TNF Family Members and Control of Fibrotic Disease

描述（由申请人提供）：人系统性硬化症（SSc）是一种自身免疫样疾病，导致皮肤以及肾、心脏和肺等组织中胶原蛋白过度产生。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作或阻断持续的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，并且炎性细胞如Th 2细胞和嗜酸性粒细胞可能在促进这些细胞类型的活性中起作用。虽然细胞因子如TGF-β、IL-13、IL-4和TNF被认为有助于终末期病理学，但新的和新颖的治疗靶点是有必要的，其可以广泛地抑制有助于纤维化疾病的许多炎性细胞类型的活性。我们最近在几种严重哮喘模型中报道了LIGHT，一种TNF超家族蛋白，可以在许多细胞类型上表达，包括活化的T细胞，树突状细胞和发炎的上皮细胞，负责介导胶原蛋白的产生，平滑肌增生和整体纤维化症状。这种活性是通过与两种TNFR超家族受体结合来介导的，即疱疹病毒进入介体（HVEM）和α-光毒素β受体（LT？R）。我们将测试新的假设，即LIGHT还控制多种炎症情况下的纤维化，并将负责胶原蛋白沉积，皮肤增厚和内脏器官的间质纤维化。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（即上皮细胞、巨噬细胞和成纤维细胞）上表达或诱导。我们还发现，由于系统性硬化症导致的肺纤维化患者在肺中具有表达LIGHT的T细胞，这与来自类似患者的支气管肺泡灌洗液中可溶性LIGHT水平升高的临床报告相关。这项提案将集中在三个小鼠模型的系统性硬化症，导致纤维化的各种器官，并概括了许多特征所表现出的人类患者。使用自发发展皮肤纤维化的紧皮肤小鼠;也导致皮肤纤维化以及内脏纤维化的GVHD的次要组织相容性模型;以及诱导肺纤维化的博来霉素注射，我们将测试缺乏LIGHT、HVEM或LT R的小鼠或细胞是否不能屈服于硬化样纤维化疾病。我们还将测试LIGHT相互作用的治疗性阻断是否改善与硬皮病和系统性硬化症相关的炎症和病理学。 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，并在所有种族群体中均有代表。它可以是局部的，影响手，手臂和面部，也可以是全身性的，影响大面积的皮肤以及内脏器官，如肺，肾和心脏。原因不明，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LIGHT及其受体HVEM和LT？R控制与硬化样炎性疾病相关的纤维化。通过确定LIGHT及其受体是否促进动物模型中的纤维化，我们将获得可能导致治疗靶向人类纤维化疾病的方法的知识。

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.