Endothelial activation and chronic allograft rejection
Authors: Orosz Charles G. 
Published: September 2024

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 Unpublished studies suggest that the steroids prednisolone and dexamethasone can synergize in vitro with suboptimal concentrations of interferon‐gamma (IFN‐γ) to promote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‐α)‐induced endothelial behavior. Yet to be determined is whether this drug and cytokine combination influences the production of growth factors by endothelia. Transplant recipients receive steroids for maintenance immunosuppression; IFN‐γ could be produced by random immune responses to environmental antigens, thus resulting in chronic endothelial stimulation in graft recipients. Finally, our lab and others have observed that a component of scrum from some high PRA (panel‐ reactive antibody) patients can activate cultured, human endothelial cells, as manifested by heightened ICAM‐1 expression. Other parameters of endothelial activation have not yet been investigated in this way. We have noted that endothelial cells arc relatively difficult to kill with antibody and complement, but that they can be activated through their receptors for products of the complement cascade. It remains to be determined whether serum from individuals with ongoing chronic rejection also can mediate this effect, or promote endothelial growth factor production. In sum, there is evidence that endothelial cells can be activated by a variety of immune and physiologic stimuli, and that the outcome of endothelial activation varies widely and depends on the combination of stimuli present, thus influencing the pattern of subsequent histopathology at the inflammatory site. This supplies the groundwork for the hypothesis that chronic allograft rejection may be a manifestation of local endothelial activation by a particular combination of physiologic, immunologic and pharmacologic stimuli.