BACKGROUND Acute rejection is one of the most important direct contributors to mortality after heart transplantation. Advances in the development of novel non-invasive approaches for the early identification of allograft rejection are necessary. We conducted a non-targeted proteome characterization focused on identifying multiple plasmatic protein differences to evaluate their diagnostic accuracy for rejection episodes. METHODS We included consecutive plasma samples from transplant recipients undergoing routine endomyocardial biopsies. A liquid chromatography-tandem mass spectrometry analysis using isobaric tags (tandem mass tag 10-plex) was performed and concentrations of CD5L were validated using a specific sandwich enzyme-linked immunosorbent assay. RESULTS A total of 17 altered proteins were identified as potential markers for detecting heart transplant rejection, most involved in inflammation and immunity. CD5L, an apoptosis inhibitor expressed by macrophages, showed the best results in the proteomic analysis (n = 30). We confirm this finding in a larger patient cohort (n = 218), obtaining a great diagnostic capacity for clinically relevant rejection (≥Grade 2R: area under the curve = 0.892, p < 0.0001) and preserving the accuracy at mild rejection (Grade 1R: area under the curve = 0.774, p < 0.0001). CD5L was a strong independent predictor, with an odds ratio of 14.74 (p < 0.0001), for the presence of rejection. CONCLUSIONS Episodes of acute cardiac allograft rejection are related to significant changes in a key inhibitor of apoptosis in macrophages, CD5L. Because of its precision to detect acute cellular rejection, even at mild grade, we propose CD5L as a potential candidate to be included in the studies of molecule combination panel assays. This finding could contribute to improving the diagnostic and preventive methods for the surveillance of cardiac transplanted patients.

中文翻译：

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血浆CD5L和无创性诊断为急性心脏排斥反应。

背景技术急性排斥反应是导致心脏移植后死亡率的最重要的直接因素之一。早期开发同种异体移植排斥反应的新型非侵入性方法的发展是必要的。我们进行了非目标蛋白质组表征，重点是鉴定多种血浆蛋白差异，以评估其对排斥反应的诊断准确性。方法我们纳入了接受常规心内膜活检的移植受者的连续血浆样本。进行了使用等压标签（串联质谱标签10-plex）的液相色谱-串联质谱分析，并使用特定的夹心酶联免疫吸附测定法验证了CD5L的浓度。结果总共鉴定出17种改变的蛋白作为检测心脏移植排斥反应的潜在标志物，其中大多数与炎症和免疫有关。CD5L是一种由巨噬细胞表达的凋亡抑制剂，在蛋白质组学分析中显示出最好的结果（n = 30）。我们在更大的患者队列（n = 218）中证实了这一发现，获得了对临床相关排斥的强大诊断能力（≥2R级：曲线下面积= 0.892，p <0.0001），并保留了轻度排斥时的准确性（1R级） ：曲线下的面积＝ 0.774，p ＜0.0001）。CD5L是有力的独立预测因子，存在排斥反应的比值比为14.74（p <0.0001）。结论急性同种异体心脏移植排斥反应的发生与巨噬细胞CD5L凋亡关键抑制剂的显着变化有关。由于其即使在轻度条件下也能检测急性细胞排斥的精度，因此我们建议CD5L作为可能的候选物包括在分子组合检测中。这一发现可能有助于改善用于监测心脏移植患者的诊断和预防方法。