Antibody-mediated rejection (AMR) is a major determinant of heart allograft loss. However, the specific effects of anti-HLA antibodies on heart allograft injury have not been addressed at a population level.

We prospectively monitored 617 heart transplant recipients referred from 4 French centers (2006-2011) for AMR. We compared patients with AMR (n=50) to a matched control group without AMR (n=50). We characterized all patients using histopathology, immunostaining, anti-HLA DSA at the time of biopsy and gene expression assessments of the allografts using microarrays. We studied an external validation cohort of 98 heart recipients transplanted in Edmonton, Canada including 27 pAMR cases and 71 controls.

240 heart transplant EMB were assessed. AMR showed a distinct pattern of injury characterized by endothelial activation with microcirculation inflammation by monocytes/macrophages and NK-cells, and selective changes in endothelial/angiogenesis and NK cell transcripts, including CD16A signaling and select IFNG-inducible genes. The AMR selective gene sets discriminated patients with AMR from those without, including NK (AUC=0.87), endothelial activation (AUC=0.80), macrophage (AUC=0.86) transcripts 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 AMR ISHLT grades (p<0.001) and association with DSA levels. The unsupervised PCA analysis projected the AMR gene sets and demonstrated a high proportion of molecular inactive pAMRI+ compared with a significant molecular overlap between pAMR1H+ and full-blown pAMR2-3 cases, reclassifying 25% of AMR cases. Endothelial activation, interferon gamma and NK transcripts showed association with chronic allograft vasculopathy. We confirmed that the molecular architecture, selective AMR transcripts and gene set discrimination capacity for AMR were highly conserved in the external validation cohort.

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 and correlate with the degree of injury and disease activity. This study illustrates the clinical potential of a molecular microscope approach in heart transplant rejection.

CITATION INFORMATION: Loupy A, Duong Van-Huyen J, Hidalgo L, Reeve J, Racapé M, Aubert O, Venner J, Viglietti D, Bruneval P, Lefaucheur C, Halloran P. Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection. Am J Transplant. 2017;17 (suppl 3).

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