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.
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