Mechanisms of Action for Colony-Stimulating-Factors In IBD

描述(申请人提供)：克罗恩病(CD)是一种慢性胃肠道炎症性疾病。其原因仍鲜为人知。目前的治疗方法是使用免疫抑制药物，并经常合并严重感染。我们从一个不同的角度看待这种疾病，基于对遗传综合征患者的观察，这些患者涉及先天免疫受损，也会发展为克罗恩病。这些患者表现出对粒细胞-巨噬细胞集落刺激因子(GM-CSF)的临床反应，GM-CSF是一种刺激天然免疫的试剂。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。治疗后克罗恩病活动度评分、内窥镜疾病、引流性瘘管和生活质量均有改善。因此，这一应用的重点是研究内源性GM-CSF在CD黏膜中的正常作用，并为CD对外源性GM-CSF的治疗反应建立机制基础。对共生菌的耐受性破坏是CD发病机制的核心。我们的一般假设是，GM-CSF调节黏膜免疫，并通过对耐受性树突状细胞的作用而对IBD模型和克罗恩病有治疗作用。这一假说有3个组成部分，每个组成部分都得到了初步数据的支持：1)粘膜产生的GM-CSF通过影响树突状细胞亚群的数量和功能而参与免疫调节。2)产生I型干扰素的血浆细胞样树突状细胞(PDC)在调节正常黏膜耐受和GM-CSF的治疗反应中发挥重要作用。3)在IBD模型中，外源性GM-CSF通过增加PDC表达I型干扰素发挥作用。这些将从3个方面进行阐述：(1)明确GM-CSF在调节固有层细胞群和粘膜免疫中的作用；(2)明确产生干扰素的浆细胞样树突状细胞在黏膜对细菌和细菌产物的反应中的作用；(3)阐明PDC和干扰素在IBD模型中对GM-CSF的反应中的作用。这些研究将为了解共生菌群使用的机制提供重要的新见解，启动与宿主免疫系统的富有成效的对话，并促进健康个体所特有的粘膜动态平衡。在最近的CD临床试验中，这些研究也将提高我们对GM-CSF治疗益处潜在机制的理解。

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.