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首页> 美国卫生研究院文献>PLoS Clinical Trials >Halofuginone Synergistically Enhances Anti-Proliferation of Rapamycin in T Cells and Reduces Cytotoxicity of Cyclosporine in Cultured Renal Tubular Epithelial Cells
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Halofuginone Synergistically Enhances Anti-Proliferation of Rapamycin in T Cells and Reduces Cytotoxicity of Cyclosporine in Cultured Renal Tubular Epithelial Cells

机译：halofuginone协同增强雷帕霉素在T细胞中的抗增殖作用，并降低培养的肾小管上皮细胞中环孢菌素的细胞毒性

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Both rapamycin (RAPA) and cyclosporin A (CsA) are commonly used for immunosuppression, however their adverse side effects limit their application. Thus, it is of interest to develop novel means to enhance or preserve the immunosuppressive activity of RAPA or CsA while reducing their toxicity. Halofuginone (HF) has been recently tested as a potential immunosuppressant. This study investigated the interaction of HF with RAPA or with CsA in cell cultures. Cell proliferation in cultures was determined using methylthiazol tetrazolium assay, and cell apoptosis assessed by flow cytometric analysis and Western blot. The drug-drug interaction was determined according to Loewe’s equation or Bliss independence. Here, we showed that addition of HF to anti-CD 3 antibody-stimulated splenocyte cultures induced synergistic suppression of T cell proliferation in the presence of RAPA, indicated by an interaction index (γ) value of < 1.0 between HF and RAPA, but not in those with CsA. The synergistic interaction of RAPA with HF in the suppression of T cell proliferation was also seen in a mixed lymphocyte reaction and Jurkat T cell growth, and was positively correlated with an increase in cell apoptosis, but not with proline depletion. In cultured kidney tubular epithelial cells, HF attenuated the cytotoxicity of CsA. In conclusion, these data indicate that HF synergistically enhances anti-T cell proliferation of RAPA and reduces the nephrotoxicity of CsA in vitro, suggesting the potential use of HF for enhancing anti-T cell proliferation of RAPA and reducing CsA-mediated nephrotoxicity.
机译：雷帕霉素（RAPA）和环孢菌素A（CsA）通常用于免疫抑制，但是它们的不良副作用限制了它们的应用。因此，感兴趣的是开发新的手段来增强或保持RAPA或CsA的免疫抑制活性，同时降低其毒性。卤夫酮（HF）最近已被测试为潜在的免疫抑制剂。这项研究调查了HF与RAPA或CsA在细胞培养物中的相互作用。使用甲基噻唑四唑鎓测定法确定培养物中的细胞增殖，并通过流式细胞术分析和蛋白质印迹评估细胞凋亡。药物相互作用是根据Loewe方程或Bliss独立性确定的。在这里，我们表明，在存在RAPA的情况下，向抗CD 3抗体刺激的脾细胞培养物中添加HF诱导了T细胞增殖的协同抑制作用，这由HF和RAPA之间的相互作用指数（γ）值<1.0表示，但不是在那些有CsA的人中。在混合淋巴细胞反应和Jurkat T细胞生长中，还可以观察到RAPA与HF协同抑制T细胞增殖的作用，并且与细胞凋亡的增加呈正相关，但与脯氨酸的消耗却没有正相关。在培养的肾小管上皮细胞中，HF减弱了CsA的细胞毒性。总之，这些数据表明，HF在体外协同增强了RAPA的抗T细胞增殖并降低了CsA的肾毒性，表明HF在增强RAPA的抗T细胞增殖和降低CsA介导的肾毒性方面的潜在用途。

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