Transgenic Animal Models Of Human Immune Defects

人类免疫缺陷的转基因动物模型

• 批准号: 8156872
• 负责人: Steven Holland
• 金额: $ 201.65万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8156872
• 关键词: Animal Model; Defect; Human; Immune; Transgenic Animals

We seek to understand the role of enzyme systems in normal host function and immune defense, specifically the NADPH oxidase. The NADPH oxidase is involved in the generation and control of inflammation, protection from infection, and cell-cell signaling. Understanding these will inform us about how to manipulate the immune system pharmacologically, immunologically, and genetically. We have a complex portfolio involving patients, animals, and laboratory specimens. We follow a large number of patients with chronic granulomatous disease (CGD), and we have been involved in characterizing their infections and the complications they develop. We have also used a mouse created in my laboratory that is deficient in the NADPH oxidase and therefore closely mimics human CGD. Numerous studies in these mice have shown a critical role for the NADPH oxidase in not only protection from infection but also in the magnitude and character of the inflammatory response. This mixed approach to understanding the NADPH oxidase in CGD has been very informative about the role of the innate immune system in both early and late aspects of the inflammatory response. Through the study of patients with CGD we have identified a new bacteria that causes infection in CGD, Granulibacter bethesdensis. This organism has been injected into animal models of CGD and shown to be a significant pathogen in CGD. We have now identified a total of 6 cases of G. bethesdensis in CGD patients, indicating that this is an important infection in CGD. The frequency of this infection in normals as determined by serology is high. This conjoined bench and bedside approach to CGD will allow us to identify important aspects of both host and bacterial physiology that will help us treat patients with CGD better, and to understand and treat CGD inflammation. Working with collaborators in the mouse model we have determined that CGD pathogens interact with CGD cells differently than do non-pathogens, giving us a set of pathways to explore to understand CGD virulence. We have identified several novel infections in CGD including Acidomonas and Methylobacter, which, in copncert with Granulibacter, suggest a role for methylotrophic organisms in CGD. Identification of the genetic and cellular basis of hyper-IgE recurrent infection syndrome (HIES or Job's syndrome), an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino-pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities, as STAT3 has activated broad areas of investigation. From clinical grounds we knew that the gene involved in Job's must be critically important to innate immunity, the early and late host immune responses, skeletal growth and development, and tooth deciduation. We have recreated STAT3 mutations in vitro to study their permutations and possible genotype-phenotype correlations. With NIAID and NIAMS collaborators we have identified abnormalities in other cytokines downstream of STAT3, most notably IL-17, which is profoundly low in cells from Job's syndrome patients. Collaborating with investigators in NIAMS we have created a mouse model of STAT3 deficiency. Collaborating with investigators in NHLBI we have studied vascular endothelial cells from patients with STAT3 deficeincy in vitro. These combined approaches continue to be productive and will lead to better understanding of the pathways of innate immunity and inflammation. We believe that these studies will help us understand several different infections, including fungal infections, at a molecular genetic and functional level.

我们试图了解酶系统在正常宿主功能和免疫防御中，特别是NADPH氧化酶的作用。 NADPH氧化酶参与炎症的产生和控制，免受感染的保护和细胞信号传导。了解这些将为我们提供有关如何在药理，免疫学和遗传上操纵免疫系统的信息。我们有一个复杂的投资组合，涉及患者，动物和实验室标本。我们遵循大量患有慢性肉芽肿性疾病（CGD）的患者，我们参与了他们的感染及其发展并发症的特征。我们还使用了在我的实验室中创建的小鼠，该小鼠缺乏NADPH氧化酶，因此密切模仿了人CGD。这些小鼠的大量研究表明，NADPH氧化酶在免受感染的保护方面具有关键作用，而且在炎症反应的大小和特征中也具有关键作用。理解CGD中NADPH氧化酶的这种混合方法对先天免疫系统在炎症反应的早期和晚期方面的作用非常有用。 通过对CGD患者的研究，我们确定了一种新的细菌，该细菌在CGD，肉芽肿杆菌伯特斯氏菌中引起感染。该生物已注入CGD动物模型中，并显示为CGD中的重要病原体。现在，我们已经确定了CGD患者中总共有6例G.贝丝斯丁斯病例，表明这是CGD中的重要感染。通过血清学确定的正常性感染的频率很高。这种CGD的台式和床边方法将使我们能够确定宿主和细菌生理学的重要方面，这些方面将帮助我们更好地治疗CGD患者，并了解和治疗CGD炎症。 与小鼠模型中的合作者合作，我们已经确定CGD病原体与CGD细胞的相互作用与非pathogens的相互作用不同，这为我们提供了一系列探索途径以了解CGD毒力。我们已经确定了CGD中的几种新型感染，包括酸-蛋白酶和甲基杆菌，这些感染在用粒细胞的Copncert中提出了CGD中甲基营养生物的作用。 鉴定高神经复发感染综合征（HIES或Job综合征）的遗传和细胞基础，这是一种常染色体显性疾病，其特征是IgE极高，复发性中 - 肺部感染，骨质造影，骨质造影症，骨sosposis，kyphsoscoliosis，knephoscoliosis，knephosisosis，keyphsosis，肺部囊肿和牙科囊肿，如统计3.从临床角度来看，我们知道，参与约伯的基因对于先天免疫，早期和晚期的宿主免疫反应，骨骼生长和发育以及牙齿固定至关重要。我们在体外重新创建了STAT3突变，以研究其排列和可能的基因型 - 表型相关性。通过NIAID和NIAMS合作者，我们已经确定了STAT3下游的其他细胞因子的异常，最著名的是IL-17，这对Job综合征患者的细胞非常低。与NIAMS的调查人员合作，我们创建了STAT3缺陷的鼠标模型。与NHLBI的研究人员合作，我们研究了来自Stat3 Deficeincy体外患者的血管内皮细胞。 这些联合方法继续发挥作用，并将更好地理解先天免疫和炎症的途径。我们认为，这些研究将有助于我们了解分子遗传和功能水平的几种不同的感染，包括真菌感染。