Jordan S. Pober
Immunobiology of Vascular EndotheliumMy laboratory is interested in three research problems related to the immunobiology of vascular endothelium. Our first area of interest is the ability of cytokines to promote inflammation by altering the properties of vascular endothelial cells. When cultured human endothelial cells are exposed to cytokines, they undergo a series of alterations in gene expression resulting in increased capacities to perform new functions (i.e. "activation"). Our studies in this area focus on how cytokines alter endothelial surface proteins which interact with T lymphocytes. We analyze the effects of various individual and combinations of cytokines upon expression of MHC molecules, (which are involved in antigen recognition by T cells) and leukocyte adhesion proteins (which localize inflammation) on different types of human endothelial cells. We also examine the second messenger pathways utilized by cytokines to alter surface protein expression and the nuclear events mediated by cytokines that lead to altered rates of gene transcription. In parallel with these surface protein changes, we also investigate how cytokines regulate endothelial cell synthesis of vasodilators such as PGI2 and NO.
Our second area of interest is the identity and nature of the signals provided by endotheliala cells that affect T cell activation. We have been exploring the effect of endothelial cell surface ligands on T cell synthesis and secretion of interleukin 2 (IL-2), the major regulatory cytokine of the immune response. We focus upon LFA-3 and upon as yet unidentified endothelial ligands which alter transcription factor expression in T cells, and upon ligands that confer T cell resistance to cyclosporin A, a drug that normally inhibits IL-2 synthesis.
Our third area of interest is to determine to what extent the observations made in vitro apply to the immunobiology of vascular endothelial cells in vivo. One current focus is upon cardiac allografts, delineating the role(s) of vascular endothelium in acute cellular rejection and more chronic lesions such as graft arteriosclerosis. A second focus is dermal inflammation, delineating functional differences among endothelial cells from different segments of the microvasculature and how these local differences change with disease. Finally, we have developed an animal model involving engraftment of human dermal microvessels and lymphocytes into SCID mice that allow us to study endothelial-lymphocyte interactions in vivo.