T LYMPHOCYTE TRANSENDOTHELIAL MIGRATION IN SARCOIDOSIS

肺结节病以CD4+(辅助)T淋巴细胞为特征 淋巴细胞性肺泡炎。肺脏中存在的效应性T细胞 结节病产生细胞因子，包括白细胞介素2和 促进炎症和维持肉芽肿的干扰素-伽马 队形。红细胞性肺泡炎在本病中的相对作用 来自血液的募集与肺内的原位增殖相比 不清楚。T细胞在组织中的募集是通过黏附迁移- 易于局部激活内皮细胞，与基质相互作用 蛋白质和对本地生产的化学诱导剂作出反应的迁移。 我们最近记录了一个专门的种群的存在 正常人血液中记忆的CD4+和CD8+T细胞 在体外通过正常或激活的内皮细胞迁移 化验。这些细胞在T细胞方面类似于正常肺的细胞。 细胞记忆和激活标记。我们已经记录了一个显著的增长 在一部分患者的血液中的这些迁移细胞中 结节病和CD4淋巴细胞性肺泡炎。我们假设这些 迁移细胞是T辅助效应细胞，它可以改变肉芽肿 结节病中的炎症。我们还记录了一个 新型CD4+细胞趋化因子(淋巴细胞趋化因子， LCF/IL-16)在4例慢性支气管炎患者的支气管肺泡灌洗(BAL)中的应用 结节病。这种化学诱导剂是在我们的 实验室发现，在正常非吸烟者的肺泡灌洗液中未发现。我们 假设从血液中招募的CD4+T细胞对 在肺结节病中的作用，以及两个相互关联的过程 有助于增加CD4+效应者T细胞募集到 肉芽肿形成：1.易迁移效应T细胞数量增加 细胞进入血液，在那里它们可以到达家到肺或其他地方 炎症部位，一旦进入组织就会引起炎症， 分解和纤维化，以及2.产生的CD4+T细胞 化学诱导剂，包括LCF.我们目前正在检验这一假设 通过：1.记录细胞的存在、表型和功能(细胞因子 正常人外周血中移行T细胞的产生) 结节病患者；2.组织、肺细胞和灌洗液的检查 来自结节病或LCF/IL-16存在的患者的样本。我们 我还将研究几种已知或建议的治疗方法的效果 结节病对CD4+T细胞黏附和跨内皮细胞迁移的影响 从正常人和结节病患者的血液中提取。这些研究可能 深入了解肉芽肿的维持机制 结节病，并可能建议有针对性的新的特定治疗形式 效应细胞募集。

Lung sarcoidosis is characterized by a CD4+ (helper) T-lymphocyte lymphocytic alveolitis. The effector T-cells present in the lung in sarcoidosis produce cytokines, including interleukin (IL)-2 and interferon-gamma, which promote inflammation and maintain granuloma formation. The relative contributions to this CD4+ T-cell alveolitis of recruitment from the blood versus in situ proliferation in the lung are not clear. T-cell recruitment to tissue occurs by adherence of migration- prone to locally activated endothelial cells, interaction with matrix proteins and migration in response to locally produced chemoattractants. We have recently documented the presence of a specialized population of memory CD4+ and CD8+ T cells in normal human blood which are highly likely to migrate through normal or activated endothelial cells in an in vitro assay. These cells resemble cells which home to normal lung in terms of T- cell memory and activation markers. We have documented a marked increase in these migrating cells in the blood of a subset of patients with sarcoidosis and CD4-lymphocytic alveolitis. We hypothesize that these migrating cells are T-helper effector cells which modify granulomatous inflammation in sarcoidosis. We have also documented the presence of a novel CD4+ cell chemoattractant (lymphocyte chemoattractant factor, LCF/IL-16) in the bronchoalveolar lavage (BAL) of 4 patients with sarcoidosis. This chemoattractant was identified and cloned in our laboratory and is not found n the BAL of normal non-smokers. We hypothesize that CD4+ T cell recruitment from the blood plays a important role in pulmonary sarcoidosis, and that two interrelated processes contribute to increased CD4+ effector T cell recruitment to sites of granuloma formation: 1. Increased numbers of migration-prone effector T- cells into the blood where they are available to home to lung or other inflammatory sites, and once in tissue contribute to inflammation, resolution and fibrosis, and 2. Production of CD4+ T cell specify chemoattractants, including LCF. We are presently testing this hypothesis by: 1. Documenting the presence, phenotype and function (cytokine production) of migrating T cells from peripheral blood of normals versa patients with sarcoidosis; and 2. Surveying tissues, lung cells and lavage samples from patients with sarcoidosis or the presence of LCF/IL-16. We will also examine the effect of several known or proposed therapies for sarcoidosis on the adhesion and transendothelial migration of CD4+ T cells from the blood of normals and patients with sarcoidosis. These studies may provide insight into the mechanisms by which granulomas are maintained in sarcoidosis, and may suggest new forms of specific therapy targeted at effector cell recruitment.