title: Negative regulation of HLA-DR expression on endothelial cells by anti-blood group A/B antibody ligation and mTOR inhibition.
abstract: Donor-specific antibody (DSA), particularly against HLA class II, is a major cause of chronic antibody-mediated rejection (CAMR) after transplantation, although ABO-incompatible kidney transplantation has recently demonstrated favorable graft outcomes. The condition of no injury even in the presence of anti-donor antibody has been referred to as "accommodation", which would be one of the key factors for successful long-term graft survival. The purpose of this study was to analyze the beneficial effect of anti-blood group A/B antibody ligation on endothelial cells against HLA-DR antibody-mediated, complement-dependent cytotoxicity (CDC). Blood group A/B-expressing endothelial cells EA.hy926 or Human Umbilical Vein Endothelia Cells (HUVEC) were incubated with IFNγ in the presence or absence of anti-blood group A/B antibody or mTOR inhibitor (mTOR-i) for 48h. The effects on signaling pathway, HLA expression, complement regulatory factors, and CDC were investigated. Expression of HLA-DR on EA.hy926 or HUVEC were successfully elicited by IFNγ treatment, although little or no expression was observed in quiescent cells. Pre-incubation with anti-blood group A/B antibody had resistance to HLA-DR antibody-mediated CDC against IFNγ-treated cells in a concentration-dependent manner. This finding was ascribed to decreased expression of HLA-DR by post-translational regulation and increased expression of CD55/59, which was related to ERK and mTOR pathway inhibition. mTOR-i also inhibited HLA-DR expression by itself. Furthermore, the combination of mTOR-I and anti-blood group A/B ligation had an additive effect in preventing HLA-DR antibody-mediated CDC. Anti-blood group A/B antibody might play a preventive role in CAMR. Inhibition of the ERK and mTOR pathways may contribute to the development of a novel treatment in the maintenance period after transplantation.
authors.affiliation: Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan. Electronic address: kentaiwasaki@aichi-med-u.ac.jp.
authors.forename: Kenta
authors.initials: K
authors.lastname: Iwasaki
authors.affiliation: Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Miwa
authors.affiliation: Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
authors.affiliation: Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagoya, Japan. Electronic address: takaaki.kobayashi@aichi-med-u.ac.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000017:ABO Blood-Group System / Q000276:immunology*; D000906:Antibodies / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D000068338:Everolimus / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D016030:Kidney Transplantation; D011499:Protein Processing, Post-Translational; D011940:Receptor Aggregation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D000017:ABO Blood-Group System; D000906:Antibodies; D006684:HLA-DR Antigens; D007371:Interferon-gamma; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ABO-incompatibility; Accommodation; Chronic antibody-mediated rejection; HLA-DR expression; Kidney transplantation