Professor of Pathology, Immunobiology & Biology

Director, Molecular Cardiobiology Program, BCMM

B.A., Biology, Chemistry and History, Haverford College, 1971; M.D., Yale Medical School, 1977; Ph.D., Molecular Biophysics and Biochemistry, Yale University; 1977; joined Yale faculty 1991.

Statement of Research Interests

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.

Savage COS, Hughes CCW, McIntyre BW, Picard JK, Pober JS. Human CD4+ T cells proliferate to HLA-DR+ allogeneic vascular endothelium:identification of accessory interactions. Transplantation 1993; 56:128-134.

Hughes CCW, Pober JS. Costimulation of peripheral blood T cell activation by human endothelial cells: enhanced IL-2 transcription correlates with increased c-fos synthesis and increased Fos content of AP-1. J Immunol. 1993 ;150-3148-3160.

Pober JS, Slowik MR, DeLuca LG, Ritchie AJ. Elevated cAMP inhibits endothelial cell synthesis and expression of TNF-induced endothelial leukocyte adhesion molecule-1 (ELAM-1) and vascular cell adhesion molecule-1 (VCAM-1) but not intercellular adhesion molecule-1 (ICAM-1). J Immunol. 1993;150:5114-5123.

Bradley JR, Johnson DR, Pober JS. Endothelial activation by hydrogen peroxide: selective increases of intercellular adhesion molecule-1 and MHC class I. Am J Path. 1993;142:1598-1609.

Bradley JR, Johnson DR, Pober JS. Four different classes of inhibitiors of receptor-mediated endocytosis decrease TNF-induced gene expression in human endothelial cells. J. Immunol. 1993;150:5544-5555.

Petzelbauer P, Bender JR, Wilson J, Pober JS. Heterogeneity of dermal microvascular endothelial cell antigen expression and cytokine responsiveness in situ and in cell culture. J Immunol. 1993; 151:5062-5072.

Slowik MR, DeLuca LG, Fiers W, Pober JS. Tumor necrosis factor (TNF) activates human endothelial cells through the P55 TNF receptor but the P75 receptor contributes to activation at low TNF concentration. Am J Pathol. 1993;134:1724-1730.

Johnson DR, Pober JS. HLA class I heavy chain gene promoter elements mediating synergy between tumor necrosis factor and interferons. Molec. Cell Biol. 1994;14:1322-1332.

Rosenkranz-Weiss P, Sessa WC, Milstien S, Kaufman S, Watson CA, Pober JS. Regulation of Nitric Oxide synthesis by proinflammatory cytokines in human umbilicial vein endothelial cells:Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J. Clin Invest. 1994; 93:2236-2243.

Birch KA, Ewenstein B, Golan D, Pober JS. Prolonged peak elevations in cytoplasmic free calcium ions, derived from intracellular stores, correlate with the extent of thrombin-stimulated exocytosis in single human umbilical vein endothelial cells. J Cell Phys. 1994 (in press).

Murray AG, Khodadoust MM, Pober JS, Bothwell ALM. Porcine aortic endothelial cells strongly activate human T cells: direct presentation of swine MHC antigens and effective costimulation by swine ligands for human CD2 and CD28. Immunity 1994;1:57-63.

Petzelbauer P, Pober JS, Keh A, Braverman IM. Inducibility and expression of microvascular endothelial adhesion molecules in lesional, perilesional and uninvolved skin of psoriatic patients. J Invest Dermatol. 1994 (in press).

DeLuca LG, Johnson DR, Whitley MZ, Collins T, Pober JS. cAMP and TNF competitively regulate transcriptional activation through and nuclear factor binding to the CRE/ATF element of the endothelial leukocyte adhesion molecule-1 (E-selectin) promoter. J Biol Chem. 1994 (in press).

Murray AG, Petzelbauer P, Hughes CCW, Costa J, Askenase P, Pober JS. Human T cell-mediated destruction of allogeneic dermal microvessels in a SCID mouse. Proc Natl Acad Sci (USA). 1994 (in press).