The role of the graft endothelium in transplant rejection: Evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection

Abstract

In this review, we discuss the role of the allograft endothelium in the recruitment and activation of leukocytes during acute and chronic rejection. We discuss associations among endothelial activation responses, the expression of adhesion molecules, chemokines and chemokine receptors, and rejection; and we propose that endothelial vascular cellular adhesion molecule-1 (VCAM-1) may be used as a surrogate marker of acute rejection and allograft vasculopathy. In addition, we describe potential mechanistic interpretations of persistent endothelial cell (EC) expression of major histocompatibility complex (MHC) class II molecules in allorecognition. The graft endothelium may provide an antigen-specific signal to transmigrating, previously activated, T cells and may induce B7 expression on locally transmigrating leukocytes to promote costimulation. Taken together, these functions of the EC provide it with a potent regulatory role in rejection and in the maintenance of T-cell activation via the direct and/or the indirect pathways of allorecognition.

Proinflammatory functions of vascular endothelial growth factor in alloimmunity

“…Multiple individual molecules have been shown to be functional in the process of rejection (49)(50)(51)(52), suggesting that there is some redundancy in the function of adhesion molecules and chemokines in vivo. It is known that VEGF induces the expression of adhesion molecules in human endothelial cells (9,10), and two recent reports have pointed to an effect of VEGF on chemokine production (53,54).…”

Expression of the Chemokine Receptor CXCR3 and Its Ligand IP-10 During Human Cardiac Allograft Rejection

“…These findings are consistent with our previous observations that persistent intragraft immunological events in the third and fourth posttransplant quartiles identify patients at an increased risk for the development of TCAD. 13 …”

Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

“…Induction of HLA-G expression in endothelial cells is of particular interest because they are primary targets of circulating T cells posttransplant due to expression of classical MHC-I and II antigens. 12 After binding to classical MHC proteins, T cells secrete a host of cytokines, leading to recruitment of inflammatory cells and proliferation of smooth muscle cells, which can eventually progress into CAV. 10,11 Endothelial HLA-G expression could represent a strategy to inhibit adjacent T cells and prevent the progression of CAV.…”

“…10,11 Furthermore, the endothelium of the coronary arteries expresses MHC antigens, which are capable of inducing immune responses. 12 T cells have also been detected in close proximity to the luminal endothelium of allograft vessels and may contribute to the progression of transplant vasculopathy. 13 Consequently, vascular HLA-G expression might inhibit the immunologic processes that lead to CAV.…”