Werner I, Bogert N V, Stock U A, Moritz A, Beiras-Fernandez A
Department of Thoracic and Cardiovascular Surgery, Johann Wolfgang Goethe University Hospital, Frankfurt/Main, Germany.
Department of Thoracic and Cardiovascular Surgery, Johann Wolfgang Goethe University Hospital, Frankfurt/Main, Germany.
Transplant Proc. 2014 Nov;46(9):2953-6. doi: 10.1016/j.transproceed.2014.06.055.
Polyclonal anti-thymocyte globulins (ATGs) and anti-CD25 antibodies are agents used for induction of immunosuppression in solid-organ transplantation. We aimed to investigate the effect of different regimens of these immunosuppressive induction agents on transendothelial migration of peripheral blood mononuclear cells (PBMC) and evaluated the endothelial apoptosis after treatment.
Human microvascular endothelial cells were either activated with tumor necrosis factor-α/interferon-γ or not and further treated with 25 or 125 μg/mL ATG (Thymoglobulin, Sanofi-Aventis, Germany) for 2 hours or 24 hours, or with 5 μg/mL Basiliximab (Simulect, Novartis, Germany) for 2 hours or 24 hours. PBMC were either activated with phytohaemagglutinin (PHA) or not and further treated with 25 or 125 μg/mL ATG or with 5 μg/mL Basiliximab for 2 h and then used for transendothelial migration assays. Apoptosis of endothelial cells was detected by means of Annexin-V staining after 2-hour incubation with either 25 or 125 μg/mL ATG or 5 μg/mL Basiliximab.
Prophylactic 24-hour administration of ATG to naive endothelial cells without PBMC treatment reduced transendothelial migration. Prophylactic 24-hour administration of ATG and Basiliximab to naive endothelial cells after PBMC treatment with the same agents reduced the transendothelial migration after 24 hours. In both cases, no effect could be observed after 2-hour treatment. Basiliximab but not ATG showed a reduction of transmigration after 2-hour treatment of PBMCs without naive EC treatment. Apoptosis of endothelial cells after treatment increased in both cases, being in case of ATG dose-dependent, increasing from 1.2% after either 25 μg/mL ATG to 8.7% after 125 μg/mL ATG.
Immunosuppressive induction agents modulate the endothelial activity in a dose- and time-dependent manner. Our results suggest that administration of induction agents over longer time periods could provide a potential benefit regarding endothelial immunomodulation. Increased doses may, however, show a deleterious effect on endothelial survival.
多克隆抗胸腺细胞球蛋白（ATG）和抗CD25抗体是实体器官移植中用于诱导免疫抑制的药物。我们旨在研究这些免疫抑制诱导药物的不同方案对外周血单个核细胞（PBMC）跨内皮迁移的影响，并评估治疗后的内皮细胞凋亡情况。
人微血管内皮细胞分别用肿瘤坏死因子-α/干扰素-γ激活或未激活，再用25或125μg/mL ATG（德国赛诺菲-安万特公司的即复宁）处理2小时或24小时，或用5μg/mL巴利昔单抗（德国诺华公司的舒莱）处理2小时或24小时。PBMC分别用植物血凝素（PHA）激活或未激活，再用25或125μg/mL ATG或5μg/mL巴利昔单抗处理2小时，然后用于跨内皮迁移试验。在用25或125μg/mL ATG或5μg/mL巴利昔单抗孵育2小时后，通过膜联蛋白-V染色检测内皮细胞凋亡情况。
在未处理PBMC的情况下，对未激活的内皮细胞预防性给予24小时ATG可减少跨内皮迁移。在用相同药物处理PBMC后，对未激活的内皮细胞预防性给予24小时ATG和巴利昔单抗可在24小时后减少跨内皮迁移。在这两种情况下，2小时处理后均未观察到效果。在未处理未激活内皮细胞的情况下，对PBMC进行2小时处理后巴利昔单抗而非ATG显示出迁移减少。两种情况下处理后内皮细胞凋亡均增加，ATG呈剂量依赖性，从25μg/mL ATG后的1.2%增加到125μg/mL ATG后的8.7%。
免疫抑制诱导药物以剂量和时间依赖性方式调节内皮细胞活性。我们的结果表明，较长时间给予诱导药物可能在内皮免疫调节方面具有潜在益处。然而，剂量增加可能对内皮细胞存活产生有害影响。
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