Anti-IL-12p40 Treatment of CVID Enteropathy: Gene Expression/Microbiota Analysis

描述（由申请人提供）：常见可变免疫缺陷（CVID）是最常见的一抗缺乏综合征，其特征是血清免疫球蛋白水平下降和反复发作的肺部感染。此外，高达50%的患者表现为非感染性吸收不良综合征，也称为CVID肠病，通常对治疗有耐药性。CVID肠病的发病机制尚不清楚，但最近的研究表明，它是肠道微生物群和肠上皮之间复杂的相互作用导致粘膜免疫反应过度活跃的结果，其特征是白细胞介素-12和干扰素- γ的产生增加。在这种肠病的小鼠模型中进一步的研究表明，在存在微生物群而非无菌动物的情况下，免疫缺陷宿主的肠上皮上调干扰素依赖性免疫基因，而牺牲代谢基因。此外，CVID患者组织的初步微阵列分析显示，在人类CVID中也存在类似的基因表达失调。我们认为选择性抑制过度活跃的粘膜免疫反应可以纠正CVID患者的基因失衡并解决吸收不良问题。Ustekinumab是一种针对白细胞介素-12/23 p40亚基的单克隆抗体。它已被批准用于治疗牛皮癣，目前正在进行治疗难治性克罗恩病的III期试验评估。我们建议用ustekinumab治疗CVID肠病患者，并评估其对临床和免疫参数以及基因表达的影响。对治疗的反应将通过评估吸收不良程度、肠道活组织检查的组织学改变、细胞因子产生和血液中的整体基因表达、肠道活组织检查和分离的肠道单核细胞来评估。将使用散弹枪测序数据的宏基因组分析来监测肠道活检中肠道微生物组成的变化，并与临床和免疫学参数相关联，以确定可能驱动过度活跃免疫反应的微生物。因此，这些研究将提供一个独特的机会来评估CVID肠病的新疗法，同时进行研究，确定动态条件下CVID肠病的机制。

DESCRIPTION (provided by applicant): Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody deficient syndrome and is characterized by decreased levels of serum immunoglobulins and recurrent sinopulmonary infections. In addition, up to 50% of patients manifest a non-infectious malabsorption syndrome, also known as CVID enteropathy, that is usually resistant to treatment. The pathogenesis of CVID enteropathy is still unclear, but recent studies have suggested that it results from a complex interaction between the gut microbiota and the intestinal epithelium leading to a hyperactive mucosal immune response characterized by increased production of Interleukin-12 and Interferon-gamma. Further work in a mouse model of this enteropathy demonstrated that in the presence of microbiota but not in germfree animals, intestinal epithelium of immunodeficient hosts upregulates interferon-dependent immune genes at the expense of metabolic genes. In addition, preliminary microarray analysis CVID patient tissue revealed a similar dysregulation of gene expression in human CVID. We propose that selective inhibition of the hyperactive mucosal immune response would correct the gene imbalance and resolve the malabsorption in CVID patients. Ustekinumab is a monoclonal antibody to the p40 subunit of interleukin-12/23. It is approved for the treatment of psoriasis, and is currently being evaluated in Phase III trials fo the treatment of refractory Crohn's disease. We propose to treat CVID enteropathy patients with ustekinumab and assess the effects on clinical and immunologic parameters as well as on gene expression. Response to therapy will be assessed by evaluation of the degree of malabsorption, histological alterations in gut biopsies, cytokine production and global gene expression in blood, gut biopsies and isolated intestinal mononuclear cells. Changes in intestinal microbial composition in gut biopsies will be monitored using metagenomic analysis of shotgun sequencing data and correlated with clinical and immunological parameters to define microbes possibly driving the hyperactive immune response. These studies will therefore provide a unique opportunity to perform an evaluation of a novel therapy of CVID enteropathy while at the same time conducting studies defining the mechanisms underlying CVID enteropathy under dynamic conditions.