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.

The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis

“…There are three general pathophysiological mechanisms leading to transplant rejection, hyperacute rejection occurring in minutes or hours due to preformed anti donor antibodies, acute rejection occurring in weeks to months of transplant which can be cellular or humoral in nature, and chronic allograft rejection which develops over a period of months to years and is described as transplant vasculopathy (TV) ( 73 ), characterized by neointima formation. Hyperacute rejection is uncommon due to advances in prescreening for anti-donor antibodies.…”

“…Disruption of the endothelial cell layer results in EC and platelet activation as well as migration of neutrophils, monocytes, and T cells via thrombin receptors. In addition ligation of anti HLA antibodies on the surface on the endothelium results in EC activation and expression of adhesion molecules and additional pro-inflammatory cytokines including intercellular cell adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and CD40 resulting in adhesion of leukocytes via Fcγ receptors ( 73 , 94 – 96 ). Platelets are the most abundant source of CD154.…”

Plasma cell biology: Foundations for targeted therapeutic development in transplantation

“…While anti‐HLA antibodies are the most important and well‐recognized cause of humoral rejection, studies showing AMR in recipients of HLA‐identical sibling kidneys have highlighted the importance of non‐HLA antigens in rejection 28‐30 . Most non‐HLA antigens are expressed on endothelial cells as they are the interface between allograft and host immune cells 31,32 . Non‐HLA antibodies come in two flavors – those directed against polymorphic proteins and those directed against self‐proteins.…”

(Cardiac allograft vasculopathy nowadays)

“…Tyto látky způsobí přesun buněk hladkých svalů do intimy, proliferaci a vznik depozit extracelulární matrix. 13 V rámci in vitro studií byla popsána úloha humorální imunity s vysokými titry HLA protilátek třídy 1 stimulujících proliferaci buněk endotelu a hladkých svalů cestou aktivace mTOR/ S6 kinázy (mammalian target of rapamycin). 14 Stejně tak dochází k redistribuci intracelulárního růstového faktoru fi broblastů do plazmatické membrány.…”