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。原因仍然知之甚少。目前的治疗方法是使用免疫抑制药物，并且常常伴有严重的感染。我们从不同的角度看待这种疾病，基于对遗传综合征患者的观察，这些患者包括先天免疫受损，也会发展为克罗恩病。这些患者对粒细胞-巨噬细胞集落刺激因子（GM-CSF）有临床反应，这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度评分、内窥镜疾病、引流瘘管和生活质量的改善。因此，本应用的重点是研究内源性GM-CSF在粘膜中的正常作用，并为外源性GM-CSF在CD中的治疗反应建立机制基础。对共生菌的耐受破坏是CD发病机制的核心。我们的一般假设是GM-CSF调节粘膜免疫，并通过对耐受原树突状细胞的作用对IBD模型和克罗恩病有治疗作用。这一假设有3个组成部分，每个部分都有初步数据支持：1)粘膜产生GM-CSF通过影响树突状细胞亚群的数量和功能参与免疫调节。2) I型干扰素（IFN）产生浆细胞样树突状细胞（pDC）在正常粘膜耐受和GM-CSF治疗反应的调节中起核心作用。3) IBD模型中外源性GM-CSF通过增加I型IFN的pDC表达起作用。这些将在三个目标中得到解决：(1)确定GM-CSF在调节固有层细胞群和粘膜免疫中的作用；(2)确定IFN产生浆细胞样树突状细胞在粘膜对细菌和细菌产物的反应中的作用；(3)描述pDC和IFN在IBD模型中对GM-CSF的反应中的作用。这些研究将为共生菌群启动与宿主免疫系统的有效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。这些研究也将提高我们对GM-CSF在近期临床试验中对乳糜泻治疗益处的机制的理解。

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.