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Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation.
Kidney Int. 2019 01; 95(1):188-198.KI

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.

Authors+Show Affiliations

Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.CEA, LIST, Laboratory for Data Analysis and Systems' Intelligence, Gif-sur-Yvette, France.Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium.Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.U1111 INSERM, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot University Hospital, Lyon, France.U1111 INSERM, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot University Hospital, Lyon, France; Claude Bernard University (Lyon-1), Lyon, France.U1111 INSERM, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot University Hospital, Lyon, France; Claude Bernard University (Lyon-1), Lyon, France.Department of Development and Regeneration, KU Leuven, Leuven, Belgium.Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.CHU Limoges, Department of Nephrology, Dialysis and Transplantation, University of Limoges, Limoges, France.Department of Nephrology, Hannover Medical School, Hannover, Germany.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.U850 INSERM, University of Limoges, CHU Limoges, Limoges, France.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30396694

Citation

Yazdani, Saleh, et al. "Natural Killer Cell Infiltration Is Discriminative for Antibody-mediated Rejection and Predicts Outcome After Kidney Transplantation." Kidney International, vol. 95, no. 1, 2019, pp. 188-198.
Yazdani S, Callemeyn J, Gazut S, et al. Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. Kidney Int. 2019;95(1):188-198.
Yazdani, S., Callemeyn, J., Gazut, S., Lerut, E., de Loor, H., Wevers, M., Heylen, L., Saison, C., Koenig, A., Thaunat, O., Thorrez, L., Kuypers, D., Sprangers, B., Noël, L. H., Van Lommel, L., Schuit, F., Essig, M., Gwinner, W., Anglicheau, D., ... Naesens, M. (2019). Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. Kidney International, 95(1), 188-198. https://doi.org/10.1016/j.kint.2018.08.027
Yazdani S, et al. Natural Killer Cell Infiltration Is Discriminative for Antibody-mediated Rejection and Predicts Outcome After Kidney Transplantation. Kidney Int. 2019;95(1):188-198. PubMed PMID: 30396694.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. AU - Yazdani,Saleh, AU - Callemeyn,Jasper, AU - Gazut,Stéphane, AU - Lerut,Evelyne, AU - de Loor,Henriette, AU - Wevers,Max, AU - Heylen,Line, AU - Saison,Carole, AU - Koenig,Alice, AU - Thaunat,Olivier, AU - Thorrez,Lieven, AU - Kuypers,Dirk, AU - Sprangers,Ben, AU - Noël,Laure-Hélène, AU - Van Lommel,Leentje, AU - Schuit,Frans, AU - Essig,Marie, AU - Gwinner,Wilfried, AU - Anglicheau,Dany, AU - Marquet,Pierre, AU - Naesens,Maarten, Y1 - 2018/11/03/ PY - 2018/06/13/received PY - 2018/07/26/revised PY - 2018/08/16/accepted PY - 2018/11/7/pubmed PY - 2019/8/20/medline PY - 2018/11/7/entrez KW - antibody-mediated rejection KW - gene expression KW - histology KW - kidney transplantation KW - natural killer cells KW - survival SP - 188 EP - 198 JF - Kidney international JO - Kidney Int. VL - 95 IS - 1 N2 - 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. SN - 1523-1755 UR - https://www.unboundmedicine.com/medline/citation/30396694/Natural_killer_cell_infiltration_is_discriminative_for_antibody_mediated_rejection_and_predicts_outcome_after_kidney_transplantation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0085-2538(18)30630-6 DB - PRIME DP - Unbound Medicine ER -