title: Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance.
abstract: Anti-apoptotic genes, including those of the Bcl-2 family, have been shown to have dual functionality inasmuch as they inhibit cell death but also regulate inflammation. Several anti-apoptotic molecules have been associated with endothelial cell (EC) survival following transplantation; however, their exact role has yet to be elucidated in respect to controlling inflammation. In this study we created mice expressing murine A1 (Bfl-1), a Bcl-2 family member, under the control of the human intercellular adhesion molecule 2 (ICAM-2) promoter. Constitutive expression of A1 in murine vascular ECs conferred protection from cell death induced by the proinflammatory cytokine tumour necrosis factor (TNF)-α. Importantly, in a mouse model of heart allograft transplantation, expression of A1 in vascular endothelium increased survival in the absence of CD8+T cells. Better graft outcome in mice receiving an A1 transgenic heart correlated with a reduced immune infiltration, which may be related to increased EC survival and reduced expression of adhesion molecules on ECs. In conclusion, constitutive expression of the anti-apoptotic molecule Bfl1 (A1) in murine vascular ECs leads to prolonged allograft survival due to modifying inflammation.
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK.|School of Health, Sports and Biosciences, University of East London, London, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Smyth
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Meader
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Peter Gorer Department of Immunobiology, Borough Wing, Guy's Hospital, King's College, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Woodward
authors.affiliation: Immunology and Infection Section, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College, London, UK.
authors.forename: H J M
authors.initials: HJ
authors.lastname: Brady
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Lechler
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes; D015815:Cell Adhesion Molecules / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D015870:Gene Expression; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D007249:Inflammation; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; C096816:BCL2-related protein A1; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha
keywords: anti-apoptotic; endothelial