Selective recruitment of lymphocytes to the lung involves adherence to endothelial cells and then transmigration into tissues. The adherence can be markedly increased by cytokine activation of endothelial cells and by activation of T lymphocytes. We describe in our grant proposal an in vitro model of blood T lymphocyte adherence and migration through human umbilical vein endothelial cell (HUVEC) monolayers which selects for cells that are also partitioned in the normal and diseased lung. In particular, the cytokine activated HUVEC model appears to match sarcoidosis and tuberculosis, diseases in which increased numbers of memory CD4+ cells are recruited to the lung. We will employ this model to study the effect of two putative CD4 ligands on surface molecules involved in lymphocyte adherence to HUVEC, and on transmigration through EC monolayers. These ligands include the Major Histocompatibility Complex antigen HLA-DR expressed on interferon-gamma activated endothelial cells, and the CD4 binding chemoattractant T lymphocyte growth factor, lymphocyte chemoattractant factor (LCF). LCF has been cloned by our laboratory, and will be provided by Project 1 within the SCOR. The characteristics of adherent and transmigrating blood T lymphocytes cells will be studied in normal humans, and the derangements in this system in granulomatous diseases, and in patients with defective granuloma formation in response to tuberculosis will be characterized. It is hoped that knowledge of the surface molecules involved in lymphocyte adherence, and the mechanisms of induction of T cell migration will lead to the development of novel therapeutic approaches to inflammatory lung diseases.
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