Abstract
Antibody-mediated rejection (AMR) is a key limiting factor for long-term graft survival in solid organ transplantation. Human leukocyte antigen (HLA) class I (HLA I) antibodies (Abs) play a major role in the pathogenesis of AMR via their interactions with HLA molecules on vascular endothelial cells (ECs). The antioxidant enzyme heme oxygenase (HO)-1 has anti-inflammatory functions in the endothelium. As complement-independent effects of HLA I Abs can activate ECs, it was the goal of the current study to investigate the role of HO-1 on activation of human ECs by HLA I Abs. In cell cultures of various primary human macro- and microvascular ECs treatment with monoclonal pan- and allele-specific HLA I Abs up-regulated the expression of inducible proinflammatory adhesion molecules and chemokines (vascular cell adhesion molecule-1 [VCAM-1], intercellular cell adhesion molecule-1 [ICAM-1], interleukin-8 [IL-8] and monocyte chemotactic protein 1 [MCP-1]). Pharmacological induction of HO-1 with cobalt-protoporphyrin IX reduced, whereas inhibition of HO-1 with either zinc-protoporphyrin IX or siRNA-mediated knockdown increased HLA I Ab-dependent up-regulation of VCAM-1. Treatment with two carbon monoxide (CO)-releasing molecules, which liberate the gaseous HO product CO, blocked HLA I Ab-dependent EC activation. Finally, in an in vitro adhesion assay exposure of ECs to HLA I Abs led to increased monocyte binding, which was counteracted by up-regulation of HO-1. In conclusion, HLA I Ab-dependent EC activation is modulated by endothelial HO-1 and targeted induction of this enzyme may be a novel therapeutic approach for the treatment of AMR in solid organ transplantation.
Highlights
Antibody (Ab)-mediated rejection (AMR) is a major limiting factor for long-term graft survival after kidney and heart transplantation [1,2,3,4]
The expression of inducible adhesion molecules (VCAM-1, ICAM-1) and chemokines (MCP-1, IL-8) in response to the pan-Human leukocyte antigen (HLA) I monoclonal antibodies (MoAbs) W6/32 was determined in cell cultures of Human umbilical vein endothelial cells (HUVECs) [36,37,38]
The current report shows that treatment with two pan-HLA I MoAbs (W6/32, G46.6) and an allele-specific HLA MoAb (BB7.2) up-regulates the gene expression of inducible proinflammatory adhesion molecules and chemokines in cell cultures of various primary human endothelial cells (ECs)
Summary
Antibody (Ab)-mediated rejection (AMR) is a major limiting factor for long-term graft survival after kidney and heart transplantation [1,2,3,4]. EC activation is critically involved in the pathogenesis of acute and chronic inflammation [14] It is characterized by alterations of intracellular endothelial signaling, which up-regulates expression of inducible adhesion molecules and chemokines [15], and in turn modulates coordinated recruitment of leukocytes to the site of inflammation [16, 17]. We hypothesized that HO-1 may modulate HLA I Abdependent activation of ECs. It is demonstrated that HLA I Abs up-regulate inducible adhesion molecules and chemokines in human ECs and cause increased endothelial adhesion of monocytes. It is demonstrated that HLA I Abs up-regulate inducible adhesion molecules and chemokines in human ECs and cause increased endothelial adhesion of monocytes Both HLA I Ab-dependent effects in ECs are modulated by specific regulation of HO-1
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