T LYMPHOCYTE TRANSENDOTHELIAL MIGRATION IN SARCOIDOSIS

肺结节病的特征是CD4+（辅助）T淋巴细胞 淋巴细胞性肺泡炎肺中存在的效应T细胞 结节病产生细胞因子，包括白细胞介素（IL）-2和 干扰素-γ，其促进炎症并维持肉芽肿 阵在这种CD4 + T细胞肺泡炎中， 从血液中募集与肺中原位增殖的关系是 不清楚T细胞向组织的募集是通过粘附迁移发生的- 易于局部激活内皮细胞，与基质相互作用 蛋白质和迁移响应本地产生的化学引诱剂。 我们最近记录了一个特殊的人口的存在， 正常人血液中的记忆性CD4+和CD8 + T细胞， 在体外通过正常或活化的内皮细胞迁移 比色法这些细胞类似于在T细胞方面回到正常肺的细胞。 细胞记忆和激活标记。我们记录到 在这些迁移的细胞在血液中的一个子集的患者， 结节病和CD4淋巴细胞性肺泡炎。我们假设这些 移行细胞是T辅助效应细胞，其修饰肉芽肿性 结节病的炎症我们还记录了 新的CD4+细胞化学引诱物（淋巴细胞化学引诱因子， LCF/IL-16）在4例支气管肺泡灌洗（BAL）中的表达 结节病这种化学引诱物是在我们的 在实验室中，在正常非吸烟者的BAL中未发现。我们 假设从血液中募集CD4 + T细胞在 在肺结节病中的作用，这两个相互关联的过程 有助于增加CD4+效应T细胞募集到 肉芽肿形成：1.迁移倾向效应T细胞数量增加， 细胞进入血液，在那里他们可以回家肺或其他 炎症部位，一旦进入组织就会导致炎症， 分辨率和纤维化，和2.产生CD4 + T细胞特异性 化学引诱剂，包括LCF。我们目前正在验证这一假设 通过：1.记录存在、表型和功能（细胞因子 正常人外周血中的迁移性T细胞 结节病患者; 2.测量组织、肺细胞和灌洗 来自患有结节病或存在LCF/IL-16的患者的样品。我们 还将检查几种已知或拟议的治疗方法的效果， 结节病对CD4 + T细胞粘附和跨内皮迁移的影响 从正常人和结节病患者的血液中分离出来。这些研究可能 提供了深入了解肉芽肿的机制， 结节病，并可能提出新的形式的具体治疗针对 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.