2. Academic Validation
  3. Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice

Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice

  • Int Immunopharmacol. 2024 Nov 15:141:112955. doi: 10.1016/j.intimp.2024.112955.
Dejun Kong 1,  Zhenglu Wang 2,  Hao Wang 3,  Ruining Yang 4,  Weiqi Zhang 5,  Lei Cao 6,  Yeqi Nian 7,  Jiashu Ren 8,  Jianing Lu 9,  Tao Chen 10,  Jinliang Duan 11,  Zhuolun Song 12,  Tao Liu 13,  Wen Hou 14,  Sei Yoshida 15,  Zhongyang Shen 16,  Jonathan S Bromberg 17,  Hong Zheng 18
Affiliations

Affiliations

  • 1 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. Electronic address: dejunk@tmu.edu.cn.
  • 2 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. Electronic address: 13920474643@163.com.
  • 3 Tianjin Medical University First Central Clinical College, Tianjin, China. Electronic address: wanghao1717@tmu.edu.cn.
  • 4 Tianjin Medical University First Central Clinical College, Tianjin, China. Electronic address: Yruining0628@163.com.
  • 5 Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China. Electronic address: drzwq2022@mail.nankai.edu.cn.
  • 6 Biological Sample Resource Sharing Center, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China. Electronic address: caolei@nankai.edu.cn.
  • 7 Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China; Institute of Transplantation Medicine, Nankai University, Tianjin, China. Electronic address: nianyeqi0314@hotmail.com.
  • 8 Tianjin Medical University First Central Clinical College, Tianjin, China. Electronic address: 1197851792@qq.com.
  • 9 Tianjin Medical University First Central Clinical College, Tianjin, China. Electronic address: lujianing2006@163.com.
  • 10 Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China. Electronic address: surgeondamon007@foxmail.com.
  • 11 Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China. Electronic address: stduan@126.com.
  • 12 Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China. Electronic address: zhuolun.song@hotmail.com.
  • 13 National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China. Electronic address: liutao@nankai.edu.cn.
  • 14 Institute of Transplantation Medicine, Nankai University, Tianjin, China. Electronic address: houwen@nankai.edu.cn.
  • 15 Institute of Transplantation Medicine, Nankai University, Tianjin, China. Electronic address: seiyoshi@nankai.edu.cn.
  • 16 Nankai University School of Medicine, Tianjin, China; 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; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China. Electronic address: zhongyangshen@nankai.edu.cn.
  • 17 Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, USA; Department of Surgery, University of Maryland School of Medicine, Baltimore, USA. Electronic address: JBromberg@som.umaryland.edu.
  • 18 Nankai University School of Medicine, Tianjin, China; 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; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China. Electronic address: zhenghongyx@139.com.
PMID: 39163685 DOI: 10.1016/j.intimp.2024.112955
Abstract

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.

Keywords

Allograft rejection; Capecitabine; Pyrimidine metabolism; Th1 cell.

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