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学形式，其中CD和UC代表了最广泛的临床分类。虽然治疗选择在过去十年中有所增加，但我们针对特定亚组患者的新生物疗法的能力却落后了。我们最近的研究表明，GM-CSF自身抗体（GM-CSF Ab）升高的CD患者发生需要手术的进展性疾病的风险很高，并且这类患者的中性粒细胞抗菌功能降低。我们假设：1)GM-CSF Ab升高预示复杂疾病和手术风险增加；2) GM-CSF Ab水平具有家族性；3) GM-CSF Ab通过抑制GM-CSF生物活性抑制中性粒细胞功能。我们将在以下目标中检验这些假设：验证GM- CSF Ab抗体预测乳糜泻行为。中和GM-CSF Ab的血清浓度将在一个前瞻性的乳糜泻患者队列中确定，并与疾病行为相关。这些数据将确定中和GM-CSF Ab是否会增加需要手术的复杂CD行为的风险，相对于当前的血清学标记物和治疗方法。目标2。测定血清GM-CSF Ab水平的遗传性。将测定指数型CD患者受影响和未受影响的一级亲属血清GM-CSF Ab浓度，并测定GM-CSF Ab的类内相关系数和家族聚集估计。这些数据将确定中和性GM-CSF Ab是否作为受CARD15和IRGM遗传多态性影响的数量性状遗传。目标3。检测GM-CSF Ab对中性粒细胞功能的调节。GM-CSF Ab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、细胞存活和抗微生物功能（包括CD11B激活、粘附、吞噬、微生物杀灭和氧化爆发）相关。这些数据将确定GM-CSF Ab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：目前IBD新药物的临床护理和试验由于缺乏生物标志物来预测和监测治疗反应而受到阻碍。如果没有这样的生物标记物，通过一种最多能使症状持续缓解50%的方法，为患者提供连续的治疗。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志物，既可以预测复杂疾病的风险，又可以指导更有可能改变疾病病程的靶向生物治疗，从而促进对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.