Antibody-mediated rejection (ABMR) is characterized by molecular changes that indicate a role for injury–repair mechanisms in the microcirculation that are likely mediated by natural killer (NK) cell signalling through CD16a Fc receptors, according to new findings. “Our study mapped the molecular landscape associated with ABMR of kidney transplants,” explains researcher Philip Halloran. “We identified a phenotype driven by microcirculation remodelling with a serious role for NK cells. IFN-γ also seems important, with strong associations of the IFN-γ-inducible molecules PLA1A and CXCL11 with ABMR.”

ABMR is a major cause of graft loss in kidney transplant recipients. Type 2 ABMR, which emerges after the first year of transplantation, is a microcirculation disease and is the leading cause of kidney transplant failure. “The process of ABMR is difficult to model in animal systems,” says Halloran. “We therefore performed microarray analysis to map transcripts associated with ABMR in indication biopsy samples taken between 3 days and 35 years after renal transplantation.”

Transcript analysis of 403 biopsy samples from 315 patients in a discovery set identified a set of 30 transcripts that were associated with ABMR. These transcripts were conserved in a second independent validation set of 300 biopsy samples from 264 patients. “The signal is highly reproducible, demonstrating that the molecular phenotype is just as robust as the histological phenotype,” notes Halloran. Analysis of the transcripts revealed three main categories: endothelial transcripts, including cadherins; NK cell-associated transcripts; and genes that are regulated by IFN-γ. The researchers performed pathway analyses to assess the potential mechanisms associated with the transcript changes. “The most characteristic pathway was endothelial remodelling related to pathways involved in microcirculation and angiopoietin,” says Halloran. “We also think that NK cells signal through CD16a to mediate antibody-dependent cellular cytotoxicity, which has effects on the endothelium.” The researchers say their goal is to use the quantitative study of molecules to identify ABMR and to guide therapy.