Endothelial activation and chronic allograft rejection

Microvascular endothelial cells are actively involved in acute and hyperacute allograft rejection. In acute rejection, inflamed graft endothelia increase their expression of cell adhesion and antigen-presentation molecules, thereby initiating and promoting various mechanisms of cellular immune rejection. In hyperacute rejection, preformed antibodies bind to graft endothelial cells and initiate endothelial procoagulant activity. These disparate immune responses appear to reflect different manifestations of endothelial cell activation. We hypothesize that chronic allograft rejection is a third manifestation of local endothelial activation. Chronic rejection is associated with interstitial and/or vascular hypertrophy. It is intriguing that among the products of activated endothelial cells are extracellular matrix components and growth factors that promote tissue reconstruction. This suggests that chronic or repetitive stimulation of endothelial cells may cause persistent or periodic release of these growth factors, eventually leading to the histopathology of chronic rejection. Chronic endothelial stimulation could be accomplished by drugs, alloantibodies, immune mediators, or some combination thereof. This leads to the question: Do different patterns of endothelial stimulation result in different manifestations of endothelial activation? Our studies of acute rejection mechanisms in murine cardiac allografts demonstrated that several stable endothelial phenotypes can develop during graft inflammation, depending on the availability of local immune stimuli (Transplantation 1993: 55: 315). Unpublished studies suggest that the steroids prednisolone and dexamethasone can synergize in vitro with suboptimal concentrations of interferon-gamma (IFN-gamma) to promote the activation of human endothelial cell lines, as manifested by enhanced expression of MHC class II but not ICAM-1. These steroids do not influence tumor necrosis factor-alpha (TNF-alpha)-induced endothelial behavior.(ABSTRACT TRUNCATED AT 250 WORDS)