Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase
Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase
复制标题
通过抑制 mTOR 和 HMG-CoA 还原酶，干扰素 γ 诱导的内皮细胞上的 HLA II 类表达降低
DOI：
10.1002/2211-5463.12854
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Kobayashi T
中科院分区：
文献类型：
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作者：
Maenaka A;Kenta I;Ota A;Miwa Y;Ohashi W;Horimi K;Matsuoka Y;Ohnishi M; Uchida K;Kobayashi T
在器官移植中，供者特异性的人类白细胞抗原抗体(DSA)被认为是造成移植排斥反应的主要原因。由于DSA主要针对移植物内皮细胞上表达的供者特异性人类白细胞抗原(HLA)，因此阻止其表达是避免或挽救DSA介导的移植物排斥反应的一种可能的策略。我们检测了不同临床用药对内皮细胞表达HLAII类分子的影响。干扰素-γ(干扰素-γ)诱导的人类白细胞抗原-DR(HLADR)被伊维莫司(EVR)和氟伐他汀(Flu，33.8%±100.6%；P<；0.01)下调。此外，EVR和Flu联合应用对人类白细胞抗原-DR的表达有较大的抑制作用。相比之下，环孢素、他克莫司、霉酚酸和强的松龙没有表现出任何明显的抑制作用。图像分析显示，HLADR在胞浆或细胞表面的表达受到EVR(胞浆：58.6%±44.9%，P<；0.01；细胞表面：80.9%±24.0%，P<；0.01)和Flu(胞液：19.0%±33.4%，P<；0.01；细胞表面：48.3%±24.8%，P<；0.01)的抑制。这些数据表明，Flu和EVR分别在转录和翻译后水平抑制了干扰素-γ诱导的人类白细胞抗原-DR的表达，提示了一种潜在的缓解器官移植中DSA相关问题的方法。
In organ transplantation, donor‐specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor‐specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvaging DSA‐mediated graft rejection. We examined the effect of various clinically used drugs on HLA class II expression on endothelial cells. Interferon‐γ (IFN‐γ)‐induced HLA class II DR (HLA‐DR) was downregulated by everolimus (EVR, 49.1% ± 0.8%;P< 0.01) and fluvastatin (FLU, 33.8% ± 0.6%;P< 0.01). Moreover, the combination of EVR and FLU showed a greater suppressive effect on HLA‐DR expression. In contrast, cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA‐DR. Imaging analysis revealed that HLA‐DR expressed in cytosol or on the cell surface was repressed by EVR (cytosol: 58.6% ± 4.9%,P< 0.01; cell surface: 80.9% ± 4.0%,P< 0.01) and FLU (cytosol: 19.0% ± 3.4%,P< 0.01; cell surface: 48.3% ± 4.8%,P< 0.01). These data indicated that FLU and EVR suppressed IFN‐γ‐induced HLA‐DR expression at the transcriptional and post‐translational level, respectively, suggesting a potential approach for alleviating DSA‐related issues in organ transplantation.