title: Heme Oxygenase-1 Inhibits HLA Class I Antibody-Dependent Endothelial Cell Activation.
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.
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Zilian
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.|Faculty of Biology, Gadjah Mada University, Yogyakarta, Indonesia.
authors.forename: Hendry
authors.initials: H
authors.lastname: Saragih
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Vijith
authors.initials: V
authors.lastname: Vijayan
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hiller
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Constanca
authors.initials: C
authors.lastname: Figueiredo
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Abid
authors.initials: A
authors.lastname: Aljabri
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Blasczyk
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Jan Ulrich
authors.initials: JU
authors.lastname: Becker
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Larmann
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Immenschuh
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D015395:Histocompatibility Antigens Class I; C573420:ICAM1 protein, human; D016209:Interleukin-8; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1