Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection
Background and aim: Solid organ transplantation remains a life-saving therapeutic option for patients with end-stage organ dysfunction. Acute cellular rejection (ACR), dominated by dendritic cells (DCs) and CD4+ T cells, is a major cause of post-transplant mortality. Inhibiting DC maturation and dir...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024054793 |
| _version_ | 1797203058040504320 |
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| author | Xu Lan Jingyi Zhang Shaohua Ren Hongda Wang Bo Shao Yafei Qin Hong Qin Chenglu Sun Yanglin Zhu Guangming Li Hao Wang |
| author_facet | Xu Lan Jingyi Zhang Shaohua Ren Hongda Wang Bo Shao Yafei Qin Hong Qin Chenglu Sun Yanglin Zhu Guangming Li Hao Wang |
| author_sort | Xu Lan |
| collection | DOAJ |
| description | Background and aim: Solid organ transplantation remains a life-saving therapeutic option for patients with end-stage organ dysfunction. Acute cellular rejection (ACR), dominated by dendritic cells (DCs) and CD4+ T cells, is a major cause of post-transplant mortality. Inhibiting DC maturation and directing the differentiation of CD4+ T cells toward immunosuppression are keys to inhibiting ACR. We propose that oxymatrine (OMT), a quinolizidine alkaloid, either alone or in combination with rapamycin (RAPA), attenuates ACR by inhibiting the mTOR–HIF–1α pathway. Methods: Graft damage was assessed using haematoxylin and eosin staining. Intragraft CD11c+ and CD4+ cell infiltrations were detected using immunohistochemical staining. The proportions of mature DCs, T helper (Th) 1, Th17, and Treg cells in the spleen; donor-specific antibody (DSA) secretion in the serum; mTOR–HIF–1α expression in the grafts; and CD4+ cells and bone marrow-derived DCs (BMDCs) were evaluated using flow cytometry. Results: OMT, either alone or in combination with RAPA, significantly alleviated pathological damage; decreased CD4+ and CD11c+ cell infiltration in cardiac allografts; reduced the proportion of mature DCs, Th1 and Th17 cells; increased the proportion of Tregs in recipient spleens; downregulated DSA production; and inhibited mTOR and HIF-1α expression in the grafts. OMT suppresses mTOR and HIF-1α expression in BMDCs and CD4+ T cells in vitro. Conclusions: Our study suggests that OMT-based therapy can significantly attenuate acute cardiac allograft rejection by inhibiting DC maturation and CD4+ T cell responses. This process may be related to the inhibition of the mTOR–HIF–1α signaling pathway by OMT. |
| first_indexed | 2024-04-24T08:13:17Z |
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| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-24T08:13:17Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
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| series | Heliyon |
| spelling | doaj.art-d5b1c08d299e44b98917def9db28481e2024-04-17T04:49:31ZengElsevierHeliyon2405-84402024-04-01108e29448Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejectionXu Lan0Jingyi Zhang1Shaohua Ren2Hongda Wang3Bo Shao4Yafei Qin5Hong Qin6Chenglu Sun7Yanglin Zhu8Guangming Li9Hao Wang10Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, 100029, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, ChinaDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin 300052, China; Corresponding author. Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Background and aim: Solid organ transplantation remains a life-saving therapeutic option for patients with end-stage organ dysfunction. Acute cellular rejection (ACR), dominated by dendritic cells (DCs) and CD4+ T cells, is a major cause of post-transplant mortality. Inhibiting DC maturation and directing the differentiation of CD4+ T cells toward immunosuppression are keys to inhibiting ACR. We propose that oxymatrine (OMT), a quinolizidine alkaloid, either alone or in combination with rapamycin (RAPA), attenuates ACR by inhibiting the mTOR–HIF–1α pathway. Methods: Graft damage was assessed using haematoxylin and eosin staining. Intragraft CD11c+ and CD4+ cell infiltrations were detected using immunohistochemical staining. The proportions of mature DCs, T helper (Th) 1, Th17, and Treg cells in the spleen; donor-specific antibody (DSA) secretion in the serum; mTOR–HIF–1α expression in the grafts; and CD4+ cells and bone marrow-derived DCs (BMDCs) were evaluated using flow cytometry. Results: OMT, either alone or in combination with RAPA, significantly alleviated pathological damage; decreased CD4+ and CD11c+ cell infiltration in cardiac allografts; reduced the proportion of mature DCs, Th1 and Th17 cells; increased the proportion of Tregs in recipient spleens; downregulated DSA production; and inhibited mTOR and HIF-1α expression in the grafts. OMT suppresses mTOR and HIF-1α expression in BMDCs and CD4+ T cells in vitro. Conclusions: Our study suggests that OMT-based therapy can significantly attenuate acute cardiac allograft rejection by inhibiting DC maturation and CD4+ T cell responses. This process may be related to the inhibition of the mTOR–HIF–1α signaling pathway by OMT.http://www.sciencedirect.com/science/article/pii/S2405844024054793OxymatrineAcute allograft rejectionImmunoregulationmTOR–HIF–1α signaling pathwayMice |
| spellingShingle | Xu Lan Jingyi Zhang Shaohua Ren Hongda Wang Bo Shao Yafei Qin Hong Qin Chenglu Sun Yanglin Zhu Guangming Li Hao Wang Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection Heliyon Oxymatrine Acute allograft rejection Immunoregulation mTOR–HIF–1α signaling pathway Mice |
| title | Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection |
| title_full | Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection |
| title_fullStr | Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection |
| title_full_unstemmed | Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection |
| title_short | Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection |
| title_sort | oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection |
| topic | Oxymatrine Acute allograft rejection Immunoregulation mTOR–HIF–1α signaling pathway Mice |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024054793 |
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