Palaniyandi Senthilnathan, Kumari Reena, Strattan Ethan, Huang Timothy, Kohler Katharina, Du Jing, Jabbour Nashwan, Kesler Melissa, Hildebrandt Gerhard C
Division of Hematology and Medical Oncology, Department of Medicine, Ellis Fischel Cancer Center, University of Missouri, Columbia, Missouri; Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
Division of Hematology & Blood and Marrow Transplantation, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
Transplant Cell Ther. 2023 Oct;29(10):608.e1-608.e9. doi: 10.1016/j.jtct.2023.07.023. Epub 2023 Jul 28.
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vascular endothelial cells are entirely exposed and damaged during the pathogenesis of acute GVHD (aGVHD). Defibrotide (DF) is a mixture of single-stranded oligonucleotides that has several pharmacologic effects that contribute to its endothelial protective properties. B10.BR mice were conditioned, followed by the infusion of donor C57BL/6J T cell-depleted bone marrow cells with or without splenocytes. The mice were either treated with DF or appropriate controls daily for the first week and then 3 times per week thereafter. Allogeneic DF-treated recipients demonstrated significantly better survival with reduced clinical GVHD. Significantly reduced organ pathology in the gut was associated with significantly decreased T cell infiltration in the ileum and colon on day +28. Serum cytokine analysis revealed significantly reduced levels of TNF and IL-6 at day +7 and of TNF at day +28 in allogeneic DF-treated recipients. Significantly reduced levels of ICAM-1 and angiopoietin-2 in serum and reduced VCAM-1 and HCAM levels in the ileum and colon of allogeneic DF-treated recipients were observed. Improved survival was seen in the graft-versus-leukemia (GVL) model (C3H.SW into C57BL/6J mice with C1498-luc). Through its anti-inflammatory and endothelial protective effects, DF treatment reduces the severity of aGVHD while not impairing GVL activity.
移植物抗宿主病（GVHD）是异基因造血干细胞移植（allo-HSCT）的主要并发症。在急性移植物抗宿主病（aGVHD）发病过程中，血管内皮细胞完全暴露并受损。去纤苷（DF）是一种单链寡核苷酸混合物，具有多种药理作用，有助于其内皮保护特性。对B10.BR小鼠进行预处理，然后输注有或无脾细胞的供体C57BL/6J T细胞去除的骨髓细胞。在第一周，小鼠每天接受DF或适当对照治疗，此后每周3次。接受同种异体DF治疗的受体生存率显著提高，临床GVHD减轻。在第28天，肠道器官病理显著减轻与回肠和结肠T细胞浸润显著减少相关。血清细胞因子分析显示，在第7天，接受同种异体DF治疗的受体中TNF和IL-6水平显著降低，在第28天，TNF水平显著降低。观察到接受同种异体DF治疗的受体血清中ICAM-1和血管生成素-2水平显著降低，回肠和结肠中VCAM-1和HCAM水平降低。在移植物抗白血病（GVL）模型（将C3H.SW小鼠移植到带有C1498-luc的C57BL/6J小鼠中）中观察到生存率提高。通过其抗炎和内皮保护作用，DF治疗降低了aGVHD的严重程度，同时不损害GVL活性。
