Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy
Background—Cardiac transplantation is an effective therapy for end-stage heart failure. As 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. Non-invasive 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 (FcR) 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 heart transplant recipients (HTRs) were evaluated using a non-invasive NK-cellular humoral activation test (NK-CHAT).
Results—Enhanced levels of CD16 expression and antibody-dependent NK cell cytotoxic function of HTRs were associated with the FCGR3A-VV genotype. The frequency of the FCGR3A-VV genotype was significantly higher in the CAV+ group (odds ratio (OR): 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 using multivariate logistic regression models. The FCGR3A-VV genotype was also identified as a baseline independent predictor of CAV risk (OR: 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 non-invasive 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://clinicaltrials.gov Unique Identifier: NCT01569334
- Natural killer cells
- Fc receptors
- antibody dependent cell cytotoxicity
- Cardiac allograft Vasculopathy
- FCGR3A polymorphism
- heart transplantation
- Received July 8, 2017.
- Revision received October 12, 2017.
- Accepted October 19, 2017.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.