首页|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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Background:Homoharringtonine(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.Methods:Healthy C57BU6 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 modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells(Tregs)differentiation.Results:HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex 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-y-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,and CD74)and upregulated the expression of IL-10 and transforming growth factor(TGF)-β pathway-related genes and Treg signature genes(CTLA4,Foxp3,CD74,and ICOS).HHT increased CD4+Foxp3+cells and Foxp3 expression ex vivo,and it enhanced the inhibitory function of inducible Tregs.Conclusions:HHT 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.

Heart transplantationHomoharringtonineImmunosuppressive agentsT-lymphocytes,RegulatoryGraft acceptance

Xia Qiu、Hedong Zhang、Zhouqi Tang、Yuxi Fan、Wenjia Yuan、Chen Feng、Chao Chen、Pengcheng Cui、Yan Cui、Zhongquan Qi、Tengfang Li、Yuexing Zhu、Liming Xie、Fenghua Peng、Tuo Deng、Xin Jiang、Longkai Peng、Helong Dai

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Medical College,Guangxi University,Nanning,Guangxi 530004,China

Department of Kidney Transplantation,Center of Organ Transplantation,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China

National Clinical Research Center for Metabolic Diseases,and Department of Metabolism and Endocrinology,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China

Department of Organ Transplantation,The Fifth Clinical Medical College of Henan University of Chinese Medicine(Zhengzhou People's Hospital),Zhengzhou,Henan 450000,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of Chinascience and Technology Innovation Program of Hunan ProvinceNatural Science Foundation of Hunan ProvinceNatural Science Foundation of Hunan Province

82070776819003708197065582270796822008492022RC30712021JJ309462022JJ30808

2024

10.1097/CM9.0000000000002813

中华医学杂志(英文版)
中华医学会

中华医学杂志(英文版)

CSTPCD
影响因子：0.838
ISSN：0366-6999
年,卷(期)：2024.137(12)
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