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.

背景：心脏移植是终末期心力衰竭的有效疗法。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，因此需要鉴定能反映炎症或细胞毒性免疫机制以促进其发作的标志物。高危患者的非侵入性和早期分层仍然是适应个体化治疗的挑战。最近，CD16（Fc-γ受体3A [FCGR3A]）受体被确定为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变中的作用知之甚少。这项研究旨在调查反映CD16依赖性循环NK细胞活化的标记物是否可以鉴定出HT后发展CAV的较高风险的患者。

方法：从103例行常规冠状动脉造影血管造影术的患者中收集血样，以诊断CAV（HT后中位5年）。比较了在CAV阳性（n = 52）和无CAV的患者（n = 51）中FCGR3A / CD16 Fc受体谱的基因组和表型分析。使用非侵入性NK细胞体液活化测试评估了HT受体周围NK细胞的CD16表达水平和利妥昔单抗依赖性细胞杀伤活性。

结果： HT受体的CD16表达水平升高和抗体依赖性NK细胞杀伤细胞功能与FCGR3A-VV基因型相关。的FCGR3A-VV基因型的频率在CAV是显著更高⁺ ;组（比值比，3.9 P比在CAV = 0.0317）^-基团。通过使用多变量逻辑回归模型，将FCGR3A-VV基因型鉴定为与冠状动脉造影时CAV的存在相关的独立标记。FCGR3A-VV基因型也被确定为CAV风险的基线独立预测因子（比值比为4.7；P = 0.023）。

结论：这项研究揭示了CD16依赖的NK细胞激活途径在一系列复杂的因素中的重要作用，这些因素有利于移植动脉硬化的发展。它强调了在CAV风险的早期分层中非侵入性评估FCGR3A / CD16的临床潜力。将CD16识别为控制免疫监视的主要检查点，可能会促进针对NK细胞的个体化治疗方法的设计，以限制高反应性敏化患者的血管损伤。

临床试验注册： URL：https://www.clinicaltrials.gov。唯一标识符：NCT01569334。