Prevention of acute graft‑vs.‑host disease by targeting glycolysis and mTOR pathways in activated T cells

Zhou,Rui-Qing; Wang,Xiaobo; Ye,Yong-Bin; Lu,Bo; Wang,Jing; Guo,Zi-Wen; Mo,Wen-Jian; Yang,Zheng; Srisuk,Pathomthat; Yan,Le-Ping; Xu,Xiao-Jun

doi:10.3892/etm.2022.11375

Prevention of acute graft‑vs.‑host disease by targeting glycolysis and mTOR pathways in activated T cells

Authors:
- Rui-Qing Zhou
- Xiaobo Wang
- Yong-Bin Ye
- Bo Lu
- Jing Wang
- Zi-Wen Guo
- Wen-Jian Mo
- Zheng Yang
- Pathomthat Srisuk
- Le-Ping Yan
- Xiao-Jun Xu
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Affiliations: Department of Hematology, Guangzhou First People's Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong 510180, P.R. China, Department of Hematology, The Seventh Affiliated Hospital, Sun Yat‑sen University, Shenzhen, Guangdong 518107, P.R. China, Department of Hematology, Zhongshan Hospital of Sun Yat‑Sen University and Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China, Nanfang‑Chunfu Children's Institute of Hematology and Oncology, TaiXin Hospital, Dongguan, Guangdong 523128, P.R. China, Department of Hematology, Zhongshan Hospital of Sun Yat‑Sen University and Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China, Department of Pathology, The Seventh Affiliated Hospital, Sun Yat‑sen University, Shenzhen, Guangdong 518107, P.R. China, Division of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
Published online on: May 16, 2022 https://doi.org/10.3892/etm.2022.11375
Article Number: 448
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Graft‑versus‑host disease (GvHD) is a common life‑threatening complication that can occur following allogeneic hematopoietic stem cell transplantation. This occurs if donor T cells recognize the host as foreign. During acute GvHD (aGVHD), activated T cells utilize glycolysis as the main source of energy generation. Therefore, inhibition of T cell glycolysis is a potential treatment strategy for aGVHD. In the present study, the effects of the combination of the glycolysis inhibitor 3‑bromopyruvate (3‑BrPA) and the mTOR inhibitor rapamycin (RAPA) on a mode of aGVHD were explored. In vitro mixed lymphocyte culture model was established by using splenocytes from C57BL/6 (H‑2b) mice as responder and inactivated splenocytes from BALB/c (H‑2d) mice as stimulator. In this model, 3‑BrPA treatment (0‑100 µmol/l) was found to suppress cell viability, increase cell apoptosis and reduce IFN‑γ secretion, in a concentration‑dependent manner., 3‑BrPA treatment (0‑100 µmol/l) was found to suppress cell viability, increase cell apoptosis and reduce IFN‑γ secretion, in a concentration‑dependent manner. In addition, combined treatment with 3‑BrPA (0‑100 µmol/l) alongside RAPA (20 µmol/l) exhibited synergistic effects on inhibiting cell viability and IFN‑γ production, compared with those following either treatment alone. An aGVHD model was established by injection of bone marrow cells and spleen cells from the donor‑C57BL/6(H‑2b) mice to the receptor‑BALB/c(H‑2d) mice which were underwent total body irradiation first. In the aGVHD model, 3‑BrPA (10 mg/kg/day), RAPA (2.5 and 5 mg/kg/day) and both in combination (5 and 2.5 mg/kg/day for 3‑BrPA and RAPA, respectively) were all found to alleviate the damage caused by aGVHD, in addition to prolonging the survival time of mice with acute GvHD. In particular, the combined 3‑BrPA and RAPA treatment resulted in the highest median survival time among all groups tested. In addition, the effects induced by combined 3‑BrPA and RAPA treatment were found to be comparable to those in the 5 mg/kg/day RAPA group but superior to the 3‑BrPA group with regards to the cumulative survival profile, GvHD score and lung histological score. The 3‑BrPA and RAPA combination group also exhibited the lowest IFN‑γ levels among all groups. Therefore, the combination of inhibiting both glycolysis and mTOR activity is a promising strategy for acute GvHD prevention.

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