Indoleamine 23-Dioxygnease in Intestinal Inflammation

吲哚胺 23-双加氧酶在肠道炎症中的作用

• 批准号: 7134887
• 负责人: WILLIAM F. STENSON
• 金额: $ 31.25万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7134887
• 关键词: CD28 molecule; aminoacid metabolism; biological signal transduction; cell proliferation; colitis; disease /disorder model; enzyme activity; enzyme induction /repression; flow cytometry; gene expression; genetically modified animals; immune response; immunocytochemistry; indoleamine; inflammation; interferon alpha; interferon gamma; intermolecular interaction; intestine disorder; laboratory mouse; leukocyte activation /transformation; lymphocyte; oxygenases; protein localization; tryptophan

DESCRIPTION (provided by applicant): IDO is an enzyme that metabolizes tryptophan resulting in depletion of tryptophan levels. Tryptophan depletion leads to an impairment of lymphocyte proliferation and a downregulation of the immune response. We have studied the role of IDO in regulating the inflammatory response in the intestine. IDO expression is induced in human inflammatory bowel disease and in the TNBS model of colitis in the mouse. Inhibition of IDO resulted in increased severity of TNBS colitis. In vivo administration of CTLA4-lg resulted in upregulation of IDO in the colon and in improved survival and diminished severity of inflammation in the TNBS model of colitis. The beneficial effects of CTLA4-lg in TNBS colitis were abrogated by the co-administration of an IDO inhibitor suggesting that the beneficial effects of CTLA4-lg were mediated through the induction of IDO. These findings have lead to the central hypothesis of this proposal which is: IDO is an important regulator of the inflammatory response in the intestine and upregulation of IDO expression has therapeutic potential in inflammatory bowel disease. To address this hypothesis we propose the following Specific Aims: 1) To define the mechanism by which IDO is upregulated in the TNBS model. Studies under this Specific Aim will include cellular localization of IDO using immunohistochemistry and flow cytometric cell sorting and definition of the roles of interferon alpha (IFNalpha) and interferon gamma (INFgamma) as mediators of IDO induction.2) To define the mechanism by which CTLA4-lg has a beneficial effect on the TNBS model. We have developed preliminary data demonstrating not only that administration of CTLA4-lg improves the TNBS model of colitis but also that the beneficial effects of CTLA4-lg are mediated through the induction of IDO. To further address the role of IDO induction in the beneficial effects of CTLA4-lg we propose to assess the affects of CTLA4-lg on TNBS colitis in the IDO knockout mouse. In addition we will determine if other agents that increase IDO expression also have beneficial effects in the TNBS model of colitis. 3) To determine if the beneficial effects that we have seen associated with increased IDO expression in the TNBS model of colitis extend to other models of intestinal inflammation, and in particular to the CD4+CD45RBhi transfer model of colitis. The long term goal of this project is to determine if there is a role for pharmacologic agents that increase IDO expression in the management of human inflammatory bowel disease.

描述（由申请人提供）：IDO是一种代谢色氨酸的酶，导致色氨酸水平消耗。色氨酸耗竭会导致淋巴细胞增殖和免疫反应下调。我们研究了IDO在调节肠道中的炎症反应中的作用。 IDO表达是在人类炎症性肠病和小鼠结肠炎模型中诱导的。 IDO的抑制导致TNBS结肠炎的严重程度增加。 CTLA4-LG的体内给药导致结肠中IDO的上调，并改善了结肠炎TNBS模型的炎症的生存率和炎症的严重程度降低。 CTLA4-LG在TNBS结肠炎中的有益作用被IDO抑制剂的共同给药消除了，这表明CTLA4-LG的有益作用是通过诱导IDO介导的。这些发现导致了该提案的中心假设，即IDO是肠道炎症反应的重要调节剂，IDO表达的上调在炎症性肠病中具有治疗潜力。为了解决这一假设，我们提出了以下特定目的：1）定义在TNBS模型中IDO上调的机制。在此特定目标下的研究将包括使用免疫组织化学和流式细胞仪分类的细胞定位，以及干扰素α（Ifnalpha）和干扰素伽马（Infgamma）作为IDO诱导的介体的作用的定义。我们已经开发了初步数据，不仅证明了CTLA4-LG的给药可改善结肠炎的TNBS模型，而且还通过诱导IDO介导了CTLA4-LG的有益作用。为了进一步解决IDO诱导在CTLA4-LG的有益作用中的作用，我们建议评估CTLA4-LG对IDO敲除小鼠中TNBS结肠炎的影响。此外，我们将确定增加IDO表达的其他药物是否在结肠炎的TNBS模型中也具有有益的作用。 3）确定我们看到的与结肠炎TNBS模型中IDO表达增加有关的有益作用是否扩展到其他肠道炎症模型，尤其是CD4+CD45RBHI结肠炎的转移模型。该项目的长期目标是确定药理学剂是否在人类炎症性肠病管理中增加了IDO表达的作用。