A Novel Model of, and Pre-clinical Therapy for, Scleroderma Lung Disease

硬皮病肺病的新模型和临床前治疗

基本信息

批准号：
8189086
负责人：
Sergei P. Atamas
金额：
$ 23.03万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189086
关键词：
Acute Address Adenoviruses Adrenal Cortex Hormones Animal Model Animals Antibodies Asthma Autoimmune Process Biology Blocking Antibodies Bronchoalveolar Lavage CD8B1 gene Cause of Death Cell Culture Techniques Cell surface Cells Cellular Infiltration Characteristics Chronic Clinical Trials Collagen Complication Data Deposition Development Disease Effectiveness Eosinophilia Exons Fibrosis Future Gene Delivery Gene Expression Goals Goblet Cells Human Hyperplasia Immune Immunosuppressive Agents Infiltration Inflammation Interleukin-4 Interleukins Interstitial Lung Diseases Life Lung Lung diseases Lymphocyte Mediating Mediator of activation protein Methods Modeling Molecular Molecular Target Monoclonal Antibodies Mus Outcome Outcomes Research Patients Pattern Play Pneumonia Production Pulmonary Eosinophilia Pulmonary Fibrosis RNA Interference RNA Splicing Reporting Research Resistance Respiratory physiology Role Scleroderma Sepsis Solid Subfamily lentivirinae System Systemic Scleroderma T-Lymphocyte Testing Therapeutic Time Tuberculosis Variant base chemokine clinically relevant cytokine design in vivo innovation neutralizing antibody novel pre-clinical pre-clinical therapy research clinical testing research study therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Interstitial lung disease - a combination of pulmonary inflammation and fibrosis - remains the main cause of death in patients with systemic sclerosis, or scleroderma. The mechanisms of scleroderma lung disease (SLD) are not well understood, and the efficiency of available therapies is limited. Previous studies by us and others have suggested that the levels of a splice variant of Interleukin(IL)-4, so-called IL-442, are elevated in association with poorer outcomes in patients with SLD. Our new Preliminary Data suggest that acute adenovirus-mediated gene delivery of mouse (m) IL-442 to mouse lung in vivo recapitulates important features of human SLD, causing infiltration of lymphocytes, disturbances in cytokine milieu, and a tendency to collagen accumulation. The changes caused by mIL-442 in the acute gene delivery model are different from those caused by mIL-4, including the effects on gene expression, pulmonary cytokine milieu, and cellular infiltration. For example, while causing the mentioned changes resembling of human SLD, mIL-442 does not induce pulmonary eosinophilia or goblet cell hyperplasia (the features that are common in asthma but not in SLD, and that are readily induced by wild-type mIL-4). Based on these observations, we hypothesize that IL-442 may play a key role in SLD, and that targeting of IL-442 in patients with SLD may prove therapeutic. Considering that SLD in humans is a chronic condition, there is a need to assess molecular, cellular, and histological changes caused by chronic IL-442 expression in the lungs. We propose, in Specific Aim 1, to establish and investigate a chronic model of mIL-442 expression utilizing lentivirus-mediated gene delivery. In contrast to the adenovirus-mediated system, which allows only for a short-term gene delivery, the lentiviral system allows for gene delivery lasting for months, up to a life-long expression. The experiments will determine whether chronic expression of mIL-442 in an animal model recapitulates key features of scleroderma lung disease, including lymphocytic inflammation (particularly CD8+ T cells), fibrosis, changes in pulmonary cytokine milieu and expression of cell surface molecules, and resistance to treatment with corticosteroids and other immunosuppressive agents. These experiments will also identify key secondary mediators induced by mIL-442, and determine whether IL-442 promotes inflammation and collagen deposition by directly acting on the lung, or indirectly, by inducing expression of cytokines and cell surface molecules. Specific Aim 2 will identify, through pre- clinical testing, effective means of targeting human (h) IL-442. Specifically, the experiments will assess the efficacy of hIL-442-blocking monoclonal antibodies, and blockade of human IL-442 production through RNA interference. These experiments will form basis for future clinical trials targeting IL-442 in humans. The anticipated outcomes of this research are 1) better understanding of the mechanistic role of IL-442, and 2) pre-clinical development or a novel therapy for SLD. The results are likely to be beneficial for not only patients with scleroderma, but also patients with asthma, sepsis, and tuberculosis, in all of which IL-442 has been suggested to play a significant role. PUBLIC HEALTH RELEVANCE: Scleroderma is a severely debilitating and deadly disease, current therapies for which have limited effectiveness. We and others discovered that a molecule called IL-4delta2 likely plays a key role in scleroderma, as well as in asthma, sepsis, and tuberculosis. In this study, we investigate the effects of IL- 4delta2 on the lung, and develop new methods of blocking this molecule, thus potentially creating new therapies for patients with these diseases.

描述（由申请人提供）：间质性肺病（肺部炎症和纤维化的结合）仍然是系统性硬化症或硬皮病患者死亡的主要原因。硬皮病肺病（SLD）的机制尚不清楚，可用疗法的效率也有限。我们和其他人之前的研究表明，白细胞介素 (IL)-4 的剪接变体（即所谓的 IL-442）的水平升高与 SLD 患者的较差预后相关。我们的新初步数据表明，小鼠 (m) IL-442 急性腺病毒介导的基因递送至小鼠肺体内，再现了人类 SLD 的重要特征，导致淋巴细胞浸润、细胞因子环境紊乱以及胶原蛋白积累的趋势。 mIL-442在急性基因递送模型中引起的变化与mIL-4引起的变化不同，包括对基因表达、肺细胞因子环境和细胞浸润的影响。例如，虽然引起与人类 SLD 类似的上述变化，但 mIL-442 不会诱导肺嗜酸性粒细胞增多或杯状细胞增生（这些特征在哮喘中常见，但在 SLD 中不存在，并且很容易由野生型 mIL-4 诱导））。基于这些观察结果，我们假设 IL-442 可能在 SLD 中发挥关键作用，并且针对 SLD 患者靶向 IL-442 可能具有治疗作用。考虑到人类 SLD 是一种慢性疾病，因此需要评估肺部慢性 IL-442 表达引起的分子、细胞和组织学变化。在具体目标 1 中，我们建议利用慢病毒介导的基因传递建立并研究 mIL-442 表达的慢性模型。与仅允许短期基因传递的腺病毒介导的系统相反，慢病毒系统允许持续数月的基因传递，直至终生表达。实验将确定动物模型中 mIL-442 的长期表达是否概括了硬皮病肺病的关键特征，包括淋巴细胞炎症（特别是 CD8+ T 细胞）、纤维化、肺细胞因子环境的变化和细胞表面分子的表达，以及对用皮质类固醇和其他免疫抑制剂治疗。这些实验还将鉴定 mIL-442 诱导的关键二级介质，并确定 IL-442 是否通过直接作用于肺部或通过诱导细胞因子和细胞表面分子的表达间接作用于肺部来促进炎症和胶原沉积。具体目标 2 将通过临床前测试确定靶向人 (h) IL-442 的有效方法。具体来说，这些实验将评估 hIL-442 阻断单克隆抗体的功效，以及通过 RNA 干扰阻断人 IL-442 产生。这些实验将为未来针对人类 IL-442 的临床试验奠定基础。这项研究的预期结果是 1) 更好地了解 IL-442 的机制作用，2) 临床前开发或 SLD 的新疗法。结果可能不仅对硬皮病患者有益，而且对哮喘、败血症和肺结核患者也有益，IL-442 被认为在所有这些患者中都发挥着重要作用。公共卫生相关性：硬皮病是一种严重使人衰弱和致命的疾病，目前的治疗方法效果有限。我们和其他人发现，一种名为 IL-4delta2 的分子可能在硬皮病以及哮喘、败血症和结核病中发挥关键作用。在这项研究中，我们研究了 IL-4delta2 对肺部的影响，并开发了阻断该分子的新方法，从而有可能为患有这些疾病的患者创造新的疗法。