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.).
Circulation. 2018 Mar 6;137(10):1049-1059. doi: 10.1161/CIRCULATIONAHA.117.030435. Epub 2017 Nov 2.
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.
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.
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; =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; =0.023).
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.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01569334.
心脏移植是治疗终末期心力衰竭的有效方法。由于心脏同种异体移植血管病（CAV）是心脏移植（HT）后晚期死亡的主要原因，因此需要确定反映导致其发生的炎症或细胞毒性免疫机制的标志物。对于适应个体化治疗，非侵入性和早期分层高危患者仍然是一个挑战。最近发现 CD16（Fc-γ 受体 3A[FCGR3A]）受体是 HT 活检中抗体介导的自然杀伤（NK）细胞激活的主要决定因素；然而，关于 CD16 在促进同种异体血管病中的作用知之甚少。本研究旨在探讨反映 CD16 依赖性循环 NK 细胞激活的标志物是否可以识别 HT 后发生 CAV 风险较高的患者。
收集 103 例行 CAV 诊断的 HT 患者（HT 后中位 5 年）的血样。比较 CAV 阳性（n=52）和 CAV 阴性（n=51）患者的 FCGR3A/CD16 Fc 受体谱的基因组和表型分析。使用非侵入性 NK 细胞体液激活试验评估 HT 受者外周 NK 细胞的 CD16 表达和利妥昔单抗依赖性细胞细胞毒性。
HT 受者 CD16 表达和抗体依赖性 NK 细胞细胞毒性增强与 FCGR3A-VV 基因型相关。CAV 组 FCGR3A-VV 基因型的频率明显高于 CAV 组（比值比，3.9；=0.0317）。使用多变量逻辑回归模型，FCGR3A-VV 基因型被确定为与冠状动脉造影时 CAV 存在相关的独立标志物。FCGR3A-VV 基因型也是 CAV 风险的基线独立预测因子（比值比，4.7；=0.023）。
本研究揭示了 CD16 依赖性 NK 细胞激活途径在促进移植动脉硬化复杂因素中的重要作用。它突出了非侵入性评估 FCGR3A/CD16 在 CAV 风险早期分层中的临床潜力。识别 CD16 作为控制免疫监视的主要检查点可能会促进设计针对 NK 细胞的个体化治疗方法，以限制高反应性致敏患者的血管损伤。
