Transforming growth factor (TGF)-β mimics and anti-TGF-β antibody abrogates the in vivo effects of cyclosporine -: Demonstration of a direct role of TGF-β in immunosuppression and nephrotoxicity of cyclosporine
Transforming growth factor (TGF)-β mimics and anti-TGF-β antibody abrogates the in vivo effects of cyclosporine -: Demonstration of a direct role of TGF-β in immunosuppression and nephrotoxicity of cyclosporine
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DOI：
10.1097/00007890-199903270-00016
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发表时间：
1999-03-27
期刊：
影响因子：
6.2
通讯作者：
Hosenpud, JD
中科院分区：
文献类型：
--
作者：
Khanna, AK;Cairns, VR;Hosenpud, JD
背景环孢霉素（CsA）已显示在体外和体内诱导转化生长因子（TGF）-β的表达。假设CsA的疗效以及副作用是由TGF-β介导的。本研究计划调查是否抗TGF-β减轻和TGF-β复制CsA的体内效应，以直接证明这一假设。将B6 AF（1）、（H2（B/k.d））小鼠分组并接受以下物质：CsA、载体（橄榄油）、CsA +抗TGF-β 1抗体、TGF-β 1或载体磷酸盐缓冲盐水/牛血清白蛋白。所有研究均在CsA给药最后一天后10天和28天进行，外源性TGF-β实验除外，其在外源性TGF-β给药后5天进行。通过[H-3]胸苷摄取法检测抗CD 3诱导的脾细胞体外增殖; ELISA法检测TGF-β蛋白水平;逆转录聚合酶链反应（RT-PCR）检测F-P、胶原和纤连蛋白基因表达;高碘酸-希夫和三色C染色肾薄切片进行组织病理学分析。CsA治疗导致离体脾细胞增殖减少，血清中TGF-β蛋白增加，肾组织病理学变化，包括肾小管肿胀，空泡化，血栓性微血管病，TGF-β，胶原和纤连蛋白基因表达增加。抗TGF-β抗体可阻断上述作用。该研究证明了通过操纵TGF-β水平对CsA作用的体内调节，并表明TGF-β至少部分介导CsA的有益和有害作用。
Background. Cyclosporine (CsA) has been shown to induce the expression of transforming growth factor (TGF)-beta both in vitro and in vivo. It is hypothesized that the efficacy as well as the side effects of CsA are mediated by TGF-P. This study was planned to investigate whether anti-TGF-p mitigated and TGF-P reproduced the in vivo effects of CsA to directly prove this hypothesis,Methods. B6AF(1), (H2(b/k.d)) mice were divided into groups and received the following: CsA, vehicle (olive oil), CsA + anti-TGF-pl antibody, TGF-beta 1, or vehicle phosphate-buffered saline/bovine serum albumin. All studies were carried out at 10 and 28 days after the last day of CsA administration with the exception of the exogenous TGF-P experiments, which were performed 5 days after exogenous TGF-P administration. The efficacy was studied by the anti-CD3-induced ex vivo proliferation of splenocytes measured by [H-3]thymidine uptake; TGF-P protein levels were quantified by ELISA, TG;F-P, collagen, and fibronectin gene expression was studied using reverse transcriptasepolymerase chain reaction, and histopathological analysis was made on periodic acid-Schiff- and trichrome C-stained thin kidney sections.Results. CsA treatment resulted in decreased ex vivo proliferation of splenocytes, an increase in TGF-P protein in the sera, and renal histopathological changes including tubular swelling, vacuolization, thrombotic microangiopathy, and increased expression of TGF-P, collagen and fibronectin genes. All of these findings were blocked by anti-TGF-p antibody.Conclusion. The study demonstrates the in vivo modulation of the effects of CsA by manipulating TGF-P levels and suggests that TGF-P at least in part mediates CsA's beneficial and detrimental effects.