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 全球700-1000个活产的发生率是唐氏综合症（DS）或人类三体性的发生率 染色体21（HSA21）是最常见的染色体异常。虽然DS最常被认可 对于智力残疾，先天性畸形和畸形特征，它也与 呼吸道感染（RTI）的速率和严重程度增加。确实，那些感染性呼吸道疾病 DS占医院入院的54％，死亡人数比任何其他医疗状况都要多。孩子们 与没有DS的儿童相比，DS的肺炎发生率高62倍。在流感A（H1N1）期间 2009年的大流行病患者中有23％的医院DS患者死亡，而没有DS的患者中只有0.1％。共同 这些数据指出迫切需要了解21三体性的状况如何促进RTI和 确定潜在的治疗靶标。目前，DS中的RTI通常归因于先天性异常 鼻咽以及上和下气道。但是，我们的初步数据支持新的假设 该肺免疫细胞功能障碍是DS中RTI发病率和严重程度增加的主要驱动力。我们的数据 表明三圆形DP16小鼠肺处于干扰素的状态，与支气管相关的状态不足 淋巴组织（BALT）。 Balts是各种免疫和炎症反应的关键控制器 许多刺激，包括RTI。 DP16小鼠肺中的这些变化紧密模仿失调的 在人类肺中长期观察到流感感染后长期观察到的细胞因子反应，是一种状态 与增加致命细菌性肺炎的敏感性有关。重要的是，DP16小鼠是三化小鼠 HSA21编码的干扰素受体和干扰素反应基因。基于这些数据，我们建议测试 我们的假设是DS肺中干扰素信号传导的组成型激活状态减少了BALT 因此，生物发生会赋予免疫抑制和易感性肺炎链球菌感染。 这种状态的表副词增加了对肺炎链球菌呼吸道感染的敏感性和严重程度的敏感性和严重性 在病毒感染过程后，在典型个体中观察到。 RTI的高死亡率与差 对疫苗接种的反应是DS的紧急医疗需求。我们的小说范式将DS概念化为 由于模仿的脂肪抑制功能，对RTI的敏感性提高了侵袭性状态 典型人群中急性病毒感染状态。直接回应NIH包括RFA，我们 提案是具有高潜力回报的DS动物模型中概念研究的证明，旨在实现 候选治疗疗法向唐氏综合症和RTI进行临床试验的有效运动。