Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance. (2nd March 2017)

• Record Type: Journal Article
• Authors: Smyth, L A; Meader, L; Xiao, F; Woodward, M; Brady, H J M; Lechler, R; Lombardi, G
• Is Part Of: Clinical and experimental immunology. Volume 188:Number 2(2017:May)
• Page Start: 219
• Page End: 225
• Publication Date: 2017-03-02
• Subjects: anti-apoptotic -- endothelial; Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12931
• Languages: English
• ISSNs: 0009-9104

Abstract

Summary: 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. Graphical Abstract: