Immunobiology of Vascular Endothelium
My 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 endothelial 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.
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