THE ACTIVITY OF ANTIBODY-MEDIATED REJECTION IN KIDNEY TRANSPLANTATION IS REFLECTED BY ACTIVATED NATURAL KILLER CELL TRANSCRIPTS: THE BIOMARGIN STUDY
Résumé
Background: Antibody-mediated rejection (ABMR) is now recognized as a foremost cause of kidney graft failure. Identification of the best therapeutic target(s) for ABMR still remains largely elusive. We therefore aimed to elucidate the principal immune cell subtypes in ABMR.
Methods: We used unbiased microarray transcriptomic analyses in the BIOMARGIN case-control study (n = 95) and in three publicly available external datasets (n = 985) of kidney transplant biopsies (in total 1080 biopsies). Given the co-occurrence of ABMR and TCMR, we built an innovative bioinformatics pipeline to discriminate ABMR-specific mRNA markers.
Results: Our pipeline showed specific differential expression of 652 ABMR-specific transcripts (503 unique genes). Pathway analysis illustrated enrichment of immune pathways in ABMR, specifically NK cell pathways. Next, we used a recent deconvolution algorithm to estimate the relative fraction of major leukocytes subtypes based on the mRNA transcripts expression. This independent analysis further corroborated the prominent role of activated NK cell transcripts in ABMR in the BIOMARGIN dataset, which was validated in the external cohorts. No other cell type differentiated ABMR from TCMR. The
estimated infiltration of activated NK cells specifically reflected histological lesions of ABMR disease activity (glomerulitis and peritubular capillaritis). Logistic regression analysis showed that activated NK cell infiltration, estimated from the micro-array gene expression data, was highly specific for ABMR vs. no rejection (AUC = 0.92), but also discriminated ABMR from TCMR
(AUC = 0.77).
Conclusion: These thoroughly validated data in 1080 kidney allograft biopsies show that NK cell activation has great potential as therapeutic target in ABMR, and that intrarenal NK cell-specific gene sets could be used as biomarker for ABMR activity.