Mechanisms of Action for Colony-Stimulating-Factors In IBD

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。原因仍然不甚明了。目前的治疗方法使用免疫抑制药物，并且经常因严重感染而复杂化。我们从一个不同的角度来探讨这种疾病的基础上所作的观察遗传综合征涉及先天免疫受损的患者，也发展克罗恩病。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。治疗导致克罗恩病活动评分、内镜疾病、引流瘘和生活质量的改善。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，并建立CD中对外源性GM-CSF的治疗反应的机制基础。对肠道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，并通过对致耐受性树突状细胞的作用在IBD模型和克罗恩病中具有治疗作用。该假设有3个组成部分，每个都得到了初步数据的支持：1）GM-CSF的粘液分泌通过影响树突状细胞亚群的数量和功能而有助于免疫调节。2)产生I型干扰素（IFN）的浆细胞样树突状细胞（pDC）在调节正常粘膜耐受性和对GM-CSF的治疗应答中起核心作用。3)在IBD模型中施用外源性GM-CSF通过增加I型IFN的pDC表达起作用。这些将在3个目标中解决：（1）确定GM-CSF在固有层细胞群和粘膜免疫调节中的作用，（2）确定产生IFN的浆细胞样树突状细胞在对细菌和细菌产物的粘膜应答中的作用，（3）描述IBD模型中pDC和IFN在对GM-CSF的应答中的作用。这些研究将提供重要的新的洞察所使用的机制，由肠道植物群启动一个富有成效的对话与宿主免疫系统和促进粘膜稳态的健康个体的特点。这些研究也将提高我们对近期CD临床试验中GM-CSF治疗获益机制的理解。

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.