Abstract 14361: Gene Expression Profiling for the Identification and Classification of Antibody-mediated Heart Rejection
Introduction: Antibody-mediated rejection (AMR) of heart transplants is a major determinant of allograft loss. Improving our understanding of the pathophysiology, disease activity and disease stage in heart AMR is an unmet need.
Hypothesis: Gene expression assessments may complement the current gold standard represented by histopathology.
Methods: We prospectively monitored 617 heart transplant recipients referred from four French heart transplant centers for AMR. We compared patients with AMR to a matched control group of patients without AMR. We characterized all patients using histopathology (ISHLT 2013), immunostaining, circulating anti-HLA DSA and gene expression at the time of biopsy. The principal effector cells were also evaluated by in vitro human cell cultures. We studied an additional external validation cohort of heart recipients transplanted in Edmonton, Alberta Canada.
Results: We included 208 heart transplant patients (110 in the test cohort 98 in the validation cohort) with 240 biopsies (98 pAMR ISHLT cases and 142 controls). The AMR selective gene sets discriminated patients with AMR from those without and included NK transcripts (AUC=0.87) (and selective changes in CD16A signaling and IFNG-inducible genes), endothelial activation transcripts (AUC=0.80), macrophage transcripts (AUC=0.86) and transcripts involved in the IFNG response (AUC=0.84, p<0.0001 for all comparisons). These 4 gene sets showed increased expression with increasing pAMR ISHLT grades (p<0.001). The unsupervised PCA analysis projected the AMR gene sets across the ISHLT pAMR categories and demonstrated a high proportion of molecular inactive pAMRI+ compared with a significant molecular overlap between pAMR1H+ and full-blown pAMR2-3 cases. The molecular architecture and selective AMR transcripts were highly conserved in the external validation cohort.
Conclusions: Antibody-mediated heart rejection is mainly driven by the NK burden, endothelial activation, macrophage burden and IFNG effects. Molecular intragraft measurements for these specific pathogenesis-based transcripts classify AMR with great accuracy, reclassify pAMR1 cases, and correlate with the degree of injury and disease activity.
Author Disclosures: M. Racapé: None. A. Loupy: None. X. Jouven: None.
- © 2016 by American Heart Association, Inc.