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: 8301522
• 负责人: Sergei P. Atamas
• 金额: $ 19.19万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301522
• 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.

描述（由申请人提供）：间质性肺病-肺部炎症和纤维化的组合-仍然是系统性硬化症或硬皮病患者死亡的主要原因。硬皮病肺疾病（SLD）的机制还没有得到很好的理解，有效的治疗是有限的。我们和其他人以前的研究表明，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患者的预后较差相关。我们的新的初步数据表明，急性腺病毒介导的小鼠（m）IL-442的基因传递到小鼠肺在体内概括了人类SLD的重要特征，导致淋巴细胞浸润，细胞因子环境的干扰，和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mIL-442引起类似于人SLD的上述变化，但它不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中不常见，并且容易由野生型mIL-4诱导）。基于这些观察，我们假设IL-442可能在SLD中起关键作用，并且IL-442在SLD患者中的靶向作用可能被证明是治疗性的。考虑到人类的SLD是一种慢性疾病，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。我们建议，在具体目标1，建立和调查的mIL-442表达的慢性模型，利用慢病毒介导的基因传递。与仅允许短期基因递送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递送，直至终身表达。实验将确定mIL-442在动物模型中的慢性表达是否重现硬皮病肺病的关键特征，包括淋巴细胞性炎症（特别是CD 8 + T细胞）、纤维化、肺细胞因子环境和细胞表面分子表达的变化以及对皮质类固醇和其他免疫抑制剂治疗的抗性。这些实验还将鉴定由mIL-442诱导的关键次级介质，并确定IL-442是否通过直接作用于肺或通过诱导细胞因子和细胞表面分子的表达间接促进炎症和胶原沉积。具体目标2将通过临床前试验确定靶向人（h）IL-442的有效方法。具体而言，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。这些实验将为未来靶向IL-442的人体临床试验奠定基础。这项研究的预期结果是：1）更好地理解IL-442的机制作用，2）临床前开发或SLD的新疗法。该结果不仅对硬皮病患者有益，对哮喘、败血症和结核病患者也有益，在所有这些患者中，IL-442都被认为发挥着重要作用。

项目成果

CCR6 is not necessary for functional effects of human CCL18 in a mouse model.

• DOI: 10.1186/1755-1536-5-2
• 发表时间: 2012-01-18
• 期刊: Fibrogenesis & tissue repair
• 作者: Luzina IG;Atamas SP
• 通讯作者: Atamas SP

Degeneracy allows for both apparent homogeneity and diversification in populations.

退化允许人口的明显同质性和多样化。

• DOI: 10.1016/j.biosystems.2012.08.003
• 发表时间: 2012-10
• 期刊: BIOSYSTEMS
• 影响因子: 1.6
• 作者: Whitacre, James M.;Atamas, Sergei P.
• 通讯作者: Atamas, Sergei P.

Natural production and functional effects of alternatively spliced interleukin-4 protein in asthma.

• DOI: 10.1016/j.cyto.2011.12.017
• 发表时间: 2012-04
• 期刊: CYTOKINE
• 影响因子: 3.8
• 作者: Luzina, Irina G.;Lockatell, Virginia;Lavania, Sachin;Pickering, Edward M.;Kang, Phillip H.;Bashkatova, Yulia N.;Andreev, Sergey M.;Atamas, Sergei P.
• 通讯作者: Atamas, Sergei P.