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 超过90%的受感染者的肺部都受到了影响 慢性 进行性肺结节病可导致终末期纤维化， 肺结核。 皮质类固醇治疗可能有毒且无效。 多达5%的肺结节病患者死于各种原因 与疾病直接相关。 在美国的发病率为11-4- 每100，000人中，结节病是一个严重的健康问题。 本建议的总体目标是进一步了解 免疫和炎症过程介导肉芽肿性 肺结节病的炎症 T细胞参与了 发病机制的疾病，因为“活化”，淋巴因子释放CD 4 + T- 细胞聚集在疾病部位，例如肺。 的积累 肺中的这些T细胞是选择性和寡克隆的，其特征在于： 优先使用T细胞反应。 分析了 在结节病肺中表达的细胞因子已经证明IFN γ和 在较小的程度上，IL 2强烈表达，而IL 4和IL 5则强烈表达。 以非常低或不可检测的水平表达。 这种两极分化， Th 1免疫应答可能在发展中起关键作用， 结节病肉芽肿性炎症自Th 1起持续存在 免疫应答在介导细胞介导的免疫应答中是至关重要的。 感染性和自身免疫性疾病。 我们的初步数据表明， IL 12是一种对Th 1免疫应答启动至关重要的细胞因子， 在结节病肺中显著上调。 本申请中提出的实验旨在测试 假设结节病是一种Th 1介导的疾病， IL-12的生产失调。 这一假设将通过研究进行检验 具体目的如下：1）确定极化是否 组织特征性Th 1相关细胞因子表达 受结节病肉芽肿性炎症的影响，2）表征和 比较类肉瘤和正常人IL 12表达的调节 肺泡巨噬细胞和外周血，和3）确定的作用， IL 12在肺结节病Th 1免疫应答偏离中的作用 这些研究应该增加我们对这些过程的理解 控制结节病中的Th 1极化， IL-12慢性表达的影响和调节决定因素 人肺 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， 导致结节病终末期肺部疾病。

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.