Vascular Signaling in Allogenic Solid Organ Transplantation - The Role of Endothelial Cells

Abstract

Graft rejection remains the major obstacle after vascularized solid organ transplantation. Endothelial cells, which form the interface between the transplanted graft and the host's immunity, are the first target for host immune cells. During acute cellular rejection endothelial cells are directly attacked by HLA I and II-recognizing NK cells, macrophages, and T cells, and activation of the complement system leads to endothelial cell lysis. The established forms of immunosuppressive therapy provide effective treatment options, but the treatment of chronic rejection of solid organs remains challenging. Chronic rejection is mainly based on production of donor-specific antibodies that induce endothelial cell activation-a condition which phenotypically resembles chronic inflammation. Activated endothelial cells produce chemokines, and expression of adhesion molecules increases. Due to this pro-inflammatory microenvironment, leukocytes are recruited and transmigrate from the bloodstream across the endothelial monolayer into the vessel wall. This mononuclear infiltrate is a hallmark of transplant vasculopathy. Furthermore, expression profiles of different cytokines serve as clinical markers for the patient's outcome. Besides their effects on immune cells, activated endothelial cells support the migration and proliferation of vascular smooth muscle cells. In turn, muscle cell recruitment leads to neointima formation followed by reduction in organ perfusion and eventually results in tissue injury. Activation of endothelial cells involves antibody ligation to the surface of endothelial cells. Subsequently, intracellular signaling pathways are initiated. These signaling cascades may serve as targets to prevent or treat adverse effects in antibody-activated endothelial cells. Preventive or therapeutic strategies for chronic rejection can be investigated in sophisticated mouse models of transplant vasculopathy, mimicking interactions between immune cells and endothelium.

Keywords: HLA I and II; donor-specific antibodies; endothelial activation; transplant vasculopathy; vascular signaling.