Pascale Paul1,2, Christophe Picard3,4, Emmanuelle Sampol5, Luc Lyonnet6, Julie Di Cristofaro5, Louise Paul-Delvaux7, Guillaume Lano8, Corinne Nicolino-Brunet6, Eleonore Ravis9, Frederic Collart9, Francoise Dignat-George6,2, Bertrand Dussol8, Florence Sabatier6,2, Annick Mouly-Bandini9. 1. 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.). pascale.paul@univ-amu.fr. 2. INSERM, Aix-Marseille Université (AMU), VRCM, UMR-1076, France (P.P., F.D.G., F.S.). 3. Immunogenetic Laboratory, Établissement Français du Sang, Marseille, France (C.P.). 4. Aix Marseille Université, Etablissement Français du Sang, CNRS, UMR 7268 ADÉS, France (C.P., J.D.C.). 5. Assistance Publique-Hôpitaux Marseille (AP-HM), Pharmacokinetics Department, France (E.S.). 6. 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.). 7. ENSAE-Paristech, Data Science & Statistics Department, Paris, France (L.P.-D.). 8. Assistance Publique-Hôpitaux Marseille (AP-HM), Aix Marseille Univ, Center for Clinical Investigation, France (G.L., B.D.). 9. Assistance Publique Hopitaux de Marseille (AP-HM), Adult Cardiac Surgery Department, France (E.R., F.C., A.M.B.).
Abstract
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.
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-freepatients (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.
Authors: Amandine Pradier; Maria Papaserafeim; Ning Li; Anke Rietveld; Charlotte Kaestel; Lyssia Gruaz; Cédric Vonarburg; Rolf Spirig; Gisella L Puga Yung; Jörg D Seebach Journal: Front Immunol Date: 2019-03-27 Impact factor: 7.561
Authors: Niken M Mahaweni; Timo I Olieslagers; Ivan Olivares Rivas; Stefan J J Molenbroeck; Mathijs Groeneweg; Gerard M J Bos; Marcel G J Tilanus; Christina E M Voorter; Lotte Wieten Journal: Sci Rep Date: 2018-10-29 Impact factor: 4.379