Mechanisms of Action for Colony-Stimulating-Factors In IBD

IBD 中集落刺激因子的作用机制

• 批准号: 7585280
• 负责人: BRIAN Keith DIECKGRAEFE
• 金额: $ 37.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585280
• 关键词: Address; Bacteria; CSF3 gene; Cell physiology; Cells; Characteristics; Chronic; Clinical; Clinical Trials; Colitis; Colony-Stimulating Factors; Crohn' s disease; DNA Sequence; Data; Defect; Dendritic Cells; Development; Dioxygenases; Disease; Disease model; Elements; Fistula; Foundations; Gastrointestinal tract structure; Genetic; Glycogen Storage Disease; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Interferon Type I; Interferons; Interleukin-10; Intestines; Lamina Propria; Mediating; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Natural Immunity; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Phase I/II Trial; Phase III Clinical Trials; Play; Population; Production; Quality of life; Reagent; Recombinant Granulocyte-Macrophage Colony-Stimulating Factors; Recombinants; Regulation; Role; Series; Signal Transduction; Sodium Dextran Sulfate; Syndrome; Therapeutic; Therapeutic Effect; Work; base; cell type; clinical efficacy; commensal microbes; granulocyte; immune function; improved; indoleamine; insight; macrophage; microbial genome; response

DESCRIPTION (provided by applicant): Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract. The cause remains poorly understood. Current treatments utilize immunosuppressive medications and are often complicated by serious infections. We approached this disease from a different perspective based on observations made in patients with genetic syndromes involving impaired innate immunity that also develop Crohn's disease. These patients showed clinical responses to granulocyte-macrophage colony stimulating factor (GM-CSF), an agent that stimulates innate immunity. Phase I and II trials of GM-CSF in patients with idiopathic CD confirmed these observations. Therapy led to improvements in Crohn's disease activity scores, endoscopic disease, draining fistulas, and quality of life. The focus of this application is therefore to study the normal role of endogenous GM-CSF in the mucosa and to establish a mechanistic basis for the therapeutic response to exogenous GM-CSF in CD. Disrupted tolerance to commensal bacteria is central in the pathogenesis of CD. Our general hypothesis is that GM-CSF regulates mucosal immunity and has a therapeutic effect in IBD models and Crohn's disease through effects on tolerogenic dendritic cells. This hypothesis has 3 components, each supported by preliminary data: 1) Mucosal production of GM-CSF contributes to the regulation of immunity by effects on the number and function of dendritic cell subsets. 2) Type I interferon (IFN) producing plasmacytoid dendritic cells (pDC) play a central role in the regulation of normal mucosal tolerance and the therapeutic response to GM-CSF. 3) Administration of exogenous GM-CSF in models of IBD works through increased pDC expression of type I IFN. These will be addressed in 3 aims: (1) Define the role of GM-CSF in the regulation of lamina propria cell populations and mucosal immunity, (2) Define the role of the IFN producing plasmacytoid dendritic cell on the mucosal response to bacteria and bacterial products, (3) Delineate the role of the pDC and IFN in the response to GM-CSF in IBD models. These studies will provide important new insight into the mechanisms used by commensal flora initiate a productive dialog with the host immune system and promote mucosal homeostasis characteristic of healthy individuals. These studies will also improve our understanding of the mechanisms underlying the therapeutic benefit from GM-CSF in recent clinical trials for CD.

描述（由申请人提供）：克罗恩病（CD）是一种胃肠道慢性炎症性疾病。其原因仍知之甚少。目前的治疗使用免疫抑制药物，并且常常因严重感染而变得复杂。根据对先天免疫受损的遗传综合征患者的观察，我们从不同的角度来研究这种疾病，这些患者也会患上克罗恩病。这些患者对粒细胞-巨噬细胞集落刺激因子（GM-CSF）表现出临床反应，粒细胞-巨噬细胞集落刺激因子是一种刺激先天免疫的药物。 GM-CSF 在特发性 CD 患者中的 I 期和 II 期试验证实了这些观察结果。治疗改善了克罗恩病活动评分、内镜疾病、引流瘘管和生活质量。因此，本申请的重点是研究内源性 GM-CSF 在粘膜中的正常作用，并为 CD 中外源性 GM-CSF 的治疗反应建立机制基础。对共生细菌的耐受性破坏是 CD 发病机制的核心。我们的一般假设是，GM-CSF 调节粘膜免疫，并通过对耐受性树突状细胞的影响，对 IBD 模型和克罗恩病具有治疗作用。该假设有 3 个组成部分，每个组成部分均得到初步数据的支持：1) GM-CSF 的粘膜产生通过影响树突状细胞亚群的数量和功能来促进免疫调节。 2) 产生浆细胞样树突状细胞 (pDC) 的 I 型干扰素 (IFN) 在调节正常粘膜耐受性和对 GM-CSF 的治疗反应中发挥核心作用。 3) 在 IBD 模型中施用外源 GM-CSF 通过增加 I 型 IFN 的 pDC 表达起作用。这些将通过 3 个目标来解决：(1) 定义 GM-CSF 在固有层细胞群和粘膜免疫调节中的作用，(2) 定义产生干扰素的浆细胞样树突状细胞对细菌粘膜反应的作用，以及(3) 描述 pDC 和 IFN 在 IBD 模型中对 GM-CSF 反应中的作用。这些研究将为共生菌群启动与宿主免疫系统进行富有成效的对话并促进健康个体的粘膜稳态特征的机制提供重要的新见解。这些研究还将提高我们对近期 CD 临床试验中 GM-CSF 治疗益处的机制的理解。