Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model
10.1097/CM9.0000000000002813
- VernacularTitle:Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model
- Author:
Xia QIU
1
;
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
Author Information
1. Medical College, Guangxi University, Nanning, Guangxi 530004, China
- Keywords:
Heart transplantation;
Homoharringtonine;
Immunosuppressive agents;
T-lymphocytes, Regulatory;
Graft acceptance
- From:
Chinese Medical Journal
2024;137(12):1453-1464
- CountryChina
- Language:Chinese
-
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.
