Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) induced monocyte subsets and their potential influence on intestinal inflammation

粘膜疾病的免疫学和遗传学的最新进展表明，单核细胞及其衍生细胞在克罗恩病的病理生理学中起着重要作用，血液单核细胞是炎症肠粘膜中巨噬细胞的唯一来源。粒细胞巨噬细胞集落刺激因子（GM-CSF），造血生长因子，刺激肠道先天免疫系统的细胞。临床试验表明，GM-CSF诱导活动性克罗恩病（CD）患者的临床反应和缓解。目前尚不清楚GM-CSF对CD的治疗作用是如何发挥的，但我们前期的研究表明，GM-CSF的作用可能是由血液单核细胞介导的。本项目的总体目标是表征GM-CSF处理的单核细胞在体内和体外的免疫调节作用。我们将集中在不同的单核细胞和巨噬细胞亚群在CD中的作用，并旨在进一步表征GMCSF诱导的特定单核细胞亚群的表型。在这方面，我们将阐明CD中所产生的巨噬细胞群体的抗炎功能，详细说明GM-CSF处理的单核细胞的分子机制和生理功能，并验证GM-CSF诱导的改善实验性结肠炎的作用，主要关注单核细胞功能。该项目可能有助于揭示CD发病机制的新见解，并确定先天免疫调节可能改变这种疾病的自然史的机制。从长远来看，了解CD的机制可能会带来新的治疗选择的潜力。

Recent developments in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role in the pathophysiology of Crohn‘s disease and that blood monocytes are the exclusive source of macrophages in inflamed intestinal mucosa. Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Clinical trials show that GM-CSF induces clinical response and remission in patients with active Crohn’s disease (CD). Up to date, it is still not clear how GM-CSF exerts its beneficial activities in CD, but our previous research data suggest that the GM-CSF effects could be mediated by blood monocytes. The overall aim of this project is the characterization of the immunomodulatory effects of GM-CSF treated monocytes in vivo and in vitro. We will focus on the roles of distinct monocyte and macrophage subsets in CD and aim to further characterize the phenotype of GMCSF induced specific monocyte subsets. In this regard, we will elucidate the anti-inflammatory functions of the resulting macrophage population in CD, specify the molecular machinery, and the physiological functions of GM-CSF treated monocytes and verify the effects of GM-CSF induced amelioration of experimental colitis with main focus on monocyte functions. The project could help to reveal novel insights into the pathogenesis of CD and to identify mechanisms by which modulation of innate immunity bears a potential of altering the natural history of this disease. Understanding the mechanism in CD may bear the potential of novel treatment options in the long run.