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The efficacy of cardiac transplant is limited by coronary allograft vasculopathy (CAV), a prevalent and irreversible process of diffuse coronary stenosis. Chronic antibody mediated rejection (CAMR), characterized by donor specific antibody and complement binding to graft endothelial cells (EC) is a risk factor for CAV, however the mechanism(s) linking CAMR to CAV is unknown.
To model CAMR, we used ‘high panel reactive antibody (PRA)’ sera taken from highly–sensitized listed patients to deposit alloantibody and sub–lytic complement on EC (Fig 1a). We assessed EC gene expression by microarray analysis and measured the ability of PRA sera–treated EC to activate and recruit alloimmune CD4+ T cells in vitro using two cell–based assays and in vivo in a humanized mouse model of CAV.
EC treated with PRA sera initiated an inflammatory gene program (1b) that increased the capacity of EC to recruit (1c) and activate (1d) alloreactive CD4+ T cells. PRA sera–treated coronaries also developed worsened CAV in vivo (e). Unexpectedly, these processes were driven by complement–induced activation of non–canonical nuclear factor kappa B (NF–kB) signaling in EC. We identified a pathologic role for non–canonical NF–kB signaling and found evidence of pathway activation in vivo in a humanized mouse model and in biopsies of patients with CAMR (1f).
Our studies identify a novel complement–mediated pathway involving non–canonical NF–kB signaling in EC that mechanistically links CAMR with development of CAV.
Special Session North, Room 120
Sunday, March 10, 2013, 8:30 a.m.–8:45 a.m.
Session Title: Young Investigator Awards Competition: ACCF/Herman K. Gold Young Investigators Award in Molecular and Cellular Cardiology
Abstract Category: Molecular and Cellular Cardiology
Presentation Number: 402–6
- 2013 American College of Cardiology Foundation