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

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.