Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-03, Vol.137 (10), p.1049-1059
• Main Authors: Paul, Pascale, Picard, Christophe, Sampol, Emmanuelle, Lyonnet, Luc, Di Cristofaro, Julie, Paul-Delvaux, Louise, Lano, Guillaume, Nicolino-Brunet, Corinne, Ravis, Eleonore, Collart, Frederic, Dignat-George, Francoise, Dussol, Bertrand, Sabatier, Florence, Mouly-Bandini, Annick
• Format: Article
• Language: English
• Subjects: Adult; Cardiology and cardiovascular system; Coronary Vessels - immunology; Cytotoxicity, Immunologic; Genotype; Graft Rejection - diagnosis; Graft Rejection - immunology; Heart Transplantation; Human health and pathology; Humans; Immunology; Immunophenotyping; Killer Cells, Natural - immunology; Life Sciences; Lymphocyte Activation; Male; Middle Aged; Precision Medicine; Predictive Value of Tests; Prognosis; Receptors, IgG - genetics; Receptors, IgG - metabolism; Rituximab - metabolism; Transplantation, Homologous
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.117.030435

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:URLhttps://www.clinical