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Review
. 2020 May 8:11:443.
doi: 10.3389/fphys.2020.00443. eCollection 2020.

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

Laura Kummer  1 , Marcin Zaradzki  2 , Vijith Vijayan  3 , Rawa Arif  2 , Markus A Weigand  1 , Stephan Immenschuh  3 , Andreas H Wagner  4 , Jan Larmann  1
Affiliations
Review

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

Laura Kummer et al. Front Physiol. .

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.

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Figures

FIGURE 1
FIGURE 1
Overview of interactions of endothelial and immune cells leading to different forms of rejection after solid organ transplantation. EC, endothelial cell; C1, complement factor; Ab, antibody; expr., expression; apopt., apoptotic (Piotti et al., 2014).
FIGURE 2
FIGURE 2
Schematic representation of known effects of antibodies towards surface antigens on endothelial cells. Binding of antibodies can either leads to acute rejection due to immune cell or complement mediated lysis or to a state of chronic rejection due to endothelial cell activation (Colvin and Smith, 2005). Elements of Figures 2, 3 and 4 were taken and adjusted from Servier Medical Art at http://smart.servier.com, licensed under a Creative Commons Attribution 3.0 Unported License.
FIGURE 3
FIGURE 3
In response to different pro-inflammatory signals the leukocyte adhesion and transmigration cascade is activated. Slow down, rolling, firm adhesion and transmigration is mediated by different cytokines and molecules on the surface of leukocytes and ECs. Para-cellular transmigration through EC junctions is the primary route for extravasation (Vestweber, 2015). Elements of Figures 2, 3 and 4 were taken and adjusted from Servier Medical Art at http://smart.servier.com, licensed under a Creative Commons Attribution 3.0 Unported License.
FIGURE 4
FIGURE 4
Changes of vascular structure due alloresponse following solid organ transplantation. Acute injury is mainly mediated by neutrophiles ans macrophages. These immune cells produce cytokines and induce expression of adhesion molecules on ECs, leading to further recruitment of immune cells. Activated ECs exert a pro-inflammatory phenotype and activate smooth muscle-like cells, resulting in their proliferation and lumen narrowing (Mitchell, 2009). Elements of Figures 2, 3 and 4 were taken and adjusted from Servier Medical Art at http://smart.servier.com, licensed under a Creative Commons Attribution 3.0 Unported License.
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