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Yan W, Zhang H, Zhang J, Zhao Y, Wu Y, Ma X, Luan X. Human placental mesenchymal stem cells regulate the antioxidant capacity of CD8 +PD-1 + T cells through the CD73/ADO/Nrf2 pathway to protect against liver damage in mice with acute graft-versus-host disease. Mol Immunol 2025; 179:71-83. [PMID: 39923662 DOI: 10.1016/j.molimm.2025.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 01/17/2025] [Accepted: 01/30/2025] [Indexed: 02/11/2025]
Abstract
Graft-versus-host disease (GVHD) constitutes a severe complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT), significantly reducing the survival rate of patients. Mesenchymal stem cells (MSCs) are capable of ameliorating the tissue damage caused by GVHD through exerting immunosuppressive effects; however, the relevant mechanisms require further investigation. This study used a GVHD mouse model to explore the therapeutic effects and mechanisms of human placental mesenchymal stem cells (hPMSCs) in mitigating GVHD-induced liver injury. The findings indicated that hPMSCs reduced the proportion of CD8+PD-1+ T cells in both the liver and spleen of GVHD mice, decreased reactive oxygen species (ROS) levels, and upregulated glutathione S transferase (GST) and glutathione (GSH) levels. Consistently, this led to a decrease in the expression of liver fibrosis markers, including alpha-smooth muscle actin (α-SMA) and fibronectin (FN). Moreover, CD8+PD-1+ T cells and ROS were positively correlated with α-SMA and FN, respectively, whereas GST and GSH were negatively correlated with them. hPMSCs with low expression in CD73 attenuated this effect. In vitro studies demonstrated that hPMSCs upregulated the expression of nuclear factor-E2-related factor 2 (Nrf2) via the CD73/adenosine (ADO) pathway, regulated oxidative metabolism, and reduced the number of CD8+PD-1+ T cells. The results suggested that hPMSCs contributed to the regulation of redox homeostasis and reduced the proportion of CD8+PD-1+ T cells through the CD73/ADO/Nrf2 signaling pathway, thereby alleviating liver injury associated with GVHD.
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Affiliation(s)
- Wei Yan
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China; Department of Reproductive Medicine, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong Province 264000, China
| | - Hengchao Zhang
- Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, Shandong Province 264000, China
| | - Jiashen Zhang
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China
| | - Yaxuan Zhao
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China
| | - Yunhua Wu
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China
| | - Xiaolin Ma
- Hematology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province 266000, China.
| | - Xiying Luan
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China.
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Kitamura W, Fujii K, Tsuge M, Mitsuhashi T, Kobayashi H, Kamoi C, Yamamoto A, Kondo T, Seike K, Fujiwara H, Asada N, Ennishi D, Matsuoka KI, Fujii N, Maeda Y. A randomized controlled trial of conventional GVHD prophylaxis with or without teprenone for the prevention of severe acute GVHD. Ann Hematol 2025; 104:1917-1929. [PMID: 39994018 PMCID: PMC12031882 DOI: 10.1007/s00277-025-06269-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 02/16/2025] [Indexed: 02/26/2025]
Abstract
Therapies that effectively suppress graft-versus-host disease (GVHD) without compromising graft-versus-leukemia/lymphoma (GVL) effects is important in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematopoietic malignancies. Geranylgeranylacetone (GGA) is a main component of teprenone, a gastric mucosal protectant commonly used in clinical practice. In preclinical models, GGA suppresses proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), which are associated with GVHD as well as induces thioredoxin-1 (Trx-1), which suppresses GVHD while maintaining GVL effects. Here, we investigated whether the addition of teprenone to standard GVHD prophylaxis could reduce the cumulative incidence of severe acute GVHD (aGVHD) without attenuating GVL effects. This open-label, randomized clinical trial enrolled 40 patients (21 control and 19 teprenone group) who received allo-HSCT between May 2022 and February 2023 in our institution. Patients in the teprenone group received 50 mg of teprenone orally thrice daily for 21 days from the initiation of the conditioning regimen. The cumulative incidence of severe aGVHD by day 100 after allo-HSCT was not significantly different in the two groups (27.9 vs. 16.1%, p = 0.25). The exploratory studies revealed no obvious changes in Trx-1 levels, but the alternations from baseline in IL-1β and TNF-α levels at day 28 after allo-HSCT tended to be lower in the teprenone group. In conclusion, we could not demonstrate that teprenone significantly prevented the development of severe aGVHD. Discrepancy with preclinical model suggests that appropriate dose of teprenone may be necessary to induce the expression of antioxidant enzymes that suppress severe aGVHD. Clinical Trial Registration number:jRCTs 061210072.
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Affiliation(s)
- Wataru Kitamura
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Division of Transfusion and Cell Therapy, Okayama University Hospital, Okayama, Japan
| | - Keiko Fujii
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan.
- Division of Clinical Laboratory, Okayama University Hospital, Okayama, Japan.
| | - Mitsuru Tsuge
- Department of Pediatric Acute Diseases, Okayama University Academic Field of Medicine Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Toshiharu Mitsuhashi
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Hiroki Kobayashi
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Chihiro Kamoi
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Division of Transfusion and Cell Therapy, Okayama University Hospital, Okayama, Japan
| | - Akira Yamamoto
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Takumi Kondo
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Keisuke Seike
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Hideaki Fujiwara
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Noboru Asada
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Daisuke Ennishi
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | - Ken-Ichi Matsuoka
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Nobuharu Fujii
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Division of Transfusion and Cell Therapy, Okayama University Hospital, Okayama, Japan
| | - Yoshinobu Maeda
- Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
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Huang Q, Jiang X, Wang B, Wu Z, Zhang F, Huang XJ, Guo H. Gallic acid enhances GVL effects of T cells without exacerbating GVHD after haematopoietic stem cell transplantation. Br J Haematol 2025; 206:120-132. [PMID: 39472128 DOI: 10.1111/bjh.19863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 10/16/2024] [Indexed: 01/19/2025]
Abstract
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for acute myeloid leukaemia (AML), predominantly due to its potent graft-versus-leukaemia (GVL) effect. However, leukaemia relapse remains a major obstacle to the success of allo-HSCT. In this study, we demonstrated that gallic acid (GA), a natural dietary compound, can enhance T-cell-mediated GVL effects both in vitro and in vivo. GA-treated T cells exhibited increased activation and elevated secretion of cytotoxic cytokines, leading to the apoptosis of AML cells in co-culture systems in vitro. In a non-irradiated leukaemia mouse model, we showed that GA treatment prolonged the survival of leukaemic mice and reduced leukaemia cell infiltration. Further analysis revealed that GA treatment increased T-cell activation and tumour necrosis factor-α secretion. Moreover, integrated transcriptomic and proteomic analyses indicated that GA augments T-cell-mediated GVL effects through the activation of the MAPK and NF-κB pathways. Blocking these pathways individually diminished the protective effect of GA in AML model mice. Importantly, GA administration did not accelerate graft-versus-host disease (GVHD) progression in a mouse model. In conclusion, our study revealed that GA can enhance the GVL effects of T cells without exacerbating GVHD, offering insights into its potential to improve outcomes for patients after HSCT.
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Affiliation(s)
- Qianqian Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Xinya Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Bixia Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Zhigui Wu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Fangqing Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China
| | - Huidong Guo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
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Xiong Y, Wang F, Mu H, Zhang A, Zhao Y, Han K, Zhang J, Zhang H, Wang Z, Ma J, Wei R, Luan X. hPMSCs prevent erythrocytes dysfunction caused by graft versus host disease via promoting GSH synthesis. Int Immunopharmacol 2024; 139:112689. [PMID: 39029234 DOI: 10.1016/j.intimp.2024.112689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 06/26/2024] [Accepted: 07/12/2024] [Indexed: 07/21/2024]
Abstract
BACKGROUND Oxidative stress is increased in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients and leads to the development of graft versus host disease (GVHD). Mesenchymal stromal cells (MSCs) can ameliorate GVHD by regulating the function of T cells. However, whether MSCs can modulate erythrocyte antioxidant metabolism and thus reduce GVHD is not known. METHODS Forty female BALB/c mice were randomly assigned to four groups: the control, GVHDhigh, hPMSC, and PBS groups. A hypoxanthine/xanthine oxidase system was used to steadily and gradually produce superoxide in an in vitro experiment. A scanning microscope was used to examine the ultrastructure of erythrocytes. Laser diffraction analyses were used to analyze erythrocyte deformability. Western blotting was used to measure the expression of the erythrocyte membrane skeleton proteins Band 3 and β-Spectrin. Corresponding kits were used to assess the levels of oxidative damage and the activity of antioxidant enzymes. RESULTS Morphological and deformability defects were significantly increased in erythrocytes from GVHD patients. Band 3 and β-Spectrin expression was also reduced in GVHD patients and model mice. Furthermore, we observed significantly increased oxidative stress-induce injury and decreased antioxidant capability in erythrocytes from both GVHD patients and model mice. Subsequent research showed that human placenta-derived MSC (hPMSC) therapy decreased the GVHD-induced redox imbalance in erythrocytes. Furthermore, our findings suggested that upregulating glucose metabolism promoted both the de novo synthesis and recycling of GSH, which is the primary mechanism by which hPMSCs mediate the increase in antioxidant capacity in erythrocytes. CONCLUSION Together, our findings suggest that hPMSCs can increase antioxidant capacity by increasing erythrocyte GSH production and thus ameliorate GVHD.
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Affiliation(s)
- Yanlian Xiong
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Feifei Wang
- Department of Anesthesiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, PR China
| | - Huanmei Mu
- Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Aiping Zhang
- Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Yaxuan Zhao
- Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Kaiyue Han
- Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Jiashen Zhang
- Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Hengchao Zhang
- Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Zhuoya Wang
- Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Junjie Ma
- Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong Province 264000, PR China
| | - Rongxia Wei
- Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong Province 264000, PR China.
| | - Xiying Luan
- Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China.
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Li W, Si Y, Wang Y, Chen J, Huo X, Xu P, Jiang B, Li Z, Shang K, Luo Q, Xiong Y. hUCMSC-derived exosomes protect against GVHD-induced endoplasmic reticulum stress in CD4 + T cells by targeting the miR-16-5p/ATF6/CHOP axis. Int Immunopharmacol 2024; 135:112315. [PMID: 38805908 DOI: 10.1016/j.intimp.2024.112315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/18/2024] [Accepted: 05/19/2024] [Indexed: 05/30/2024]
Abstract
Exosomes generated from mesenchymal stem cells (MSCs) are thought to be a unique therapeutic strategy for several autoimmune deficiency illnesses. The purpose of this study was to elucidate the protective effects of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exo) on CD4+ T cells dysfunction during graft-versus-host disease (GVHD) and to identify the underlying processes involved. Here, we showed that hUCMSC-Exo treatment can effectively attenuate GVHD injury by alleviating redox metabolism disorders and inflammatory cytokine bursts in CD4+ T cells. Furthermore, hUCMSC-Exo ameliorate ER stress and ATF6/CHOP signaling-mediated apoptosis in CD4+ T cells and promote the development of CD4+IL-10+ T cells during GVHD. Moreover, downregulating miR-16-5p in hUCMSC-Exo impaired their ability to prevent CD4+ T cells apoptosis and weakened their ability to promote the differentiation of CD4+IL-10+ T cells. Collectively, the obtained data suggested that hUCMSC-Exo suppress ATF6/CHOP signaling-mediated ER stress and apoptosis in CD4+ T cells, enhance the differentiation of CD4+IL-10+ T cells, and reverse the imbalance of immune homeostasis in the GVHD process by transferring miR-16-5p. Our study provided further evidence that GVHD patients can benefit from hUCMSC-Exo-mediated therapy.
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Affiliation(s)
- Weihan Li
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, PR China; Shanghai Mebo Life Science & Technology Co., Shanghai, PR China
| | - Yaru Si
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Yueming Wang
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, PR China
| | - Juntong Chen
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Xingyu Huo
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Pengzhan Xu
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Bingzhen Jiang
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Zile Li
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Kangdi Shang
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China
| | - Qianqian Luo
- Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China.
| | - Yanlian Xiong
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, PR China; Department of Histology and Embryology, School of Basic Medicine, Binzhou Medical University, Yantai, PR China.
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Zhang N, Zhou J, Li S, Cai W, Ru B, Hu J, Liu W, Liu X, Tong X, Zheng X. Advances in Nanoplatforms for Immunotherapy Applications Targeting the Tumor Microenvironment. Mol Pharm 2024; 21:410-426. [PMID: 38170627 DOI: 10.1021/acs.molpharmaceut.3c00846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Cancer immunotherapy is a treatment method that activates or enhances the autoimmune response of the body to fight tumor growth and metastasis, has fewer toxic side effects and a longer-lasting efficacy than radiotherapy and chemotherapy, and has become an important means for the clinical treatment of cancer. However, clinical results from immunotherapy have shown that most patients lack responsiveness to immunotherapy and cannot benefit from this treatment strategy. The tumor microenvironment (TME) plays a critical role in the response to immunotherapy. The TME typically prevents effective lymphocyte activation, reducing their infiltration, and inhibiting the infiltration of effector T cells. According to the characteristic differences between the TME and normal tissues, various nanoplatforms with TME targeting and regulation properties have been developed for more precise regulation of the TME and have the ability to codeliver a variety of active pharmaceutical ingredients, thereby reducing systemic toxicity and improving the therapeutic effect of antitumor. In addition, the precise structural design of the nanoplatform can integrate specific functional motifs, such as surface-targeted ligands, degradable backbones, and TME stimulus-responsive components, into nanomedicines, thereby reshaping the tumor microenvironment, improving the body's immunosuppressive state, and enhancing the permeability of drugs in tumor tissues, in order to achieve controlled and stimulus-triggered release of load cargo. In this review, the physiological characteristics of the TME and the latest research regarding the application of TME-regulated nanoplatforms in improving antitumor immunotherapy will be described. Furthermore, the existing problems and further applications perspectives of TME-regulated platforms for cancer immunotherapy will also be discussed.
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Affiliation(s)
- Nannan Zhang
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Junyu Zhou
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Shun Li
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Wenjun Cai
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Bin Ru
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Jiaqi Hu
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Wenlong Liu
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Xuanxi Liu
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Xiangmin Tong
- Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang 310006, China
- Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Xiaoyan Zheng
- Department of Clinical Laboratory, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang 324000, China
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Zhao X, Sun Y, Xu Z, Cai L, Hu Y, Wang H. Targeting PRMT1 prevents acute and chronic graft-versus-host disease. Mol Ther 2023; 31:3259-3276. [PMID: 37735873 PMCID: PMC10638063 DOI: 10.1016/j.ymthe.2023.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/15/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023] Open
Abstract
Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4+ T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of T helper (Th)17 cells, germinal center B cells, and plasma cells. The PRMT1 inhibitor also controlled acute GVHD (aGVHD) in mice by decreasing the percentage of Th17 cells. Moreover, inhibiting PRMT1 also weakened Th17 cell differentiation, B cell proliferation, and antibody production in cells from cGVHD patients. Additionally, further studies revealed that PRMT1 regulated B cell proliferation and antibody secretion by methylating isocitrate dehydrogenase 2 (IDH2). We observed asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 promoted IDH2 homodimerization, which enhanced IDH2 activity, further increasing B cell proliferation and antibody production. Collectively, this study provides a rationale for the application of PRMT1 inhibitors in the prevention of aGVHD and cGVHD.
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Affiliation(s)
- Xiaoyan Zhao
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yan Sun
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ziwei Xu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Li Cai
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu Hu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Huafang Wang
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Li Q, Wang X, Song Q, Yang S, Wu X, Yang D, Marié IJ, Qin H, Zheng M, Nasri U, Kong X, Wang B, Lizhar E, Cassady K, Tompkins J, Levy D, Martin PJ, Zhang X, Zeng D. Donor T cell STAT3 deficiency enables tissue PD-L1-dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity. J Clin Invest 2023; 133:e165723. [PMID: 37526084 PMCID: PMC10378157 DOI: 10.1172/jci165723] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 06/02/2023] [Indexed: 08/02/2023] Open
Abstract
STAT3 deficiency (STAT3-/-) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3-/- donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose-dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling-mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects.
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Affiliation(s)
- Qinjian Li
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Qingxiao Song
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Xiwei Wu
- Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Dongyun Yang
- Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Isabelle J Marié
- Department of Pathology, NYU Grossman School of Medicine, New York, USA
| | - Hanjun Qin
- Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Moqian Zheng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Ubaydah Nasri
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Xiaohui Kong
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Bixin Wang
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
| | - Elizabeth Lizhar
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Kaniel Cassady
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Josh Tompkins
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
| | - David Levy
- Department of Pathology, NYU Grossman School of Medicine, New York, USA
| | - Paul J Martin
- Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
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Apostolova P. Allo-HCT: damaged T cells don't bite. Blood 2023; 141:1507-1508. [PMID: 36995707 DOI: 10.1182/blood.2022019242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023] Open
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10
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Hong T, Wang R, Yang G, Wang X, Zeng L, Yang S, Wei J, Gao Q, Zhang X. Human umbilical cord mesenchymal stem cells ameliorate acute graft versus host disease by elevating phytosphingosine. Exp Hematol 2023:S0301-472X(23)00070-X. [PMID: 36931619 DOI: 10.1016/j.exphem.2023.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/28/2023] [Accepted: 03/08/2023] [Indexed: 03/17/2023]
Abstract
Acute graft-versus-host disease (aGVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (allo-HSCT) and even leads to death after HSCT. Human umbilical cord mesenchymal stem cells (HUCMSCs) are effective in aGVHD treatment and have mild side effects, but the underlying mechanisms remain unclear. Phytosphingosine (PHS) is known to prevent loss of moisture from the skin; regulate epidermal cell growth, differentiation, and apoptosis; and exert bactericidal and anti-inflammatory effects. In this study, our results revealed the efficacy of HUCMSCs in alleviating aGVHD in a murine model, with striking changes in metabolism and significantly elevated PHS levels due to sphingolipid metabolism. In vitro, PHS reduced CD4+ T cell proliferation, enhanced apoptosis and reduced T helper 1 (Th1) cell differentiation. Transcriptional analysis of donor CD4+ T cells treated with PHS revealed significant decreases in transcripts regulating proinflammatory pathways, such as NF-κB. In vivo, the administration of PHS significantly ameliorated aGVHD development. Collectively, these beneficial effects indicate proof-of-concept that sphingolipid metabolites could be a safe and effective means to prevent aGVHD in the clinic.
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Affiliation(s)
- Tao Hong
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China
| | - Rui Wang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China; Jinfeng Laboratory, Chongqing, 401329, China
| | - Guancui Yang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China; Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637002, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China
| | - Lingyu Zeng
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221008, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China; Jinfeng Laboratory, Chongqing, 401329, China
| | - Jin Wei
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637002, China
| | - Qiangguo Gao
- Department of Cell Biology, College of Basic Medicine, Army Medical University, Chongqing, 400038, China..
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China; Jinfeng Laboratory, Chongqing, 401329, China..
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11
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Yoshikawa S, Taniguchi K, Sawamura H, Ikeda Y, Tsuji A, Matsuda S. Advantageous tactics with certain probiotics for the treatment of graft-versus-host-disease after hematopoietic stem cell transplantation. World J Hematol 2023; 10:15-24. [DOI: 10.5315/wjh.v10.i2.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/03/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) becomes a standard form of cellular therapy for patients with malignant diseases. HSCT is the first-choice of immunotherapy, although HSCT can be associated with many complications such as graft-versus-host disease (GVHD) which is a major cause of morbidity and mortality after allogeneic HSCT. It has been shown that certain gut microbiota could exert protective and/or regenerative immunomodulatory effects by the production of short-chain fatty acids (SCFAs) such as butyrate in the experimental models of GVHD after allogeneic HSCT. Loss of gut commensal bacteria which can produce SCFAs may worsen dysbiosis, increasing the risk of GVHD. Expression of G-protein coupled receptors such as GPR41 seems to be upre-gulated in the presence of commensal bacteria, which might be associated with the biology of regulatory T cells (Tregs). Treg cells are a suppressive subset of CD4 positive T lymphocytes implicated in the prevention of GVHD after allogeneic HSCT. Here, we discuss the current findings of the relationship between the modification of gut microbiota and the GVHD-related immunity, which suggested that tactics with certain probiotics for the beneficial symbiosis in gut-immune axis might lead to the elevation of safety in the allogeneic HSCT.
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Affiliation(s)
- Sayuri Yoshikawa
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Kurumi Taniguchi
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Haruka Sawamura
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Yuka Ikeda
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Ai Tsuji
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Satoru Matsuda
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
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12
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Chi M, Jiang T, He X, Peng H, Li Y, Zhang J, Wang L, Nian Q, Ma K, Liu C. Role of Gut Microbiota and Oxidative Stress in the Progression of Transplant-Related Complications following Hematopoietic Stem Cell Transplantation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:3532756. [PMID: 37113743 PMCID: PMC10129428 DOI: 10.1155/2023/3532756] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/12/2022] [Accepted: 11/24/2022] [Indexed: 04/29/2023]
Abstract
Hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplantation, has curative potential for various hematologic malignancies but is associated with risks such as graft-versus-host disease (GvHD), severe bloodstream infection, viral pneumonia, idiopathic pneumonia syndrome (IPS), lung fibrosis, and sinusoidal obstruction syndrome (SOS), which severely deteriorate clinical outcomes and limit the wide application of HSCT. Recent research has provided important insights into the effects of gut microbiota and oxidative stress (OS) on HSCT complications. Therefore, based on recent studies, we describe intestinal dysbiosis and OS in patients with HSCT and review recent molecular findings underlying the causal relationships of gut microbiota, OS, and transplant-related complications, focusing particularly on the involvement of gut microbiota-mediated OS in postengraftment complications. Also, we discuss the use of antioxidative and anti-inflammatory probiotics to manipulate gut microbiota and OS, which have been associated with promising effects in improving HSCT outcomes.
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Affiliation(s)
- Mingxuan Chi
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China
| | - Tao Jiang
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China
- Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province 610072, China
| | - Xing He
- School of Clinical Medicine, Chengdu Medical College, China
| | - Haoyu Peng
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yunlong Li
- Department of Urology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jiong Zhang
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China
| | - Li Wang
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China
| | - Qing Nian
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China
- Department of Blood Transfusion, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Kuai Ma
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Chi Liu
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China
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13
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Zhao H, Li Y, Shi H, Niu M, Li D, Zhang Z, Feng Q, Zhang Y, Wang L. Prodrug nanoparticles potentiate tumor chemo-immunometabolic therapy by disturbing oxidative stress. J Control Release 2022; 352:909-919. [PMID: 36370878 DOI: 10.1016/j.jconrel.2022.11.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 11/15/2022]
Abstract
Constant oxidative stress and lactate accumulation are two main causes of tumor immunosuppression, their concurrent reduction plays a dominant role in effective antitumor immunity, but remains challenging. Herein, reactive oxygen species (ROS) responsive prodrug nanoparticles (designed as DHCRJ) are constructed for metabolic amplified chemo-immunotherapy against triple-negative breast cancer (TNBC) by modulating oxidative state and hyperglycolysis. Specifically, DHCRJ is prepared by the self-assembly of DOX prodrug-tethered ROS consuming bond-bridged copolymers with the loading of bromodomain-containing protein 4 inhibitor (BRD4i) JQ1. Interestingly, the nanoparticle polymer network could reduce ROS to relieve tumor hypoxia and realize the dense-to-loose structure inversion arising from ROS-triggered network collapse, which favors JQ1 release and hyaluronidase (Hyal)-activatable DOX prodrugs generation. More importantly, disruption of oxidative stress decreases glucose uptake and assists JQ1 to down-regulate oncogene c-Myc driven tumor glycolysis for blocking the source of lactate and reshaping immunosuppressive tumor microenvironment (ITME). Meanwhile, benefiting from the synergistic effect of DOX prodrugs and JQ1, DHCRJ is able to facilitate tumor immunogenicity and potentiate systemic immune responses through antigen processing and presentation pathway. In this manner, DHCRJ significantly suppresses tumor growth and metastasis with prolonged survival. Collectively, this study represents a proof of concept antioxidant-enhanced chemo-immunometabolic therapy strategy using ROS-reducing nanoparticles for efficient synergistic therapeutic modality of TNBC.
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Affiliation(s)
- Hongjuan Zhao
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, PR China
| | - Yatong Li
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Haiyu Shi
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Mengya Niu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Dan Li
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Zhenzhong Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, PR China
| | - Qianhua Feng
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, PR China.
| | - Yi Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China.
| | - Lei Wang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, PR China.
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14
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Kalyanaraman B. NAC, NAC, Knockin' on Heaven's door: Interpreting the mechanism of action of N-acetylcysteine in tumor and immune cells. Redox Biol 2022; 57:102497. [PMID: 36242913 PMCID: PMC9563555 DOI: 10.1016/j.redox.2022.102497] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/05/2022] [Indexed: 11/17/2022] Open
Abstract
N-acetylcysteine (NAC) has been used as a direct scavenger of reactive oxygen species (hydrogen peroxide, in particular) and an antioxidant in cancer biology and immuno-oncology. NAC is the antioxidant drug most frequently employed in studies using tumor cells, immune cells, and preclinical mouse xenografts. Most studies use redox-active fluorescent probes such as dichlorodihydrofluorescein, hydroethidine, mitochondria-targeted hydroethidine, and proprietary kit-based probes (i.e., CellROX Green and CellROX Red) for intracellular detection of superoxide or hydrogen peroxide. Inhibition of fluorescence by NAC was used as a key experimental observation to support the formation of reactive oxygen species and redox mechanisms proposed for ferroptosis, tumor metastasis, and redox signaling in the tumor microenvironment. Reactive oxygen species such as superoxide and hydrogen peroxide stimulate or abrogate tumor cells and immune cells depending on multiple factors. Understanding the mechanism of antioxidants is crucial for interpretation of the results. Because neither NAC nor the fluorescent probes indicated above react directly with hydrogen peroxide, it is critically important to reinterpret the results to advance our understanding of the mechanism of action of NAC and shed additional mechanistic insight on redox-regulated signaling in tumor biology. To this end, this review is focused on how NAC could affect multiple pathways in cancer cells, including iron signaling, ferroptosis, and the glutathione-dependent antioxidant and redox signaling mechanism, and how NAC could inhibit oxidation of the fluorescent probes through multiple mechanisms.
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Affiliation(s)
- Balaraman Kalyanaraman
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, USA.
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15
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Jiang S, Yin C, Dang K, Zhang W, Huai Y, Qian A. Comprehensive ceRNA network for MACF1 regulates osteoblast proliferation. BMC Genomics 2022; 23:695. [PMID: 36207684 PMCID: PMC9541005 DOI: 10.1186/s12864-022-08910-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies have shown that microtubule actin crosslinking factor 1 (MACF1) can regulate osteoblast proliferation and differentiation through non-coding RNA (ncRNA) in bone-forming osteoblasts. However, the role of MACF1 in targeting the competing endogenous RNA (ceRNA) network to regulate osteoblast differentiation remains poorly understood. Here, we profiled messenger RNA (mRNA), microRNA (miRNA), and long ncRNA (lncRNA) expression in MACF1 knockdown MC3TC‑E1 pre‑osteoblast cells. RESULTS In total, 547 lncRNAs, 107 miRNAs, and 376 mRNAs were differentially expressed. Significantly altered lncRNAs, miRNAs, and mRNAs were primarily found on chromosome 2. A lncRNA-miRNA-mRNA network was constructed using a bioinformatics computational approach. The network indicated that mir-7063 and mir-7646 were the most potent ncRNA regulators and mef2c was the most potent target gene. Pathway enrichment analysis showed that the fluid shear stress and atherosclerosis, p53 signaling, and focal adhesion pathways were highly enriched and contributed to osteoblast proliferation. Importantly, the fluid shear stress and atherosclerosis pathway was co-regulated by lncRNAs and miRNAs. In this pathway, Dusp1 was regulated by AK079370, while Arhgef2 was regulated by mir-5101. Furthermore, Map3k5 was regulated by AK154638 and mir-466q simultaneously. AK003142 and mir-3082-5p as well as Ak141402 and mir-446 m-3p were identified as interacting pairs that regulate target genes. CONCLUSION This study revealed the global expression profile of ceRNAs involved in the differentiation of MC3TC‑E1 osteoblasts induced by MACF1 deletion. These results indicate that loss of MACF1 activates a comprehensive ceRNA network to regulate osteoblast proliferation.
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Affiliation(s)
- Shanfeng Jiang
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
| | - Chong Yin
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- Department of Clinical Laboratory, Academician (expert) workstation, Lab of epigenetics and RNA therapy, Affiliated Hospital of North Sichuan Medical College, 637000, Nanchong, China
| | - Kai Dang
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
| | - Wenjuan Zhang
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
| | - Ying Huai
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China
| | - Airong Qian
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China.
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China.
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, 710072, Xi'an, Shaanxi, China.
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16
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Morris G, Gevezova M, Sarafian V, Maes M. Redox regulation of the immune response. Cell Mol Immunol 2022; 19:1079-1101. [PMID: 36056148 PMCID: PMC9508259 DOI: 10.1038/s41423-022-00902-0] [Citation(s) in RCA: 204] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/29/2022] [Indexed: 12/20/2022] Open
Abstract
AbstractThe immune-inflammatory response is associated with increased nitro-oxidative stress. The aim of this mechanistic review is to examine: (a) the role of redox-sensitive transcription factors and enzymes, ROS/RNS production, and the activity of cellular antioxidants in the activation and performance of macrophages, dendritic cells, neutrophils, T-cells, B-cells, and natural killer cells; (b) the involvement of high-density lipoprotein (HDL), apolipoprotein A1 (ApoA1), paraoxonase-1 (PON1), and oxidized phospholipids in regulating the immune response; and (c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor-κB, HIF1α, the mechanistic target of rapamycin, the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, mitogen-activated protein kinases, 5' AMP-activated protein kinase, and peroxisome proliferator-activated receptor. The performance and survival of individual immune cells is under redox control and depends on intracellular and extracellular levels of ROS/RNS. They are heavily influenced by cellular antioxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2, and the HDL/ApoA1/PON1 complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.
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17
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Ceramide synthase 6 impacts T-cell allogeneic response and graft-versus-host disease through regulating N-RAS/ERK pathway. Leukemia 2022; 36:1907-1915. [PMID: 35513703 PMCID: PMC9256768 DOI: 10.1038/s41375-022-01581-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 04/09/2022] [Accepted: 04/20/2022] [Indexed: 02/02/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for various hematologic malignances, predominantly through potent graft-versus-leukemia (GVL) effect. However, the mortality after allo-HCT is because of relapse of primary malignancy and followed by graft-vs-host-disease (GVHD) as a major cause of transplant-related mortality. Hence, strategies to limit GVHD while preserving the GVL effect are highly desirable. Ceramide, which serves a central role in sphingolipid metabolism, is generated by ceramide synthases (CerS1–6). In this study, we found that genetic or pharmacologic targeting of CerS6 prevented and reversed chronic GVHD (cGVHD). Furthermore, specific inhibition of CerS6 with ST1072 significantly ameliorated acute GVHD (aGVHD) while preserving the GVL effect, which differed from FTY720 that attenuated aGVHD but impaired GVL activity. At the cellular level, blockade of CerS6 restrained donor T cells from migrating into GVHD target organs and preferentially reduced activation of donor CD4 T cells. At the molecular level, CerS6 was required for optimal TCR signaling, CD3/PKCθ co-localization, and subsequent N-RAS activation and ERK signaling, especially on CD4+ T cells. The current study provides rationale and means for targeting CerS6 to control GVHD and leukemia relapse, which would enhance the efficacy of allo-HCT as an immunotherapy for hematologic malignancies in the clinic.
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18
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Karl F, Hudecek M, Berberich-Siebelt F, Mackensen A, Mougiakakos D. T-Cell Metabolism in Graft Versus Host Disease. Front Immunol 2021; 12:760008. [PMID: 34777373 PMCID: PMC8586445 DOI: 10.3389/fimmu.2021.760008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/11/2021] [Indexed: 01/23/2023] Open
Abstract
Allogeneic-hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for numerous hematological malignancies. Elimination of malignant cells depends on the T-cells' Graft-versus-Tumor (GvT) effect. However, Graft-versus-Host-Disease (GvHD), often co-occurring with GvT, remains an obstacle for therapeutic efficacy. Hence, approaches, which selectively alleviate GvHD without compromising GvT activity, are needed. As already explored for autoimmune and inflammatory disorders, immuno-metabolic interventions pose a promising option to address this unmet challenge. Being embedded in a complex regulatory framework, immunological and metabolic pathways are closely intertwined, which is demonstrated by metabolic reprograming of T-cells upon activation or differentiation. In this review, current knowledge on the immuno-metabolic signature of GvHD-driving T-cells is summarized and approaches to metabolically interfere are outlined. Furthermore, we address the metabolic impact of standard medications for GvHD treatment and prophylaxis, which, in conjunction with the immuno-metabolic profile of alloreactive T-cells, could allow more targeted interventions in the future.
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Affiliation(s)
- Franziska Karl
- Department of Medicine 5, Hematology and Clinical Oncology, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Hudecek
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | | | - Andreas Mackensen
- Department of Medicine 5, Hematology and Clinical Oncology, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Dimitrios Mougiakakos
- Department of Medicine 5, Hematology and Clinical Oncology, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
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19
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Mohamed FA, Thangavelu G, Rhee SY, Sage PT, O’Connor RS, Rathmell JC, Blazar BR. Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease. Front Immunol 2021; 12:757836. [PMID: 34712243 PMCID: PMC8546182 DOI: 10.3389/fimmu.2021.757836] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/13/2021] [Indexed: 01/14/2023] Open
Abstract
The therapeutic efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the development of graft-versus-host disease (GVHD). In GVHD, rigorous pre-conditioning regimen resets the immune landscape and inflammatory milieu causing immune dysregulation, characterized by an expansion of alloreactive cells and a reduction in immune regulatory cells. In acute GVHD (aGVHD), the release of damage- and pathogen- associated molecular patterns from damaged tissue caused by the conditioning regimen sets the stage for T cell priming, activation and expansion further exacerbating tissue injury and organ damage, particularly in the gastrointestinal tract. Studies have shown that donor T cells utilize multiple energetic and biosynthetic pathways to mediate GVHD that can be distinct from the pathways used by regulatory T cells for their suppressive function. In chronic GVHD (cGVHD), donor T cells may differentiate into IL-21 producing T follicular helper cells or tissue resident T helper cells that cooperate with germinal center B cells or memory B cells, respectively, to produce allo- and auto-reactive antibodies with subsequent tissue fibrosis. Alternatively, donor T cells can become IFN- γ/IL-17 cytokine expressing T cells that mediate sclerodermatous skin injury. Patients refractory to the first line standard regimens for GVHD treatment have a poor prognosis indicating an urgent need for new therapies to restore the balance between effector and regulatory immune cells while preserving the beneficial graft-versus-tumor effect. Emerging data points toward a role for metabolism in regulating these allo- and auto-immune responses. Here, we will discuss the preclinical and clinical data available on the distinct metabolic demands of acute and chronic GVHD and recent efforts in identifying therapeutic targets using metabolomics. Another dimension of this review will examine the changing microbiome after allo-HSCT and the role of microbial metabolites such as short chain fatty acids and long chain fatty acids on regulating immune responses. Lastly, we will examine the metabolic implications of coinhibitory pathway blockade and cellular therapies in allo-HSCT. In conclusion, greater understanding of metabolic pathways involved in immune cell dysregulation during allo-HSCT may pave the way to provide novel therapies to prevent and treat GVHD.
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Affiliation(s)
- Fathima A. Mohamed
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Govindarajan Thangavelu
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Stephanie Y. Rhee
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Peter T. Sage
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Roddy S. O’Connor
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Center for Cellular Immunotherapies, Perelman School of Medicine, Philadelphia, PA, United States
| | - Jeffrey C. Rathmell
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Bruce R. Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota Cancer Center, Minneapolis, MN, United States
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20
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Cheng X, Hao Z, Chu S, Zhang T, Cong C, Liu L, Zhang W, Gu J, Ni S, Wang D, Gao D. Plasmonic enhanced enzyme activity by catalytic cascade induced mutual benefit tumor starvation/immune/photothermal therapy. Biomater Sci 2021; 9:6116-6125. [PMID: 34519735 DOI: 10.1039/d1bm00551k] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Single tumor starvation therapy can activate other signaling pathways in tumor cells and easily induce tumor cell metastasis. This research proposes an intelligent nanoparticle, which is effectively combined with plasmonic and immunotherapy to realize a new strategy of "upstream consumption and downstream blocking" of nutrients in tumor sites. The intelligent nanoparticle (Ag-G/C@M) was composed of Ag NCs loaded with glucose oxidase (GOx), catalase (CAT) and coated with the tumor cytomembrane (M). Homologous targeting of tumor cytomembrane facilitated more delivery of Ag-G/C@M to tumor sites and then the plasmonic excited from Ag-G/C@M can increase the catalytic efficiency of the enzymatic reaction. Hydrogen peroxide (H2O2) produced by Ag-G/C@M through the consumption of glucose is further catalyzed by CAT to produce oxygen (O2). This self-reinforcing cascade reaction not only consumes the nutrients of tumor cells, but also the plasmonic-induced photothermal therapy can further stimulate the immune system to produce interferon-γ (IFN-γ), blocking angiogenesis and restricting the nutrient supply of tumor cells. This strategy takes the nutrition necessary for cell survival as the entry point, through endogenous continuous consumption of intracellular nutrients and containment of exogenous supplementation, combined with plasmonic thermal effect and immunotherapy to kill tumor cells, which provides a new way of treating cancer safely and effectively.
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Affiliation(s)
- Xin Cheng
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.
| | - Zining Hao
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.
| | - Shuzhen Chu
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.
| | - Tiantian Zhang
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.
| | - Cong Cong
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.
| | - Lanxiang Liu
- Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, P. R. China
| | - Weidong Zhang
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China. .,Department of Magnetic Resonance Imaging, Qinhuangdao Municipal No. 1 Hospital, Qinhuangdao, P. R. China
| | - Jianmin Gu
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.
| | - Song Ni
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Desong Wang
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.
| | - Dawei Gao
- State Key Laboratory of Metastable Materials Science and Technology, Key Laboratory of Nanobiotechnology of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.
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21
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Ogawa Y, Kawakami Y, Tsubota K. Cascade of Inflammatory, Fibrotic Processes, and Stress-Induced Senescence in Chronic GVHD-Related Dry Eye Disease. Int J Mol Sci 2021; 22:ijms22116114. [PMID: 34204098 PMCID: PMC8201206 DOI: 10.3390/ijms22116114] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/30/2021] [Accepted: 05/31/2021] [Indexed: 01/12/2023] Open
Abstract
Ocular graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Ocular GVHD affects recipients' visual function and quality of life. Recent advanced research in this area has gradually attracted attention from a wide range of physicians and ophthalmologists. This review highlights the mechanism of immune processes and the molecular mechanism, including several inflammation cascades, pathogenic fibrosis, and stress-induced senescence related to ocular GVHD, in basic spectrum topics in this area. How the disease develops and what kinds of cells participate in ocular GVHD are discussed. Although the classical immune process is a main pathological pathway in this disease, senescence-associated changes in immune cells and stem cells may also drive this disease. The DNA damage response, p16/p21, and the expression of markers associated with the senescence-associated secretory phenotype (SASP) are seen in ocular tissue in GVHD. Macrophages, T cells, and mesenchymal cells from donors or recipients that increasingly infiltrate the ocular surface serve as the source of increased secretion of IL-6, which is a major SASP driver. Agents capable of reversing the changes, including senolytic reagents or those that can suppress the SASP seen in GVHD, provide new potential targets for the treatment of GVHD. Creating innovative therapies for ocular GVHD is necessary to treat this intractable ocular disease.
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Affiliation(s)
- Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan;
- Correspondence: ; Tel.: +81-3-3353-1211
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan;
- Department of Immunology, School of Medicine, International University of Health and Welfare, Chiba 286-8686, Japan
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan;
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22
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Immunometabolism in haematopoietic stem cell transplantation and adoptive cellular therapies. Curr Opin Hematol 2021; 27:353-359. [PMID: 33003083 DOI: 10.1097/moh.0000000000000615] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE OF REVIEW Controlling T cell activity through metabolic manipulation has become a prominent feature in immunology and practitioners of both adoptive cellular therapy (ACT) and haematopoietic stem cell transplantation (HSCT) have utilized metabolic interventions to control T cell function. This review will survey recent metabolic research efforts in HSCT and ACT to paint a broad picture of immunometabolism and highlight advances in each area. RECENT FINDINGS In HSCT, recent publications have focused on modifying reactive oxygen species, sirtuin signalling or the NAD salvage pathway within alloreactive T cells and regulatory T cells. In ACT, metabolic interventions that bolster memory T cell development, increase mitochondrial density and function, or block regulatory signals in the tumour microenvironment (TME) have recently been published. SUMMARY Metabolic interventions control immune responses. In ACT, efforts seek to improve the in-vivo metabolic fitness of T cells, while in HSCT energies have focused on blocking alloreactive T cell expansion or promoting regulatory T cells. Methods to identify new, metabolically targetable pathways, as well as the ability of metabolic biomarkers to predict disease onset and therapeutic response, will continue to advance the field towards clinically applicable interventions.
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23
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Zhang J, Duan D, Osama A, Fang J. Natural Molecules Targeting Thioredoxin System and Their Therapeutic Potential. Antioxid Redox Signal 2021; 34:1083-1107. [PMID: 33115246 DOI: 10.1089/ars.2020.8213] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: Thioredoxin (Trx) and thioredoxin reductase are two core members of the Trx system. The system bridges the gap between the universal reducing equivalent NADPH and various biological molecules and plays an essential role in maintaining cellular redox homeostasis and regulating multiple cellular redox signaling pathways. Recent Advance: In recent years, the Trx system has been well documented as an important regulator of many diseases, especially tumorigenesis. Thus, the development of potential therapeutic molecules targeting the system is of great significance for disease treatment. Critical Issues: We herein first discuss the physiological functions of the Trx system and the role that the Trx system plays in various diseases. Then, we focus on the introduction of natural small molecules with potential therapeutic applications, especially the anticancer activity, and review their mechanisms of pharmacological actions via interfering with the Trx system. Finally, we further discuss several natural molecules that harbor therapeutic potential and have entered different clinical trials. Future Directions: Further studies on the functions of the Trx system in multiple diseases will not only improve our understanding of the pathogenesis of many human disorders but also help develop novel therapeutic strategies against these diseases. Antioxid. Redox Signal. 34, 1083-1107.
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Affiliation(s)
- Junmin Zhang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
- Shaanxi Key Laboratory of Phytochemistry, Baoji University of Arts and Sciences, Baoji, China
| | - Dongzhu Duan
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
- Shaanxi Key Laboratory of Phytochemistry, Baoji University of Arts and Sciences, Baoji, China
| | - Alsiddig Osama
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
- Shaanxi Key Laboratory of Phytochemistry, Baoji University of Arts and Sciences, Baoji, China
| | - Jianguo Fang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
- Shaanxi Key Laboratory of Phytochemistry, Baoji University of Arts and Sciences, Baoji, China
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24
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Song Q, Wang X, Wu X, Qin H, Li Y, Riggs AD, Martin PJ, Chen YZ, Zeng D. Tolerogenic anti-IL-2 mAb prevents graft-versus-host disease while preserving strong graft-versus-leukemia activity. Blood 2021; 137:2243-2255. [PMID: 33511398 PMCID: PMC8063091 DOI: 10.1182/blood.2020006345] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 01/01/2021] [Indexed: 12/15/2022] Open
Abstract
Donor T cells mediate both graft-versus-leukemia (GVL) activity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Development of methods that preserve GVL activity while preventing GVHD remains a long-sought goal. Tolerogenic anti-interleukin-2 (IL-2) monoclonal antibody (JES6-1) forms anti-IL-2/IL-2 complexes that block IL-2 binding to IL-2Rβ and IL-2Rγ on conventional T cells that have low expression of IL-2Rα. Here, we show that administration of JES6 early after allo-HCT in mice markedly attenuates acute GVHD while preserving GVL activity that is dramatically stronger than observed with tacrolimus (TAC) treatment. The anti-IL-2 treatment downregulated activation of the IL-2-Stat5 pathway and reduced production of granulocyte-macrophage colony-stimulating factor (GM-CSF). In GVHD target tissues, enhanced T-cell programmed cell death protein 1 (PD-1) interaction with tissue-programmed cell death-ligand 1 (PD-L1) led to reduced activation of protein kinase-mammalian target of rapamycin pathway and increased expression of eomesodermin and B-lymphocyte-induced maturation protein-1, increased T-cell anergy/exhaustion, expansion of Foxp3-IL-10-producing type 1 regulatory (Tr1) cells, and depletion of GM-CSF-producing T helper type 1 (Th1)/cytotoxic T cell type 1 (Tc1) cells. In recipient lymphoid tissues, lack of donor T-cell PD-1 interaction with tissue PD-L1 preserved donor PD-1+TCF-1+Ly108+CD8+ T memory progenitors and functional effectors that have strong GVL activity. Anti-IL-2 and TAC treatments have qualitatively distinct effects on donor T cells in the lymphoid tissues, and CD8+ T memory progenitor cells are enriched with anti-IL-2 treatment compared with TAC treatment. We conclude that administration of tolerogenic anti-IL-2 monoclonal antibody early after allo-HCT represents a novel approach for preventing acute GVHD while preserving GVL activity.
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Affiliation(s)
- Qingxiao Song
- Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Xiaoning Wang
- Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Xiwei Wu
- Department of Integrative Genomics Core, The Beckman Research Institute of City of Hope, Duarte, CA
| | - Hanjun Qin
- Department of Integrative Genomics Core, The Beckman Research Institute of City of Hope, Duarte, CA
| | - Yingfei Li
- The Third People's Hospital of Shenzhen, Shenzhen, Guangdong, China; and
| | - Arthur D Riggs
- Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA
| | | | - Yuan-Zhong Chen
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Defu Zeng
- Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
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25
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Sofi MH, Wu Y, Ticer T, Schutt S, Bastian D, Choi HJ, Tian L, Mealer C, Liu C, Westwater C, Armeson KE, Alekseyenko AV, Yu XZ. A single strain of Bacteroides fragilis protects gut integrity and reduces GVHD. JCI Insight 2021; 6:136841. [PMID: 33554953 PMCID: PMC7934839 DOI: 10.1172/jci.insight.136841] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 12/16/2020] [Indexed: 12/20/2022] Open
Abstract
Graft-versus-host disease (GVHD) is a pathological process caused by an exaggerated donor lymphocyte response to host antigens after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells undergo extensive clonal expansion and differentiation, which culminate in damage to recipient target organs. Damage to the gastrointestinal tract is a main contributor to morbidity and mortality. The loss of diversity among intestinal bacteria caused by pretransplant conditioning regimens leads to an outgrowth of opportunistic pathogens and exacerbated GVHD after allo-HCT. Using murine models of allo-HCT, we found that an increase of Bacteroides in the intestinal microbiota of the recipients was associated with reduced GVHD in mice given fecal microbial transplantation. Administration of Bacteroides fragilis through oral gavage increased gut microbiota diversity and beneficial commensal bacteria and significantly ameliorated acute and chronic GVHD development. Preservation of gut integrity following B. fragilis exposure was likely attributed to increased short chain fatty acids, IL-22, and regulatory T cells, which in turn improved gut tight junction integrity and reduced inflammatory cytokine production of pathogenic T cells. The current study provides a proof of concept that a single strain of commensal bacteria can be a safe and effective means to protect gut integrity and ameliorate GVHD after allo-HCT.
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Affiliation(s)
- M Hanief Sofi
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Yongxia Wu
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Taylor Ticer
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Steven Schutt
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - David Bastian
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Hee-Jin Choi
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Linlu Tian
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Corey Mealer
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Chen Liu
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Caroline Westwater
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.,Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Kent E Armeson
- Biomedical Informatics Center and Department of Public Health Sciences, College of Medicine, and Department of Healthcare Leadership & Management, College of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Alexander V Alekseyenko
- Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.,Biomedical Informatics Center and Department of Public Health Sciences, College of Medicine, and Department of Healthcare Leadership & Management, College of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Hollings Cancer Center, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
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26
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Brown RA, Byersdorfer CA. Metabolic Pathways in Alloreactive T Cells. Front Immunol 2020; 11:1517. [PMID: 32793207 PMCID: PMC7393946 DOI: 10.3389/fimmu.2020.01517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative therapy for a range of hematologic illnesses including aplastic anemia, sickle cell disease, immunodeficiency, and high-risk leukemia, but the efficacy of aHSCT is often undermined by graft-versus-host disease (GVHD), where T cells from the donor attack and destroy recipient tissues. Given the strong interconnection between T cell metabolism and cellular function, determining the metabolic pathways utilized by alloreactive T cells is fundamental to deepening our understanding of GVHD biology, including its initiation, propagation, and potential mitigation. This review summarizes the metabolic pathways available to alloreactive T cells and highlights key metabolic proteins and pathways linking T cell metabolism to effector function. Our current knowledge of alloreactive T cell metabolism is then explored, showing support for glycolysis, fat oxidation, and glutamine metabolism but also offering a potential explanation for how these presumably contradictory metabolic findings might be reconciled. Examples of additional ways in which metabolism impacts aHSCT are addressed, including the influence of butyrate metabolism on GVHD resolution. Finally, the caveats and challenges of assigning causality using our current metabolic toolbox is discussed, as well as likely future directions in immunometabolism, both to highlight the strengths of the current evidence as well as recognize some of its limitations.
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Affiliation(s)
- Rebecca A Brown
- Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Craig A Byersdorfer
- Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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27
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Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients. Leukemia 2020; 35:910-915. [PMID: 32704160 DOI: 10.1038/s41375-020-0956-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/25/2020] [Indexed: 01/13/2023]
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28
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Berberine combined with cyclosporine A alleviates acute graft-versus-host disease in murine models. Int Immunopharmacol 2020; 81:106205. [DOI: 10.1016/j.intimp.2020.106205] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/25/2019] [Accepted: 01/07/2020] [Indexed: 12/22/2022]
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29
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Hippen KL, Aguilar EG, Rhee SY, Bolivar-Wagers S, Blazar BR. Distinct Regulatory and Effector T Cell Metabolic Demands during Graft-Versus-Host Disease. Trends Immunol 2020; 41:77-91. [PMID: 31791718 PMCID: PMC6934920 DOI: 10.1016/j.it.2019.11.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 11/08/2019] [Accepted: 11/08/2019] [Indexed: 02/07/2023]
Abstract
Despite graft-versus-host disease (GVHD) prophylactic agents, the success and wider utilization of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by GVHD. Increasing donor graft regulatory T cell (Treg):effector T cell (Teff) ratios can substantially reduce GVHD in cancer patients, but pre-HSCT conditioning regimens and GVHD create a challenging inflammatory environment for Treg stability, persistence, and function. Metabolism plays a crucial role in T cell and Treg differentiation, and development of effector function. Although glycolysis is a main driver of allogeneic T cell-driven GVHD, oxidative phosphorylation is a main driver of Treg suppressor function. This review focuses on recent advances in our understanding of Treg metabolism in the context of GVHD, and discusses potential therapeutic applications of Tregs in the prevention or treatment of GVHD in cancer patients.
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Affiliation(s)
- Keli L Hippen
- University of Minnesota Cancer Center, Minneapolis, MN 55455, USA; Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Ethan G Aguilar
- University of Minnesota Cancer Center, Minneapolis, MN 55455, USA; Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
| | - Stephanie Y Rhee
- University of Minnesota Cancer Center, Minneapolis, MN 55455, USA; Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
| | - Sara Bolivar-Wagers
- University of Minnesota Cancer Center, Minneapolis, MN 55455, USA; Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
| | - Bruce R Blazar
- University of Minnesota Cancer Center, Minneapolis, MN 55455, USA; Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
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