TNF Family Members and Control of Fibrotic Disease

描述（由申请人提供）：人类系统性硬化症（SSc）是一种自身免疫样疾病，导致皮肤以及肾、心、肺等组织中胶原蛋白的过量产生。如果这种纤维化是广泛的，它可以阻止正常的器官功能。纤维化是与其他综合征（如严重哮喘和COPD）共有的特征，因此预防纤维化的发生或阻断持续纤维化对许多破坏性疾病具有重要意义。胶原沉积被认为是由上皮细胞、巨噬细胞和成纤维细胞的失调介导的，炎症细胞如Th2细胞和嗜酸性粒细胞可能在促进这些细胞类型的活性中发挥作用。虽然TGF-、IL-13、IL-4和TNF等细胞因子被认为与终末期病理有关，但新的治疗靶点可能会广泛抑制许多导致纤维化疾病的炎症细胞类型的活性。我们最近在几种严重哮喘模型中报道，LIGHT是一种TNF超家族蛋白，可在多种细胞类型（包括活化的T细胞、树突状细胞和炎症上皮细胞）上表达，负责介导胶原生成、平滑肌增生和整体纤维化症状。这种活性是通过结合两个TNFR超家族受体，疱疹病毒进入介质（HVEM）和淋巴毒素受体（LT¿R）介导的。我们将验证新的假设，即LIGHT也控制多种炎症情况下的纤维化，并将负责胶原沉积，皮肤增厚和内脏间质纤维化。我们有证据表明，HVEM和LT¿R在所有被认为介导纤维化活性的细胞类型上表达或诱导，即上皮细胞、巨噬细胞和成纤维细胞。我们还发现，系统性硬化症导致的肺纤维化患者的肺中有表达LIGHT的T细胞，这与类似患者支气管肺泡洗液中可溶性LIGHT水平升高的临床报告相关。该提案将重点研究导致各种器官纤维化的三种系统性硬化症小鼠模型，并概括人类患者所表现出的许多特征。使用自发发生皮肤纤维化的紧致皮肤小鼠；GVHD的次要组织相容性模型，也会导致皮肤纤维化和内脏纤维化；我们将测试缺乏LIGHT、HVEM或LT¿R的小鼠或细胞是否不会屈服于硬化样纤维化疾病。我们还将测试治疗性阻断LIGHT相互作用是否能改善硬皮病和系统性硬化症相关的炎症和病理。

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.