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Kidney Int. 2019 Jan;95(1):188-198. doi: 10.1016/j.kint.2018.08.027. Epub 2018 Nov 3.

Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation.

Author information

1
Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
2
CEA, LIST, Laboratory for Data Analysis and Systems' Intelligence, Gif-sur-Yvette, France.
3
Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium.
4
Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
5
U1111 INSERM, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot University Hospital, Lyon, France.
6
U1111 INSERM, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot University Hospital, Lyon, France; Claude Bernard University (Lyon-1), Lyon, France.
7
Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
8
Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
9
Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
10
CHU Limoges, Department of Nephrology, Dialysis and Transplantation, University of Limoges, Limoges, France.
11
Department of Nephrology, Hannover Medical School, Hannover, Germany.
12
Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France; Paris Descartes, Sorbonne Paris Cité University, Paris, France; Department of Nephrology and Kidney Transplantation, RTRS Centaure, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
13
U850 INSERM, University of Limoges, CHU Limoges, Limoges, France.
14
Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. Electronic address: maarten.naesens@uzleuven.be.

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

PMID:
30396694
DOI:
10.1016/j.kint.2018.08.027
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