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Heme oxygenase-1 as a therapeutic target in anti-HLA antibody-triggered transplant vasculopathy

Subject Area Rheumatology
Term from 2014 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 265437184
 
Final Report Year 2021

Final Report Abstract

The antioxidant inducible enzyme heme oxygenase (HO)-1 has major anti-inflammatory effects mediated by metabolic degradation of pro-inflammatory heme and production of carbon monoxide (CO) and biliverdin. In addition, overexpression of HO-1 has been shown to be beneficial in various experimental models of solid organ transplantation. The goal of this project was to gain a better understanding of the specific role of HO-1 and its substrate heme in inflammatory processes involved in organ transplantation and ischemia-reperfusion injury (IRI) with a particular focus on the endothelium and dedicated immune cells. Because anti-human leukocyte antigen (HLA) antibody-mediated rejection is a major limiting factor for graft survival after solid organ transplantation, the role of HO-1 was determined in cell culture models of anti-HLA I and II antibody interaction with human endothelial cells. Specifically, targeted induction of HO-1 was able to counteract inflammatory activation of endothelial cells in response to treatment with anti-HLA class I antibodies (1). In contrast, HO-1 did not interfere with the effects of anti-HLA II antibody ligation to endothelial cells. Endothelial binding of anti-HLA II antibodies led to necrotic cell death via a defined lysosomal membrane permeabilization-mediated pathway involving the generation of mitochondrial reactive oxygen species (2). We also examined the role of the heme/ HO-1-system for inflammatory processes related to transplantation and IRI in various experimental murine disease models. It was demonstrated in a renal IRI model with subsequent fibrosis that anti-inflammatory protective effects of the complement 5a receptor 2, a key receptor for inflammatory kidney diseases, was mediated via a HO-1-dependent mechanism. This pathway involved the anti-inflammatory cytokine interleukin-10 and activation of the AKT signaling cascade (3). In a model of unilateral renal IRI, local release of free heme in kidney was associated with a marked inflammatory response and up-regulation of HO-1. In this model, pro-inflammatory effects of free heme were attenuated by administration of the heme-binding protein human serum albumin suggesting that scavenging of prooxidant free heme might be a therapeutic approach for treating renal IRI and other IRI-mediated inflammatory conditions associated with heme toxicity (4). Along this line, we also showed that human α1-antitrypsin, an acute-phase serum protein with high heme-binding affinity, counteracted inflammatory activation and cytotoxicity of free heme in human endothelial cells and neutrophils. Notably, α1-antitrypsin mediated anti-inflammatory effects via a mechanism that was different from that of other heme-binding proteins including hemopexin and serum albumin (5, 6). In conclusion, the findings of this project contribute to a better understanding of the immuno-modulatory role of the heme/ HO-1 system in inflammatory processes associated with solid organ transplantation and IRI. Further studies will help to improve diagnostic approaches and anti-inflammatory therapies in these conditions.

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