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

• 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
• 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

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）：间质性肺疾病 - 肺部炎症和纤维化的结合 - 是全身性硬化症患者或硬皮病患者死亡的主要原因。硬皮病肺疾病（SLD）的机制尚不清楚，可用疗法的效率受到限制。我们和其他人的先前研究表明，与SLD患者的剪接变体（IL）-4，所谓的IL-442的剪接变异水平相关。我们的新初步数据表明，急性腺病毒介导的小鼠（M）IL-442向小鼠肺在体内递送的基因递送概括了人类SLD的重要特征，从而导致淋巴细胞的浸润，细胞因子环境中的干扰以及趋于胶原蛋白的趋势。急性基因输送模型中MIL-442引起的变化与MIL-4引起的变化不同，包括对基因表达的影响，肺细胞因子环境和细胞浸润。例如，虽然引起类似人类SLD的变化，但MIL-442不会诱导肺嗜酸性粒细胞或杯状细胞增生（在哮喘中常见，但在SLD中不常见，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中起关键作用，并且SLD患者的IL-442靶向可能证明是治疗性的。考虑到人类中的SLD是一种慢性疾病，因此需要评估肺中慢性IL-442表达引起的分子，细胞和组织学变化。在特定的目标1中，我们建议建立和研究使用慢病毒介导的基因递送的MIL-442表达的慢性模型。与仅允许短期基因递送的腺病毒介导的系统相比，慢病毒系统允许持续数月的基因递送，直至终身表达。 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.这些实验还将确定由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间接作用，通过诱导细胞因子和细胞表面分子的表达来促进炎症和胶原蛋白沉积。特定的目标2将通过临床测试来鉴定靶向人类IL-442的有效手段。具体而言，这些实验将评估HIL-442阻断单克隆抗体的功效，并通过RNA干扰对人IL-442产生的阻断。这些实验将构成针对人类IL-442的未来临床试验的基础。这项研究的预期结果是1）更好地理解IL-442的机械作用，以及2）临床前发育或SLD的新疗法。结果不仅对硬皮病患者，而且对患有哮喘，败血症和结核病患者的患者也可能有益，在所有这些患者中，所有这些患者均建议在所有这些患者中发挥重要作用。 公共卫生相关性：硬皮病是一种严重的衰弱和致命的疾病，目前的疗法的有效性有限。我们和其他人发现，称为IL-4DELTA2的分子可能在硬皮病以及哮喘，败血症和结核病中起关键作用。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，从而有可能为这些疾病患者产生新的疗法。