TNF Family Members and Control of Fibrotic Disease

TNF 家族成员与纤维化疾病的控制

• 批准号: 8342674
• 负责人: Michael Croft
• 金额: $ 26.1万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-02 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8342674
• 关键词: Affect; Age; Age of Onset; Animal Model; Antibiotics; Area; Asthma; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autopsy; Binding; Bleomycin; Blood Vessels; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cells; Cessation of life; Characteristics; Child; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; Collagen; Cutaneous; Data; Dendritic Cells; Deposition; Dermal; Development; Diagnosis; Diffuse; Disease; Environmental Risk Factor; Epithelial Cells; Ethnic group; Event; Exhibits; Extracellular Protein; Face; Family member; Fibroblasts; Fibrosis; Genetic; Genetic Predisposition to Disease; Hand; Heart; Herpesviridae; Histocompatibility; Human; Hyperplasia; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-13; Interleukin-4; Interleukin-5; Journals; Kidney; Knowledge; Lead; Light; Longevity; Lung; Lymphoid Cell; Mediating; Mediator of activation protein; Medicine; Minor; Minor Histocompatibility Loci; Modeling; Mouse Strains; Mus; Nature; Organ; Pathology; Patients; Phase; Phenotype; Play; Process; Production; Proteins; Publishing; Pulmonary Fibrosis; Reporting; Role; Scleroderma; Sclerosis; Signal Transduction; Skin; Smooth Muscle; Staging; Structure of parenchyma of lung; Subcutaneous Injections; Symptoms; Syndrome; Systemic Scleroderma; T memory cell; T-Lymphocyte; TNF gene; Testing; Th2 Cells; Therapeutic; Tissues; Transplantation; Tumor Necrosis Factor Receptor; age group; arm; cell type; cytokine; eosinophil; graft vs host disease; herpesvirus entry mediator; interstitial; lymphotoxin beta receptor; macrophage; mouse model; novel; outcome forecast; prevent; receptor; selective expression; skin disorder; tsk mouse

DESCRIPTION (provided by applicant): Human systemic sclerosis (SSc) is an autoimmune-like disease that results in excessive production of collagen in the skin as well as tissues such as kidney, heart, and lung. If this fibrosis is extensive it can prevent normal organ function. Fibrosis is a feature that is shared with other syndromes such as severe asthma and COPD, and therefore preventing the onset of fibrosis or blocking continued fibrosis is of great significance to a number of damaging diseases. Collagen deposition is thought mediated by deregulation of epithelial cells, macrophages, and fibroblasts, and inflammatory cells such as Th2 cells and eosinophils may play roles in promoting the activity of these cell types. Although cytokines such as TGF-¿, IL-13, IL-4, and TNF are acknowledged to contribute to end-stage pathology, new and novel targets for therapy are warranted that may broadly suppress the activity of many of the inflammatory cell types that contribute to fibrotic disease. We recently reported in several models of severe asthma that LIGHT, a TNF superfamily protein, that can be expressed on a number of cell types including activated T cells, dendritic cells, and inflamed epithelial cells, was responsible for mediating collagen production, smooth muscle hyperplasia, and overall fibrotic symptoms. This activity was mediated through binding to two TNFR superfamily receptors, the herpes virus entry mediator (HVEM) and the lymphotoxin beta receptor (LT¿R). We will test the novel hypothesis that LIGHT also controls fibrosis in multiple inflammatory situations and will be responsible for collagen deposition, skin thickening, and interstitial fibrosis of internal organs. We have evidence that HVEM and LT¿R are expressed or induced on all of the cell types thought to mediate fibrotic activity, namely epithelial cells, macrophages, and fibroblasts. We also have found that patients with pulmonary fibrosis due to systemic sclerosis have T cells in the lungs that express LIGHT, which correlates with clinical reports of enhanced levels of soluble LIGHT in bronchoalveolar lavages from similar patients. This proposal will focus on three mouse models of systemic sclerosis that result in fibrosis in various organs and recapitulate many of the features exhibited by human patients. Using the tight- skin mouse that spontaneously develops skin fibrosis; a minor histocompatibility model of GVHD that also results in skin fibrosis as well as fibrosis of internal organs; and bleomycin injection that induces pulmonary fibrosis, we will test whether mice or cells lacking LIGHT, HVEM, or LT¿R cannot succumb to sclerosis-like fibrotic disease. We will additionally test if therapeutic blockade of LIGHT interactions ameliorates inflammation and pathology associated with scleroderma and systemic sclerosis. PUBLIC HEALTH RELEVANCE: Systemic sclerosis is a type of autoimmune disease present throughout the world and represented in all ethnic groups. It can either be localized and affect the hands, arms, and face, or can be systemic affecting both a large area of skin as well as internal organs such as the lungs, kidneys, and heart. The cause is unknown and treatment options involve non-specific immune suppression. This proposal will test the novel hypothesis that the extracellular protein LIGHT, and its receptors HVEM and LT¿R, control fibrosis associated with sclerosis- like inflammatory diseases. By determining whether LIGHT and its receptors promote fibrosis in animal models, we will gain knowledge that might lead to ways to therapeutically target human fibrotic disease.

描述(申请人提供)：人类系统性硬化症(SSC)是一种自身免疫性疾病，导致皮肤以及肾脏、心脏和肺等组织中胶原蛋白的过度产生。如果这种纤维化是广泛的，它可以阻止正常的器官功能。纤维化是严重哮喘和慢性阻塞性肺疾病等其他证候的共同特征，因此预防纤维化的发生或阻止纤维化的持续对许多破坏性疾病具有重要意义。胶原沉积被认为是通过解除对上皮细胞、巨噬细胞和成纤维细胞的调节而实现的，而Th2细胞和嗜酸性粒细胞等炎性细胞可能在促进这些细胞类型的活性方面发挥作用。尽管细胞因子如转化生长因子β、白介素13、白介素4和肿瘤坏死因子被认为在终末期病理中起作用，但新的和新的治疗靶点是有必要的，可以广泛地抑制导致纤维化疾病的许多炎性细胞类型的活性。我们最近在几个重症哮喘模型中报道，LIGH是一种可以在多种细胞类型上表达的肿瘤坏死因子超家族蛋白，包括活化的T细胞、树突状细胞和炎症的上皮细胞，它负责介导胶原的产生、平滑肌增生和整体纤维化症状。这种活性是通过与两个TNFR超家族受体结合而实现的，即疱疹病毒进入介体(HVEM)和淋巴毒素β受体(LT？R)。我们将测试这一新的假设，即光还可以控制多种炎症情况下的纤维化，并将负责胶原沉积、皮肤增厚和内脏器官的间质纤维化。我们有证据表明，在所有被认为介导纤维化活动的细胞类型上，即上皮细胞、巨噬细胞和成纤维细胞上都表达或诱导了HVEM和LT？R。我们还发现，系统性硬化症引起的肺纤维化患者肺中有表达光的T细胞，这与临床报道类似患者的支气管肺泡灌洗液中可溶性光水平升高有关。这项建议将重点放在导致不同器官纤维化的三种系统性硬化症小鼠模型上，并概括人类患者表现出的许多特征。使用自发性皮肤纤维化的紧密皮肤小鼠；也会导致皮肤纤维化和内脏纤维化的GVHD轻微组织相容性模型；以及注射博莱霉素导致肺纤维化，我们将测试缺乏光、HVEM或LT？R的小鼠或细胞是否不会死于硬化性纤维性疾病。我们还将测试光相互作用的治疗阻断是否可以改善与硬皮病和系统性硬化症相关的炎症和病理。 公共卫生相关性：系统性硬化症是一种自身免疫性疾病，存在于世界各地，并存在于所有种族群体中。它既可以是局部性的，影响到手、手臂和面部，也可以是全身性的，既影响到大片皮肤，也影响到肺、肾和心脏等内脏。病因尚不清楚，治疗方案涉及非特异性免疫抑制。这项提议将检验新的假设，即细胞外蛋白LIGH及其受体HVEM和LT？R控制与硬化性炎症性疾病相关的纤维化。通过确定光及其受体是否促进动物模型的纤维化，我们将获得可能导致针对人类纤维化疾病的治疗方法的知识。