Organ Transplantation Research Institute of Sun Yat-sen University, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Medical Ultrasound, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
EBioMedicine. 2018 Nov;37:236-245. doi: 10.1016/j.ebiom.2018.10.061. Epub 2018 Oct 29.
C4d is a specific biomarker for the diagnosis of antibody-mediated rejection (AMR) after cardiac transplantation. Although strongly recommended, routine C4d surveillance is hindered by the invasive nature of endomyocardial biopsy. Targeted ultrasound (US) has high sensitivity, and C4d is abundantly expressed within the graft of patients experiencing AMR, which makes it possible to visualize C4d deposition in vivo using targeted US.
We designed a serial dilution of C4d-targeted microbubbles (MB) using a streptavidin-biotin conjugation system. A rat model of AMR with C4d deposition was established by pre-sensitization with skin transplantation before cardiac transplantation. MB were injected into recipients and then qualitatively and quantitatively analyzed using the destruction-replenishment method with a clinical US imaging system and analyzed by software.
We successfully obtained qualitative images of C4d deposition in a wide cardiac allograft section, which, for the first time, reflected real-time C4d distribution. Moreover, normal intensity difference was used for quantitative analysis and exhibited an almost nearly linear correlation with the grade of C4d deposition according to the pathologic evidence. In addition, MB injection did not affect the survival and aggravate injury, which demonstrates its safety.
This study demonstrates a noninvasive, quantitative and safe evaluation method for C4d. As contrast-enhanced US has been widely used in clinical settings, this technology is expected to be applied quickly to clinical practice. FUND: National Natural Science Foundation of China and Guangdong Province, Leading Scientific Talents of Guangdong special support program, the Science and Technology Project of Guangdong Province and Guangzhou City.
C4d 是心脏移植后诊断抗体介导排斥反应（AMR）的特定生物标志物。尽管强烈推荐，但由于心内膜活检的侵袭性，常规 C4d 监测受到阻碍。靶向超声（US）具有很高的灵敏度，并且在经历 AMR 的移植物中 C4d 大量表达，这使得使用靶向 US 体内可视化 C4d 沉积成为可能。
我们使用链霉亲和素-生物素缀合系统设计了一系列 C4d 靶向微泡（MB）的稀释液。通过在心脏移植前进行皮肤移植预致敏，建立了 AMR 伴有 C4d 沉积的大鼠模型。将 MB 注入受者体内，然后使用临床 US 成像系统的破坏-补充法进行定性和定量分析，并通过软件进行分析。
我们成功地获得了心脏移植物整个宽段 C4d 沉积的定性图像，这首次反映了实时 C4d 分布。此外，正常强度差异用于定量分析，并根据病理证据与 C4d 沉积程度表现出几乎线性相关。此外，MB 注射不会影响存活并加重损伤，这证明其安全性。
本研究证明了一种非侵入性、定量和安全的 C4d 评估方法。由于对比增强超声已广泛应用于临床环境，因此预计该技术将很快应用于临床实践。
国家自然科学基金和广东省、广东省和广州市科技项目、广东省领军人才特殊支持计划。
