Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model
Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model
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在小鼠模型中，同杉碱通过增强调节性T细胞诱导促进同种异体心脏移植接受
DOI：
10.1097/cm9.0000000000002813
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发表时间：
2024-06-20
影响因子：
6.1
通讯作者：
Dai，Helong
中科院分区：
文献类型：
--
作者：
Qiu，Xia;Zhang，Hedong;Dai，Helong
研究背景高三尖杉酯碱（Homoharringtonine，HHT）是一种有效的抗炎、抗病毒、抗肿瘤蛋白质合成抑制剂，已应用于临床。在此，我们探讨了HHT在小鼠心脏移植模型中的治疗效果。方法采用健康C57BL/6小鼠观察HHT在肝脏、肾脏和血液学方面的毒性。构建了小鼠心脏移植模型，并使用 Kaplan-Meier 分析、免疫染色和批量 RNA 测序分析评估了 HHT 延长同种异体移植物存活的潜在机制。体外建立HHT-T细胞串扰模型，进一步验证HHT诱导调节性T细胞（Tregs）分化的分子机制。结果HHT在体外抑制T细胞的活化和增殖，促进其凋亡。 0.5 mg/kg HHT处理10天可显着延长同种异体移植物的平均移植物存活时间，从7天延长至48天（P<0.001），且无非免疫毒性。连续HHT治疗28天后，同种异体移植物具有长期存活。 HHT显着减少了移植物中的淋巴细胞浸润以及脾脏中分泌干扰素-γ的CD4+和CD8+T细胞（P<0.01）。 HHT显着增加外周Treg细胞数量（约20%，P<0.001）和血清白细胞介素（IL）-10水平。 HHT下调T细胞受体（TCR）信号通路相关基因（CD4、H2-Eb1、TRAT1和CD74）的表达，上调IL-10和转化生长因子（TGF）-β通路相关基因和Treg特征基因（CTLA4、Foxp3、CD74和ICOS）的表达。 HHT可增加体外CD4+Foxp3+细胞和Foxp3的表达，并增强诱导性Treg的抑制功能。结论HHT通过减弱TCR信号通路、上调Treg特征基因的表达和IL-10水平，促进Treg细胞分化并增强Treg抑制功能，从而促进小鼠心脏同种异体移植接受。这些发现可能对器官移植接受者具有治疗意义，特别是那些患有病毒感染和恶性肿瘤的接受者，他们需要更合适的抗排斥药物。
BackgroundHomoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.MethodsHealthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan–Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeledex vivoto further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation.ResultsHHT inhibited the activation and proliferation of T cells and promoted their apoptosisex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days (P<0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4+and CD8+T cells in the spleen (P<0.01). HHT significantly increased the number of peripheral Tregs (about 20%,P<0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes (CD4,H2-Eb1,TRAT1, andCD74) and upregulated the expression of IL-10 and transforming growth factor (TGF) -β pathway-related genes and Treg signature genes (CTLA4,Foxp3,CD74, andICOS). HHT increased CD4+Foxp3+cells and Foxp3 expressionex vivo, and it enhanced the inhibitory function of inducible Tregs.ConclusionsHHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.