卡培他滨通过抑制 TYMS 介导的小鼠 Th1 分化来减轻心脏同种异体移植排斥。
Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice.
发表日期:2024 Aug 19
作者:
Dejun Kong, Zhenglu Wang, Hao Wang, Ruining Yang, Weiqi Zhang, Lei Cao, Yeqi Nian, Jiashu Ren, Jianing Lu, Tao Chen, Jinliang Duan, Zhuolun Song, Tao Liu, Wen Hou, Sei Yoshida, Zhongyang Shen, Jonathan S Bromberg, Hong Zheng
来源:
CYTOKINE & GROWTH FACTOR REVIEWS
摘要:
先前的研究阐明卡培他滨 (CAP) 作为一种抗肿瘤药物,具有假定的免疫抑制作用。然而,支撑这些效应的复杂机制仍有待阐明。在本研究中,我们旨在揭示 CAP 发挥免疫抑制作用以减少同种异体移植排斥的分子途径。将男性 BALB/c 供体的心脏移植到男性 C57BL/6 受体,并用 CAP 治疗 7 天。使用一系列技术评估这些心脏移植的排斥反应,包括 H
Previous studies elucidated that capecitabine (CAP) works as an anti-tumor agent with putative immunosuppressive effects. However, the intricate mechanisms underpinning these effects remain to be elucidated. In this study, we aimed to unravel the molecular pathways by which CAP exerts its immunosuppressive effects to reduce allograft rejection.Hearts were transplanted from male BALB/c donors to male C57BL/6 recipients and treated with CAP for seven days. The rejection of these heart transplants was assessed using a range of techniques, including H&E staining, immunohistochemistry, RNA sequencing, LS-MS/MS, and flow cytometry. In vitro, naïve CD4+ T cells were isolated and cultured under Th1 condition medium with varying treatments, flow cytometry, LS-MS/MS were employed to delineate the role of thymidine synthase (TYMS) during Th1 differentiation.CAP treatment significantly mitigated acute allograft rejection and enhanced graft survival by reducing graft damage, T cell infiltration, and levels of circulating pro-inflammatory cytokines. Additionally, it curtailed CD4+ T cell proliferation and the presence of Th1 cells in the spleen. RNA-seq showed that TYMS, the target of CAP, was robustly increased post-transplantation in splenocytes. In vitro, TYMS and its metabolic product dTMP were differentially expressed in Th0 and Th1, and were required after activation of CD4+ T cell and Th1 differentiation. TYMS-specific inhibitor, raltitrexed, and the metabolite of capecitabine, 5-fluorouracil, could inhibit the proliferation and differentiation of Th1. Finally, the combined use of CAP and the commonly used immunosuppressant rapamycin can induce long-term survival of allograft.CAP undergoes metabolism conversion to interfere pyrimidine metabolism, which targets TYMS-mediated differentiation of Th1, thereby playing a significant role in mitigating acute cardiac allograft rejection in murine models.Copyright © 2024. Published by Elsevier B.V.