptors, such as vitamin D and fatty acids) to decrease morbidity and mortality in deficient populations. Understanding these same mechanisms will also help us determine safe upper limits for nutrient intake in the U.S. population, where chronic inflammatory conditions (mediated by both Th2 and Th1 cells) are highly prevalent. Finally, this work may suggest novel intervention strategies to modulate chronic inflammatory conditions. In addition, receptor-selective retinoids are currently used in cancer therapy and are being evaluated for diabetes. This work will help evaluate possible side effects of these therapies.