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: 7406643
• 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/7406643
• 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; Disruption; 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; Numbers; 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; Score; 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）是胃肠道的慢性炎症性疾病。原因仍然很少理解。当前的治疗方法利用免疫抑制药物，经常因严重感染而复杂化。我们根据遗传综合症患者的观察结果从不同的角度解决了这种疾病，涉及涉及先天免疫受损的患者，这也发展了克罗恩病。这些患者表现出对粒细胞 - 巨噬细胞刺激因子（GM-CSF）的临床反应，这是一种刺激先天免疫力的药物。 GM-CSF对特发性CD患者的I阶段和II试验证实了这些观察结果。治疗导致克罗恩病活动得分，内窥镜疾病，排泄瘘管和生活质量的改善。因此，该应用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的治疗反应建立机械基础。对共生细菌的耐受性破坏是CD发病机理的核心。我们的总体假设是，GM-CSF调节粘膜免疫，并通过对耐受性树突状细胞的影响在IBD模型和克罗恩病中具有治疗作用。该假设具有3个组成部分，每个组成部分得到了初步数据的支持：1）GM-CSF的粘膜产生有助于通过对树突状细胞亚群的数量和功能的影响来调节免疫。 2）I型干扰素（IFN）产生浆细胞样树突状细胞（PDC）在调节正常粘膜耐受性和对GM-CSF的治疗反应中起着核心作用。 3）IBD模型中的外源GM-CSF通过增加I型IFN的PDC表达来起作用。这些目的将在3个目的中解决：（1）定义GM-CSF在调节椎上植物细胞群体和粘膜免疫调节中的作用，（2）定义产生纤溶酶树突状细胞对粘膜膜对细菌和细菌产物响应的IFN的作用，（（3）DELINEATE，（3）DELINEATE对PDC和IFN的作用。这些研究将为Consensal Flora使用的机制提供重要的新见解，该机制启动了与宿主免疫系统的富有成效的对话，并促进了健康个体的粘膜稳态特征。这些研究还将提高我们对最近CD临床试验中GM-CSF治疗益处的机制的理解。