title: Antibody-Dependent NK Cell Activation Is Associated with Late Kidney Allograft Dysfunction and the Complement-Independent Alloreactive Potential of Donor-Specific Antibodies.
abstract: Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs). The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR) of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK) cells as innate immune effectors of antibody-dependent cellular cytotoxicity (ADCC), but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT) was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1(+) cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years). Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate over a 1-year period (hazard ratio: 2.83). In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration of immunosuppressive treatments, robust ADCC responsiveness can be maintained in some KTRs. Because it evaluates both the Fab recognition of alloantigens and Fc-driven NK cell activation, the NK-CHAT represents a potentially valuable tool for the non-invasive and individualized evaluation of humoral risk during transplantation.
authors: Nephrology Dialysis Renal Transplantation Center, Assistance Publique des Hôpitaux de Marseille, Hospital de la Conception , Marseille , France.
authors: Tristan
authors: T
authors: Legris
authors: Établissement Français du Sang Alpes Méditerranée, Marseille, France; ADES UMR 7268, CNRS, EFS, Aix-Marseille Université, Marseille, France.
authors: Christophe
authors: C
authors: Picard
authors: UMR 1076, Vascular Research Center of Marseille, INSERM, Aix-Marseille University , Marseille , France.
authors: Dilyana
authors: D
authors: Todorova
authors: Hematology Unit, Assistance Publique des Hôpitaux de Marseille, Hopital de la Conception , Marseille , France.
authors: Luc
authors: L
authors: Lyonnet
authors: Hematology Unit, Assistance Publique des Hôpitaux de Marseille, Hopital de la Conception , Marseille , France.
authors: Cathy
authors: C
authors: Laporte
authors: Hematology Unit, Assistance Publique des Hôpitaux de Marseille, Hopital de la Conception , Marseille , France.
authors: Chloé
authors: C
authors: Dumoulin
authors: Hematology Unit, Assistance Publique des Hôpitaux de Marseille, Hopital de la Conception , Marseille , France.
authors: Corinne
authors: C
authors: Nicolino-Brunet
authors: Laboratory for Anatomy, Pathology, Neuropathology, Hôpital de la Timone, Aix-Marseille University , Marseille , France.
authors: Laurent
authors: L
authors: Daniel
authors: Unité d'Aide méthodologique à la Recherche Clinique et Epidémiologique, DRRC, Assistance Publique Hôpitaux de Marseille , Marseille , France.
authors: Anderson
authors: A
authors: Loundou
authors: Centre d'Investigation Clinique, Hôpital de la Conception , Marseille , France.
authors: Sophie
authors: S
authors: Morange
authors: Nephrology Dialysis Renal Transplantation Center, Assistance Publique des Hôpitaux de Marseille, Hospital de la Conception , Marseille , France.
authors: Stanislas
authors: S
authors: Bataille
authors: Nephrology Dialysis Renal Transplantation Center, Assistance Publique des Hôpitaux de Marseille, Hospital de la Conception , Marseille , France.
authors: Henri
authors: H
authors: Vacher-Coponat
authors: Nephrology Dialysis Renal Transplantation Center, Assistance Publique des Hôpitaux de Marseille, Hospital de la Conception , Marseille , France.
authors: Valérie
authors: V
authors: Moal
authors: Nephrology Dialysis Renal Transplantation Center, Assistance Publique des Hôpitaux de Marseille, Hospital de la Conception , Marseille , France.
authors: Yvon
authors: Y
authors: Berland
authors: UMR 1076, Vascular Research Center of Marseille, INSERM, Aix-Marseille University, Marseille, France; Hematology Unit, Assistance Publique des Hôpitaux de Marseille, Hopital de la Conception, Marseille, France.
authors: Francoise
authors: F
authors: Dignat-George
authors: Nephrology Dialysis Renal Transplantation Center, Assistance Publique des Hôpitaux de Marseille, Hospital de la Conception, Marseille, France; UMR 1076, Vascular Research Center of Marseille, INSERM, Aix-Marseille University, Marseille, France.
authors: Stéphane
authors: S
authors: Burtey
authors: UMR 1076, Vascular Research Center of Marseille, INSERM, Aix-Marseille University, Marseille, France; Hematology Unit, Assistance Publique des Hôpitaux de Marseille, Hopital de la Conception, Marseille, France.
authors: Pascale
authors: P
authors: Paul
keywords: antibody-dependent cellular cytotoxicity; antibody-mediated rejection; donor-specific antibodies; kidney transplantation; natural killer cells