Transplantation Unit, Renal Division, Department of Medicine, University Health Center of Quebec, Faculty of Medicine, Laval University, Québec, QC, Canada.
Department of Medicine, University Health Center of Quebec, Faculty of Medicine, Laval University, Québec, QC, Canada.
Am J Transplant. 2018 Sep;18(9):2314-2321. doi: 10.1111/ajt.14944. Epub 2018 Jun 11.
Little is known about the endothelial injury caused directly by circulating donor-specific antibodies (DSAs) during antibody-mediated rejection. von Willebrand factor (vWF) is a highly thrombotic glycoprotein stored in Weibel-Palade bodies in endothelial cells. It has been shown that its secretion is triggered by allostimulation. Calcineurin-like phosphatases regulate pathways involved in vWF secretion. Therefore, we hypothesized that tacrolimus would prevent alloantibody-induced glomerular lesions, in part via inhibition of vWF secretion from endothelial cells. Here, we used a human in vitro model of glomerular endothelium expressing HLA class I and II antigens and demonstrated that anti-HLA class II antibodies elicit a higher endothelial release of vWF than do anti-HLA class I antibodies in cell supernatants. We observed that tacrolimus treatment decreased vWF secretion after stimulation with both classes of anti-HLA antibodies and decreased platelet adhesion on allostimulated endothelial cells in a microfluidic chamber. In kidney recipients, tacrolimus trough levels were negatively associated with vWF blood levels. These results indicate that direct disruption of hemostasis via vWF secretion is a potential mechanism of antibody-mediated injury in patients with DSAs. Our results further suggest that the targeting of microcirculation hemostasis may be beneficial to prevent the development of microangiopathic lesions in antibody-mediated rejection.
关于循环供体特异性抗体（DSA）在抗体介导的排斥反应中直接引起的内皮损伤，目前知之甚少。血管性血友病因子（vWF）是一种高度血栓形成的糖蛋白，储存在血管内皮细胞的 Weibel-Palade 小体中。已经表明，它的分泌是由同种异体刺激触发的。钙调神经磷酸酶样磷酸酶调节 vWF 分泌途径。因此，我们假设他克莫司将通过抑制内皮细胞 vWF 的分泌，部分预防同种抗体诱导的肾小球病变。在这里，我们使用表达 HLA Ⅰ类和Ⅱ类抗原的人肾小球内皮体外模型，证明与抗 HLA Ⅰ类抗体相比，抗 HLA Ⅱ类抗体在细胞上清液中引起更高的内皮 vWF 释放。我们观察到，他克莫司治疗可降低两类抗 HLA 抗体刺激后 vWF 的分泌，并在微流控室中降低同种刺激的内皮细胞上的血小板黏附。在肾移植受者中，他克莫司谷浓度与 vWF 血浓度呈负相关。这些结果表明，通过 vWF 分泌直接破坏止血是 DSA 患者抗体介导损伤的潜在机制。我们的结果进一步表明，针对微循环止血的靶向治疗可能有益于预防抗体介导排斥反应中微血管病变的发生。
