Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model

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

doi:10.1097/CM9.0000000000002813

Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model

Chin Med J (Engl). 2023 Nov 14. doi: 10.1097/CM9.0000000000002813. Online ahead of print.

Authors

Xia Qiu^{1

2}, Hedong Zhang², Zhouqi Tang², Yuxi Fan², Wenjia Yuan², Chen Feng², Chao Chen^{1

2}, Pengcheng Cui^{1

2}, Yan Cui^{1

2}, Zhongquan Qi¹, Tengfang Li², Yuexing Zhu^{1

2}, Liming Xie³, Fenghua Peng², Tuo Deng³, Xin Jiang⁴, Longkai Peng^{2

3}, Helong Dai^{1

2

4}

Affiliations

¹ Medical College, Guangxi University, Nanning, Guangxi 530004, China.
² Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
³ 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.
⁴ Department of Organ Transplantation, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, Henan 450000, China.

PMID: 37962205
DOI: 10.1097/CM9.0000000000002813

Abstract

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 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 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-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, 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.