REGULATION OF THL RESPONSES IN PULMONARY SARCOIDOSIS

结节病是一种病因不明的多系统肉芽肿性疾病。 这涉及到90%以上受影响的人的肺部。慢性 进行性肺结节病可导致终末期纤维化和心脏病 肺气肿。使用皮质类固醇治疗可能是有毒和无效的。 多达5%的肺结节病患者死于病因 与疾病有直接关系。在美国的发病率为11-4- 每10万人中，结节病是一个重大的健康问题。 这项建议的总体目标是加深我们对 介导肉芽肿的免疫学和炎症过程 肺结节病的炎症。T细胞参与了 本病发病机制自“活化”，释放淋巴因子CD4+T细胞 细胞聚集在疾病部位，如肺部。积攒的 肺中的这些T细胞是选择性和寡克隆性的，其特征是 优先使用T细胞应答。试析中国经济发展的新格局 在结节样肺中表达的细胞因子已经证明，IFN-γ和 在较小程度上，IL2被强烈表达，而IL4和IL5被强烈表达 表达水平很低或检测不到。这种两极分化向 Th1免疫反应可能在疾病的发生和发展中发挥关键作用 结节病自Th1以来肉芽肿性炎症的永久化 在许多情况下，反应在调节细胞介导的免疫反应中起着关键作用 传染病和自身免疫性疾病。我们的初步数据表明 IL12是一种对启动Th1免疫反应至关重要的细胞因子 结节样肺中明显上调。 本申请中提出的实验旨在测试 假设结节病是一种Th1介导的疾病，由 白介素12的生产失调。这一假设将得到研究的检验。 有以下具体目标：1)确定极化是否 Th1相关细胞因子在组织特征中的表达 受结节病肉芽肿性炎症的影响，2)特征和 IL-12在结节瘤和正常人中表达调控的比较 肺泡巨噬细胞和外周血，以及3)确定的作用 IL-12在肺结节病免疫应答Th1偏离中的作用 这些研究应该会增加我们对这一过程的理解 控制结节病中的Th1极化并为深入了解 白细胞介素12慢性表达对血管内皮细胞的影响及调控因素 人类的肺。因此，这些研究可能有助于开发新的 旨在阻止肉芽肿和纤维化反应的治疗方法 结节病可导致终末期肺部疾病。

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that involves the lungs in over 90% of affected individuals. Chronic progressive pulmonary sarcoidosis can result in end-stage fibrosis and cor pulmonale. Treatment with corticosteroids may be toxic and ineffective. As many as 5% of individuals with pulmonary sarcoidosis die of causes directly related to the disease. With an incidence in the U.S. of 11-4- per 100,000 people, sarcoidosis represents a significant health problem. The overall objective of this proposal is to further our understanding of the immunologic and inflammatory processes mediating granulomatous inflammation in pulmonary sarcoidosis. T-cells are involved in the pathogenesis of the disease since "activated", lymphokine-releasing CD4+ T- cells accumulate at sites of disease such as the lung. The accumulation of these T-cells in the lung is selective and oligoclonal, characterized by the preferential usage of T-cell response. Analysis of the pattern of cytokines expressed in the sarcoid lung have demonstrated that IFNgamma and to a lesser extent, IL2 are strongly expressed while IL4 and IL5 are expressed at very low or nondetectable levels. This polarization towards a Th1 immune response is likely playing a key role in the development and perpetuation of granulomatous inflammation in sarcoidosis since Th1 responses are critical in mediating cell-mediated immune responses in many infectious and autoimmune diseases. Our preliminary data demonstrate that IL12, a cytokine critical to the initiation of Th1 immune responses, is markedly upregulated in the sarcoid lung. The experiments proposed in this application are aimed at testing the hypothesis that sarcoidosis is a Th1-mediated disease driven by the dysregulated production of Il12. This hypothesis will be tested by studies with the following Specific Aims; 1) Determine whether polarization towards Th1 associated cytokine expression in characteristic of tissues affected by granulomatous inflammation in sarcoidosis, 2) characterize and compare the regulation of IL12 expression in sarcoid and normal human alveolar macrophages and peripheral blood, and 3) determine the role of IL12 in the Th1 deviation of immune responses in pulmonary sarcoidosis. These studies should increase our understanding of the processes controlling Th1 polarization in sarcoidosis and provide insights into the effects and regulatory determinants of chronic expression of Il12 in the human lung. Thus, these studies may assist in the development of new therapies designed to halt the granulomatous and fibrotic responses that lead to end-stage pulmonary disease in sarcoidosis.