Assistance Publique-Hôpitaux Marseille (AP-HM), Vascular Biology and Cell Therapy Department, France (P.P., L.L., C.N.B., F.D.G., F.S.).INSERM, Aix-Marseille Université (AMU), VRCM, UMR-1076, France (P.P., F.D.G., F.S.).Immunogenetic Laboratory, Établissement Français du Sang, Marseille, France (C.P.).Aix Marseille Université, Etablissement Français du Sang, CNRS, UMR 7268 ADÉS, France (C.P., J.D.C.).Assistance Publique-Hôpitaux Marseille (AP-HM), Pharmacokinetics Department, France (E.S.).ENSAE-Paristech, Data Science & Statistics Department, Paris, France (L.P.-D.).Assistance Publique-Hôpitaux Marseille (AP-HM), Aix Marseille Univ, Center for Clinical Investigation, France (G.L., B.D.).Assistance Publique Hopitaux de Marseille (AP-HM), Adult Cardiac Surgery Department, France (E.R., F.C., A.M.B.).
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Background:Cardiac transplantation is an effective therapy for end-stage heart failure. Because cardiac allograft vasculopathy (CAV) is the major cause of late mortality after heart transplant (HT), there is a need to identify markers that reflect inflammatory or cytotoxic immune mechanisms contributing to its onset. Noninvasive and early stratification of patients at risk remains a challenge for adapting individualized therapy. The CD16 (Fc-gamma receptor 3A [FCGR3A]) receptor was recently identified as a major determinant of antibody-mediated natural killer (NK) cell activation in HT biopsies; however, little is known about the role of CD16 in promoting allograft vasculopathy. This study aimed to investigate whether markers that reflect CD16-dependent circulating NK cell activation may identify patients at higher risk of developing CAV after HT.Methods:Blood samples were collected from 103 patients undergoing routine coronarography angiography for CAV diagnosis (median 5 years since HT). Genomic and phenotypic analyses of FCGR3A/CD16 Fc-receptor profiles were compared in CAV-positive (n=52) and CAV-free patients (n=51). The levels of CD16 expression and rituximab-dependent cell cytotoxic activity of peripheral NK cells in HT recipients were evaluated using a noninvasive NK-cellular humoral activation test.Results:Enhanced levels of CD16 expression and antibody-dependent NK cell cytotoxic function of HT recipients were associated with the FCGR3A-VV genotype. The frequency of the FCGR3A-VV genotype was significantly higher in the CAV+ group (odds ratio, 3.9; P=0.0317) than in the CAV- group. The FCGR3A-VV genotype was identified as an independent marker correlated with the presence of CAV at the time of coronary angiography by using multivariate logistic regression models. The FCGR3A-VV genotype was also identified as a baseline-independent predictor of CAV risk (odds ratio, 4.7; P=0.023).Conclusions:This study unravels a prominent role for the CD16-dependent NK cell activation pathway in the complex array of factors that favor the progression of transplant arteriosclerosis. It highlights the clinical potential of a noninvasive evaluation of FCGR3A/CD16 in the early stratification of CAV risk. The recognition of CD16 as a major checkpoint that controls immune surveillance may promote the design of individualized NK cell–targeted therapies to limit vascular damage in highly responsive sensitized patients.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT01569334.