Biomarkers of Therapeutic Response in the IL-23 Pathway in Inflammatory Bowel Disease
Biomarkers of Therapeutic Response in the IL-23 Pathway in Inflammatory Bowel Disease
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DOI：
10.1038/ctg.2012.2
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发表时间：
2012-02-01
影响因子：
3.6
通讯作者：
Beaumont, Maribel
中科院分区：
文献类型：
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作者：
Cayatte, Corinne;Joyce-Shaikh, Barbara;Beaumont, Maribel
白细胞介素-23（IL-23）已成为治疗炎症性肠病（IBD）的新靶点。随着疾病状态和治疗功效的生物标志物在药物开发中变得越来越重要，我们试图鉴定克罗恩病（CD）中抗IL-23疗法的功效生物标志物。候选IL-23生物标志物，IL-23信号传导的下游，使用鸟枪蛋白质组学分析从短期小鼠IBD模型获得的粪便和结肠灌洗液鉴定（抗-CD 40 Rag 2（-/-））用IL-23受体（IL-23 R）的单克隆抗体（mAb）预防性治疗。然后在用抗IL-23（p19）的mAb治疗性处理的IBD T细胞转移模型中测量生物标志物，证实其与IBD的关联。为了评估这些标志物的临床相关性，我们评估了它们在临床血清，结肠组织和CD patients.RESULTS粪便中的浓度：我们确定了57个蛋白质上调或下调的患病动物，当小鼠用单克隆抗体治疗IL-23 R时，这些蛋白质返回到对照值。其中，S100 A8、S100 A9、再生蛋白3 β（REG）、REG 3 γ、脂质运载蛋白2（LCN 2）、恶性肿瘤缺失1（DMBT 1）和巨噬细胞迁移抑制因子（MIF）mRNA水平与疾病评分和IL-23 R或IL-23 mAb剂量滴定（p19）相关。在T细胞转移IBD小鼠模型中，治疗性给予IL-23（p19）mAb后，除DMBT 1外的所有生物标志物均下调。在CD患者的血清中，我们证实了S100 A8/A9（43%）、MIF（138%）、胰腺炎相关蛋白（PAP，REG 3 β/γ的人同源物; 49%）、LCN 2（520%）和CCL 20（1280%），以及S100 A8/A9（887%）、PAP（401%）、和LCN 2（783%）在人类粪便中从CD患者与正常controls.CONCLUSIONS：这些研究确定了多种蛋白质生物标志物下游的IL-23，可能是有价值的工具，以评估这种新的治疗剂的疗效。
OBJECTIVES: Interleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD).METHODS: Candidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2(-/-)) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients.RESULTS: We identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3 beta (REG), REG3 gamma, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3 beta/gamma; 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls.CONCLUSIONS: These studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.