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

抗 IL-12p40 治疗 CVID 肠病：基因表达/微生物群分析

• 批准号: 8726282
• 负责人: Andriy Morgun
• 金额: $ 30.12万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726282
• 关键词: Address; Adrenal Cortex Hormones; Aftercare; Animals; Antibodies; Automobile Driving; B-Lymphocytes; Biopsy; Blood; Cells; Clinical; Common Variable Immunodeficiency; Complex; Complication; Crohn' s disease; Data; Development; Disease; Dose; Environment; Evaluation; Exhibits; Extramural Activities; Functional disorder; Future; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Genes; Genomics; Germ-Free; Growth; Human; Immune; Immune System Diseases; Immune response; Immunoglobulins; Immunologic Deficiency Syndromes; Immunologics; Immunology; Infection; Interferon Type I; Interferon Type II; Interferons; Interleukin-12; Interleukin-17; Intestines; Lamina Propria; Lead; Left; Life; Malabsorption Syndromes; Medicine; Metabolic; Metagenomics; Microarray Analysis; Microbe; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Monitor; Monoclonal Antibodies; Mononuclear; Mucosal Immune Responses; Mus; Nutrient; Pathogenesis; Patients; Phase III Clinical Trials; Pilot Projects; Play; Production; Psoriasis; Recurrence; Refractory; Repression; Resistance; Role; Secondary to; Serum; Shotgun Sequencing; Solutions; Specific Pathogen Frees; Syndrome; T cell response; T-Lymphocyte; Therapeutic Agents; Time; Tissues; United States National Institutes of Health; Up-Regulation; Villous Atrophy; Viral; Work; base; cohort; cytokine; efficacy testing; gastrointestinal; gene correction; germ free condition; gut microbiota; insight; interleukin-12 subunit p40; interleukin-23; intestinal epithelium; microbial; mouse model; novel; public health relevance; response; success

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.

描述(申请人提供)：共同变量免疫缺陷(CVID)是最常见的症状主要抗体缺乏综合征，其特征是血清免疫球蛋白水平下降和反复鼻肺感染。此外，多达50%的患者表现出非传染性吸收不良综合征，也称为CVID肠病，通常对治疗有抵抗力。CVID肠病的发病机制尚不清楚，但最近的研究表明，它是肠道微生物区系和肠上皮之间复杂相互作用的结果，导致以IL-12和干扰素-γ产生增加为特征的过度活跃的粘膜免疫反应。在这种肠病的小鼠模型中的进一步工作表明，在有微生物区系存在的情况下，但在无菌动物中，免疫缺陷宿主的肠道上皮上调了干扰素依赖的免疫基因，而牺牲了代谢基因。此外，对CVID患者组织的初步微阵列分析显示，人类CVID的基因表达也存在类似的失调。我们认为选择性抑制过度活跃的粘膜免疫反应将纠正CVID患者的基因失衡和吸收不良。Ustekinumab是针对白细胞介素12/23的p40亚单位的单抗。它被批准用于治疗牛皮癣，目前正在评估治疗难治性克罗恩病的第三阶段试验。我们建议使用Ustekinumab治疗CVID肠病患者，并评估其对临床和免疫学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的程度、肠道活检的组织学变化、血液、肠道活检和分离的肠道单核细胞中细胞因子的产生和全球基因表达来评估。肠道活检组织中肠道微生物组成的变化将使用鸟枪式测序数据的元基因组分析进行监测，并与临床和免疫学参数相关联，以确定可能驱动过度活跃的免疫反应的微生物。因此，这些研究将提供一个独特的机会，对CVID肠病的新疗法进行评估，同时进行研究，确定动态条件下CVID肠病的发病机制。