Novel Reagents in Mouse Models of Autoimmune COPD

自身免疫性慢性阻塞性肺病小鼠模型中的新型试剂

• 批准号: 8313878
• 负责人: Michael Borchers
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313878
• 关键词: Animal Model; Antigens; Autoantibodies; Autoimmune Process; B-Lymphocytes; CD4 Positive T Lymphocytes; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clonal Expansion; Complex; Data; Development; Disease; Disease Progression; Epithelial Cells; Exposure to; Functional disorder; Goals; Hybridomas; Immunoglobulin G; Immunoprecipitation; Investigation; Lead; Link; Literature; Long-Term Effects; Lung; Mass Spectrum Analysis; Morbidity - disease rate; Mus; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Population; Public Health; Pulmonary Emphysema; Quality of life; Reagent; Research; Risk Factors; Role; Self Concept; Serum; Smoking; T-Cell Receptor; T-Lymphocyte; Tissues; Two-Dimensional Gel Electrophoresis; acquired immunity; adaptive immunity; air filter; autoreactive T cell; autoreactivity; cigarette smoke-induced; cigarette smoking; frontier; global health; immune function; innate immune function; innovation; mortality; mouse model; novel; response; smoking cessation; therapeutic development

DESCRIPTION (provided by applicant): Long-term exposure to cigarette smoke (CS) is the major risk factor in the development of chronic obstructive pulmonary disease (COPD). COPD, which includes chronic bronchitis and emphysema, is a major global health burden and morbidity and mortality are expected to expand in the next decades. Recent studies demonstrate oligoclonal expansions of T and B cells in emphysema patients, persistent oligoclonal CD4 T cell expansions following smoking cessation in a mouse model of COPD, and the presence of autoantibodies against lung components in COPD. Presently, it is unknown whether autoreactivity against pulmonary tissue contributes to disease pathogenesis. Given the limitations of associative clinical findings, the development of novel animal models to investigate autoimmune components in COPD is necessary to investigate the mechanisms whereby CS exposure leads to the development of autoreactivity. Our goal is to identify potential lung antigens and isolate autoreactive T cell clones in a mouse model of COPD. The CENTRAL HYPOTHESIS is that long-term exposure to CS induces aberrant expansions of T cells that are reactive against lung components which contribute to tissue destruction and pulmonary remodeling. This hypothesis is supported by preliminary evidence demonstrating i) excessive accumulation of IgG in the lungs of CS-exposed mice, ii) serum from CS- exposed mice recognizes unique antigens in naive lung, and iii) transfer of IgG from CS-exposed mice, leads to an emphysema-like pathology. We will achieve the objective of this proposal by pursuing two aims: 1) Identify relevant antigens that specifically react with IgG from CS-exposed mice. Using serum from CS-exposed mice, we will perform immunoprecipitation against lung antigens followed by 2D gel electrophoresis and mass spectroscopy analyses, and 2) Isolate autoreactive T cell clones that develop in response a mouse model of COPD. We will also generate T cell hybridomas and screen for reactivity against putative antigens. The concept of self-reactive T cells developing in response to CS exposure is supported by extensive preliminary data from our lab and a growing body of literature. Isolating these reagents will allow us to examine the expanded T cell populations in the lung and define their role in the development of pulmonary changes pathognomonic of COPD. Successful completion of this project will lead to novel reagents (novel T cell clones, autoreactive T cell receptor sequences, and putative antigens) which are critically needed to investigate the complex pathophysiology of COPD. A more complete understanding of autoreactive T cell effector function in COPD will open new frontiers into specific approaches towards therapeutic development in this devastating disease.

描述（由申请人提供）：长期暴露于香烟烟雾（CS）是慢性阻塞性肺疾病（COPD）发展的主要危险因素。慢性阻塞性肺病，包括慢性支气管炎和肺气肿，是一个主要的全球健康负担，发病率和死亡率预计将在未来几十年扩大。最近的研究表明，肺气肿患者的T细胞和B细胞的低克隆扩增，COPD小鼠模型戒烟后持续的低克隆CD4 T细胞扩增，以及COPD中针对肺成分的自身抗体的存在。目前尚不清楚针对肺组织的自身反应性是否有助于疾病的发病机制。鉴于相关临床发现的局限性，有必要开发新的动物模型来研究慢性阻塞性肺病的自身免疫成分，以研究CS暴露导致自身反应性发展的机制。我们的目标是在COPD小鼠模型中鉴定潜在的肺抗原并分离自身反应性T细胞克隆。中心假设是，长期暴露于CS会导致T细胞异常扩增，这些T细胞对肺部成分产生反应，从而导致组织破坏和肺部重塑。这一假设得到了以下初步证据的支持：1)暴露于CS的小鼠肺中IgG的过度积累，2)暴露于CS的小鼠血清可识别幼稚肺中的独特抗原，3)暴露于CS的小鼠体内IgG的转移可导致肺气肿样病理。我们将通过追求两个目标来实现本提案的目标：1)从cs暴露小鼠中鉴定出与IgG特异性反应的相关抗原。使用cs暴露小鼠的血清，我们将对肺抗原进行免疫沉淀，然后进行2D凝胶电泳和质谱分析。2)分离对COPD小鼠模型产生反应的自身反应性T细胞克隆。我们还将生成T细胞杂交瘤，并筛选对假定抗原的反应性。我们实验室的大量初步数据和越来越多的文献支持了自反应性T细胞在CS暴露后发育的概念。分离这些试剂将使我们能够检查肺中扩增的T细胞群，并确定它们在慢性阻塞性肺疾病的肺部病变发展中的作用。该项目的成功完成将导致新型试剂（新型T细胞克隆、自身反应性T细胞受体序列和推定抗原）的产生，这对于研究COPD的复杂病理生理至关重要。更全面地了解自身反应性T细胞效应在慢性阻塞性肺病中的作用，将为这种毁灭性疾病的治疗开发开辟新的领域。