Natural Killer cells (NK) are immune effectors of antibody-dependent cellular cytotoxicity (ADCC). Their role in mediating adverse effects of Donor-specific anti-HLA antibodies (DSA) towards cardiac allograft remains unexplored. We tested whether FcγRIIIa/CD16 Fc-receptor profiles can be associated with coronary artery vasculopathy (CAV). CD16 expression and polymorphism was evaluated in 103 heart transplant recipients (HTR) enrolled at time of coronary angiography. A cellular humoral activation test (NK-CHAT) was designed to monitor NK-cell activation potential of serum samples obtained during longitudinal follow-up in DSA⁺ patients. Serum-driven CD16 engagement towards allogeneic cell targets allowed to quantify activity of sera.

Of 103 patients, 53 were diagnosed as CAV⁺. DSA⁺ patients (18%) had higher rates of CAV compared with DSA^– patients (28 vs 8%, p=0.014). Frequency of the CD16/158VV polymorphic variant (with high-affinity for the Fc Fragment of Ig) was significantly higher in the CAV⁺ group (25 vs 8%), while that of the low-responsive CD16/158FF variant was higher in the CAV^– group (40 vs 7%). Median CD16 expression, analyzed by flowcytometry within peripheral NK cells, was significantly higher in the CAV⁺ group. Multivariate analysis confirmed that CD16 polymorphism and expression remained significantly associated with CAV. When coated on B-cell targets expressing cognate HLA alloantigens, DSA⁺ sera exhibited enhanced capacity to engage CD16 and stimulate NK cell cytotoxic functions in vitro, when analyzed in reference with DSA^– serum samples obtained before immunisation (p<0.0001). Our study suggests that the potential of HTR to mount CD16-dependent cytotoxic responses may condition intensity of cellular humoral responses, when the allograft graft is chronically challenged with DSA. NK-CHAT non-invasive monitoring may allow identification of patients at higher risk to develop CAV when high humoral scores and CD16 responsiveness are detected.

CITATION INFORMATION: Paul P, Picard C, Sampol E, Lyonnet L, Di Cristofaro J, Lano G, Dussol B, Collart F, Sabatier F, Dignat George F, Mouly Bandini A. Natural Killer CD16/FcR Profiles May Associate with Enhanced Humoral Responsiveness in Heart Transplant Recipients with Cardiac Allograft Vasculopathy. Am J Transplant. 2016;16 (suppl 3).

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