Biomarkers for Inflammatory Bowel Disease Behavior and Treatment Response

描述(由申请人提供)：IBD可能有几种免疫遗传形式，CD和UC代表最广泛的临床分类。虽然在过去的十年中，治疗方法的选择有所增加，但我们针对特定患者亚群进行新的生物治疗的能力一直落后。我们最近的研究表明，GM-CSF自身抗体(GM-CSF Ab)升高的CD患者患进展性疾病的风险很高，需要手术治疗，这类患者的中性粒细胞抗菌功能降低。我们假设：1)GM-CSF抗体升高预示着复杂疾病和手术风险的增加；2)GM-CSF抗体水平是家族性特征；3)GM-CSF抗体通过抑制GM-CSF生物活性而抑制中性粒细胞功能。我们将在以下目标检验这些假说：目的1.验证GM-CSF抗体对CD行为的预测。中和性GM-CSF抗体的血清浓度将在CD患者的预期队列中进行测定，并与疾病行为有关。这些数据将决定与目前的血清标志物和治疗方法相比，中和GM-CSF抗体是否会增加需要手术的复杂CD行为的风险。目的2.测定血清GM-CSF抗体水平的遗传度。测定CD患者患病和未发病一级亲属的血清GM-CSFAb浓度，并测定其类内相关系数和家族聚集性估计。这些数据将决定中和GM-CSF抗体是否是受CARD15和IRGM基因多态影响的数量性状遗传。目的3.检测GM-CSF单抗对中性粒细胞功能的调节作用。GM-CSF抗体的血清浓度将被测定，并与基础和GM-CSF依赖的中性粒细胞STAT3/5激活、细胞存活和抗菌功能(包括CD11b激活、黏附、吞噬、微生物杀伤和氧化爆发)有关。这些数据将决定GM-CSF抗体是否抑制中性粒细胞STAT5的激活和抗菌功能，同时促进STAT3的激活和细胞存活。公共卫生相关性：由于缺乏预测和监测治疗反应的生物标志物，目前IBD的临床护理和新药试验受到阻碍。如果没有这样的生物标志物，患者可以通过一种最多50%的持续症状缓解率的方法获得连续的治疗。在拟议的研究中，我们将验证一种新的生物标志物--抗GM-CSF抗体。这些研究将首次提供一种生物标记物，既可以预测复杂疾病的风险，又可以指导更有可能改变病程的有针对性的生物治疗，从而促进IBD患者的护理。

DESCRIPTION (provided by applicant): It is likely that there are several immunogenetic forms of IBD, with CD and UC representing the broadest clinical classifications. While therapeutic options have increased over the past decade, our ability to target newer biologic therapies to specific subgroups of patients has lagged behind. Our recent studies have shown that CD patients with elevated GM-CSF auto-antibodies (GM-CSF Ab) are at high risk for progressive disease requiring surgery, and that neutrophil antimicrobial functions are reduced in this subset of patients. We hypothesize that: 1) elevated GM-CSF Ab will predict increased risk for complicated disease and surgery; 2) GM-CSF Ab level is a familial trait; and 3) GM-CSF Ab suppress neutrophil function by inhibiting GM-CSF bioactivity. We will test these hypotheses in the following Aims: Aim 1. Validate GM- CSF Ab antibody prediction of CD behavior. The serum concentration of neutralizing GM-CSF Ab will be determined in a prospective cohort of CD patients and related to disease behavior. These data will determine whether neutralizing GM-CSF Ab increase risk for complicated CD behavior requiring surgery, relative to current serologic markers and therapies. Aim 2. Determine the heritability of serum GM-CSF Ab levels. The serum concentration of GM-CSF Ab will be determined in affected and unaffected first degree relatives of index CD patients and the intra-class correlation coefficient and estimate of familial aggregation for GM-CSF Ab will be determined. These data will determine whether neutralizing GM-CSF Ab are inherited as a quantitative trait influenced by CARD15 and IRGM genetic polymorphisms. Aim 3. Examine GM-CSF Ab regulation of neutrophil function. The serum concentration of GM-CSF Ab will be determined and related to basal and GM-CSF dependent neutrophil STAT3/5 activation, cell survival, and antimicrobial functions including CD11B activation, adhesion, phagocytosis, microbial killing, and oxidative burst. These data will determine whether GM-CSF Ab suppress neutrophil STAT5 activation and antimicrobial function, while promoting STAT3 activation and cell survival. PUBLIC HEALTH RELEVANCE: Current clinical care and trials of new medications in IBD are hampered by a lack of biomarkers to predict and monitor response to therapy. Without such biomarkers, patients are offered successive therapies via an approach which results in at best a fifty percent rate of sustained relief of symptoms. In the proposed studies, we will validate a novel biomarker, the anti-GM-CSF antibody. These studies will advance the care of IBD patients by providing for the first time a biomarker which will both predict risk for complicated disease, and guide targeted biologic therapy more likely to modify the disease course.