Endothelial molecules decipher the mechanisms and functional pathways in antibody-mediated rejection.

Microvascular endothelium is the main target of injury in antibody-mediated rejection of human organ transplants. Hence, antibody-mediated rejection histologically presents with microvascular inflammation (pulmonary or myocardial or peritubular capillaritis, glomerulitis), thrombosis, and endothelial remodeling (duplication and/or multilayering of glomerular and capillary basement membranes). We previously observed upregulation of several endothelial genes in kidney transplant biopsies from patients with donor specific antibodies, indicating active antibody-mediated rejection and poor graft survival. Furthermore, endothelial molecular signals discovered a previously unknown clinical phenotype: C4d negative antibody-mediated rejection. With the recognition of C4d negative antibody-mediated rejection, data from multiple transplant centers now show that antibody-mediated rejection is the most common cause of late kidney transplant failure. This paper reviews the current understanding of endothelial cell biology in antibody-mediated rejection, emphasizing recent advances and pending questions. Furthermore, the paper discusses functionally active pathways in human antibody-mediated rejection, which include aspects of endothelial activation with increased endothelial adhesive and pro-coagulant signals facilitating leukocyte trafficking and attachment, cell-to-basement membrane interactions, platelet activation, coagulation, and endothelial repair responses. To understand effector mechanisms of antibody-mediated rejection and quantify the degree of antibody-mediated tissue injury in clinical transplants, endothelial cells provide a useful read-out.