Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation
Saleh Yazdani, Jasper Callemeyn, Stéphane Gazut, Evelyne Lerut, Henriette de Loor, Max Wevers, Line Heylen, Carole Saison, Alice Koenig, Olivier Thaunat, Lieven Thorrez, Dirk Kuypers, Ben Sprangers, Laure-Hélène Noël, Leentje Van Lommel, Frans Schuit, Marie Essig, Wilfried Gwinner, Dany Anglicheau, Pierre Marquet, Maarten Naesens, Saleh Yazdani, Jasper Callemeyn, Stéphane Gazut, Evelyne Lerut, Henriette de Loor, Max Wevers, Line Heylen, Carole Saison, Alice Koenig, Olivier Thaunat, Lieven Thorrez, Dirk Kuypers, Ben Sprangers, Laure-Hélène Noël, Leentje Van Lommel, Frans Schuit, Marie Essig, Wilfried Gwinner, Dany Anglicheau, Pierre Marquet, Maarten Naesens
Abstract
Despite partial elucidation of the pathophysiology of antibody-mediated rejection (ABMR) after kidney transplantation, it remains largely unclear which of the involved immune cell types determine disease activity and outcome. We used microarray transcriptomic data from a case-control study (n=95) to identify genes that are differentially expressed in ABMR. Given the co-occurrence of ABMR and T-cell-mediated rejection (TCMR), we built a bioinformatics pipeline to distinguish ABMR-specific mRNA markers. Differential expression of 503 unique genes was identified in ABMR, with significant enrichment of natural killer (NK) cell pathways. CIBERSORT (Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts) deconvolution analysis was performed to elucidate the corresponding cell subtypes and showed increased NK cell infiltration in ABMR in comparison to TCMR and normal biopsies. Other leukocyte types (including monocytes/macrophages, CD4 and CD8 T cells, and dendritic cells) were increased in rejection, but could not discriminate ABMR from TCMR. Deconvolution-based estimation of NK cell infiltration was validated using computerized morphometry, and specifically associated with glomerulitis and peritubular capillaritis. In an external data set of kidney transplant biopsies, activated NK cell infiltration best predicted graft failure amongst all immune cell subtypes and even outperformed a histologic diagnosis of acute rejection. These data suggest that NK cells play a central role in the pathophysiology of ABMR and graft failure after kidney transplantation.
Keywords: antibody-mediated rejection; gene expression; histology; kidney transplantation; natural killer cells; survival.
Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Source: PubMed