Bronchus-Associated Lymphoid Tissue & Lung Infection in Down Syndrome

支气管相关淋巴组织

• 批准号: 9894473
• 负责人: MICHAEL E. YEAGER
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894473
• 关键词: Acute; Address; Adult; Agonist; Animal Model; Antibodies; Autoimmune Responses; B-Lymphocytes; Bacterial Pneumonia; Biogenesis; Bronchus-Associated Lymphoid Tissue; Cell physiology; Cells; Cessation of life; Child; Chromosome abnormality; Chromosomes, Human, Pair 21; Clinical Trials; Congenital Abnormality; Cytometry; Data; Depressed mood; Development; Disease; Down Syndrome; Eye; Functional disorder; Genes; Health; Hospitalization; Human; Human Chromosomes; Hypersensitivity; Immune; Immune Cell Activation; Immune response; Immune system; Immunization; Immunosuppression; Impairment; Incidence; Individual; Infection; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Intellectual functioning disability; Interferon Receptor; Interferon Type I; Interferons; Investigation; Learning; Leukocytes; Life; Link; Live Birth; Lung; Lung diseases; Lung infections; Medical; Memory B-Lymphocyte; Movement; Mus; Nasopharynx; Patients; Persons; Phagocytes; Phenocopy; Play; Pneumonia; Population; Predisposition; Respiratory Tract Infections; Role; Severities; Siblings; Signal Transduction; Stimulus; Streptococcus pneumoniae; Testing; Trisomy; United States National Institutes of Health; Vaccination; Vaccines; Virus Diseases; base; clinically significant; comparative; cytokine; improved; lung injury; mortality; mouse model; novel; novel therapeutics; pandemic disease; peripheral blood; response; therapeutic candidate; therapeutic target

PROJECT SUMMARY With an incidence of one in 700-1000 live births worldwide, Down Syndrome (DS), or trisomy of human chromosome 21 (Hsa21), is the most common chromosomal abnormality. While DS is most often recognized for intellectual disability, congenital malformations, and dysmorphic features, it is also associated with seriously increased rates and severity of respiratory tract infection (RTI). Indeed, infectious respiratory disease in those with DS accounts for 54% of hospital admissions and more deaths than any other medical condition. Children with DS have a 62-fold higher rate of pneumonia than children without DS. During the influenza A (H1N1) pandemic in 2009, 23% of hospitalized patients with DS died vs. only 0.1% of those without DS. Collectively, these data point to an urgent need to understand how the condition of trisomy 21 contributes to RTI and to identify potential therapeutic targets. Currently, RTI in DS is commonly attributed to congenital abnormalities of the nasopharynx and upper and lower airways. However, our preliminary data support the novel hypothesis that lung immune cell dysfunction is a primary driver of increased incidence and severity of RTI in DS. Our data show that the trisomic Dp16 mouse lung is in a state of interferonpathy and is deficient in bronchus-associated lymphoid tissue (BALT). BALTs are key controllers of a variety of immune and inflammatory responses to numerous stimuli, including RTI. These changes in the Dp16 mouse lung closely mimic the dysregulated cytokine response in the human lung that has long been observed following influenza infection, and is a state linked to increased susceptibility to lethal bacterial pneumonia. Importantly, Dp16 mice are trisomic for the Hsa21-encoded interferon receptors and interferon-responsive genes. Based on these data, we propose to test our hypothesis that the constitutive activation state of interferon signaling in the DS lung reduces BALT biogenesis thus imparting immune suppression and predisposition to respiratory infection with S. pneumoniae. This state phenocopies the increased susceptibility to and severity of S. pneumoniae respiratory infection that is observed in typical individuals after a course of viral infection. The high mortality of RTI combined with poor response to vaccination is an urgent medical need in DS. Our novel paradigm conceptualizes DS as an interferonopathic state of heightened susceptibility to RTI due to depressed BALT function that mimics the state of acute viral infection in the typical population. In direct response to the NIH INCLUDE RFA, our proposal is a proof of concept study in an animal model of DS with high potential payoff that aims to enable efficient and effective movement of candidate therapeutics towards clinical trials for Down syndrome and RTI.

项目摘要 唐氏综合征（Down Syndrome，DS）或人类染色体三体综合征（Trisomy of human births）的发病率在全世界范围内为700-1000例活产婴儿中的1例。 21号染色体（Hsa 21）是最常见的染色体异常。虽然DS最常被认为是 对于智力残疾、先天畸形和畸形特征，它也与严重的 呼吸道感染（RTI）的发生率和严重程度增加。事实上，在那些 DS占住院人数的54%，死亡人数超过任何其他医疗条件。儿童 患有DS的儿童比没有DS的儿童患肺炎的几率高62倍。在甲型H1N1流感期间 在2009年的大流行中，23%的DS住院患者死亡，而没有DS的患者仅为0.1%。总的来说， 这些数据表明，迫切需要了解21三体是如何导致RTI的， 确定潜在的治疗靶点。目前，DS中的RTI通常归因于先天性异常， 鼻咽和上下呼吸道。然而，我们的初步数据支持新的假设， 肺免疫细胞功能障碍是DS患者RTI发病率和严重程度增加的主要驱动因素。我们的数据 显示三体Dp 16小鼠肺处于干扰素病状态，并且缺乏支气管相关的 淋巴组织（BALT）。BALT是多种免疫和炎症反应的关键控制者， 许多刺激，包括RTI。Dp 16小鼠肺中的这些变化密切地模拟了Dp 16小鼠肺中的调节异常。 长期以来，在流感感染后观察到人肺中的细胞因子应答， 与致命性细菌性肺炎易感性增加有关。重要的是，Dp 16小鼠是三体的， hsa 21编码的干扰素受体和干扰素应答基因。基于这些数据，我们建议测试 我们假设DS肺中干扰素信号传导的组成性激活状态降低BALT 生物发生，从而赋予免疫抑制和易感性的呼吸道感染与S。肺炎。 这种状态表现为对S.肺炎呼吸道感染， 在病毒感染过程后的典型个体中观察到。RTI的高死亡率与贫困 接种疫苗是DS的紧急医疗需求。我们的新范式将DS概念化为 由于BALT功能抑制而导致的干扰素病状态对RTI的易感性增加， 典型人群中的急性病毒感染状态。作为对NIH INCLUDE RFA的直接回应，我们的 该提案是一项在DS动物模型中进行的概念验证研究，具有高潜在回报，旨在使 有效和高效地将候选疗法推向唐氏综合征和RTI的临床试验。