Missing Self-Induced Activation of NK Cells Combines with Non-Complement-Fixing Donor-Specific Antibodies to Accelerate Kidney Transplant Loss in Chronic Antibody-Mediated Rejection
- 25 November 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 32 (2), 479-494
- https://doi.org/10.1681/asn.2020040433
Abstract
Background Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules (“missing self”) on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR. Methods and Results Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (n=73, 54%) had a higher risk of transplant failure (P=0.002). Among the remaining patients with complement-independent chronic AMR (n=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (P=0.02). In multivariable analysis, only proteinuria (HR: 7.24; P=0.01) and the presence of missing self (HR: 3.57; P=0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage. Conclusions The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.Keywords
Funding Information
- Agence Nationale de la Recherche (ANR-16-CE17-0007-01)
- Fondation pour la Recherche Médicale (PME20180639518)
This publication has 51 references indexed in Scilit:
- Comparative Survival and Economic Benefits of Deceased Donor Kidney Transplantation and Dialysis in People with Varying Ages and Co-MorbiditiesPLOS ONE, 2012
- Understanding the Causes of Kidney Transplant Failure: The Dominant Role of Antibody-Mediated Rejection and NonadherenceAmerican Journal of Transplantation, 2011
- A Novel Pathway of Chronic Allograft Rejection Mediated by NK Cells and AlloantibodyAmerican Journal of Transplantation, 2011
- Long-Term Renal Allograft Survival in the United States: A Critical ReappraisalAmerican Journal of Transplantation, 2011
- Innate or Adaptive Immunity? The Example of Natural Killer CellsScience, 2011
- Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutationsImmunology, 2011
- NK Cell Transcripts and NK Cells in Kidney Biopsies from Patients with Donor-Specific Antibodies: Evidence for NK Cell Involvement in Antibody-Mediated RejectionAmerican Journal of Transplantation, 2010
- Complement Independent Antibody‐Mediated Endarteritis and Transplant Arteriopathy in MiceAmerican Journal of Transplantation, 2010
- Antibody-Mediated Microcirculation Injury Is the Major Cause of Late Kidney Transplant FailureAmerican Journal of Transplantation, 2009
- Comparison of Mortality in All Patients on Dialysis, Patients on Dialysis Awaiting Transplantation, and Recipients of a First Cadaveric TransplantThe New England Journal of Medicine, 1999