卡培他滨通过抑制 TYMS 介导的 Th1 分化减轻小鼠心脏移植排斥反应。
Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice.
机构信息
Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, USA.
Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China; Institute of Transplantation Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Science, Tianjin, China; Biological Sample Resource Sharing Center, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China.
出版信息
Int Immunopharmacol. 2024 Nov 15;141:112955. doi: 10.1016/j.intimp.2024.112955. Epub 2024 Aug 20.
OBJECTIVES
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
目的
先前的研究阐明，卡培他滨（CAP）作为一种具有潜在免疫抑制作用的抗肿瘤药物发挥作用。然而，这些作用背后的复杂机制仍有待阐明。在这项研究中，我们旨在揭示 CAP 发挥其免疫抑制作用以减少同种异体移植排斥的分子途径。
方法
将雄性 BALB/c 供体的心脏移植到雄性 C57BL/6 受体，并接受 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&E 染色、免疫组织化学、RNA 测序、LS-MS/MS 和流式细胞术。在体外，分离并培养幼稚 CD4 T 细胞，在不同处理条件下在 Th1 条件培养基中培养，采用流式细胞术、LS-MS/MS 来阐明胸腺嘧啶合酶（TYMS）在 Th1 分化过程中的作用。
结果
CAP 治疗通过减少移植物损伤、T 细胞浸润和循环促炎细胞因子水平，显著减轻急性同种异体移植排斥反应并延长移植物存活时间。此外，它还抑制了 CD4 T 细胞增殖和脾脏中 Th1 细胞的存在。RNA-seq 显示，CAP 的靶标 TYMS 在移植后脾脏细胞中强烈增加。在体外，TYMS 及其代谢产物 dTMP 在 Th0 和 Th1 中差异表达，并且在 CD4 T 细胞激活和 Th1 分化后是必需的。TYMS 特异性抑制剂雷替曲塞和卡培他滨的代谢产物 5-氟尿嘧啶可抑制 Th1 的增殖和分化。最后，CAP 与常用免疫抑制剂雷帕霉素联合使用可诱导移植物的长期存活。
结论
CAP 经历代谢转化以干扰嘧啶代谢，该代谢靶向 TYMS 介导的 Th1 分化，从而在减轻小鼠模型中的急性心脏同种异体移植排斥中发挥重要作用。
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