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Yu X, Chen Y, Lei L, Li P, Lin D, Shen Y, Hou C, Chen J, Fan Y, Jin Y, Lu H, Wu D, Xu Y. Mendelian randomization analysis of blood metabolites and immune cell mediators in relation to GVHD and relapse. BMC Med 2025; 23:201. [PMID: 40189523 PMCID: PMC11974087 DOI: 10.1186/s12916-025-04026-w] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 03/19/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Graft-versus-host disease (GVHD) and relapse are major complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Metabolites play crucial roles in immune regulation, but their causal relationships with GVHD and relapse remain unclear. METHODS We utilized genetic variants from genome-wide association studies (GWAS) of 309 known metabolites as instrumental variables to evaluate their causal effects on acute GVHD (aGVHD), gut GVHD, chronic GVHD (cGVHD), and relapse in different populations. Multiple causal inference methods, heterogeneity assessments, and pleiotropy tests were conducted to ensure result robustness. Multivariable MR analysis was performed to adjust for potential confounders, and validation MR analysis further confirmed key findings. Mediation MR analysis was employed to explore indirect causal pathways. RESULTS After correction for multiple testing, we identified elevated pyridoxate and proline levels as protective factors against grade 3-4 aGVHD (aGVHD3) and relapse, respectively. Conversely, glycochenodeoxycholate increased the risk of aGVHD3, whereas 1-stearoylglycerophosphoethanolamine had a protective effect. The robustness and stability of these findings were confirmed by multiple causal inference approaches, heterogeneity, and horizontal pleiotropy analyses. Multivariable MR analysis further excluded potential confounding pleiotropic effects. Validation MR analyses supported the causal roles of pyridoxate and 1-stearoylglycerophosphoethanolamine, while mediation MR revealed that pyridoxate influences GVHD directly and indirectly via CD39 + Tregs. Pathway analyses highlighted critical biochemical alterations, including disruptions in bile acid metabolism and the regulatory roles of vitamin B6 derivatives. Finally, clinical metabolic analyses, including direct fecal metabolite measurements, confirmed the protective role of pyridoxate against aGVHD. CONCLUSIONS Our findings provide novel insights into the metabolic mechanisms underlying GVHD and relapse after allo-HSCT. Identified metabolites, particularly pyridoxate, may serve as potential therapeutic targets for GVHD prevention and management.
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Affiliation(s)
- Xinghao Yu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yiyin Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Lei Lei
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Pengfei Li
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Dandan Lin
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ying Shen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Chang Hou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Jia Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yi Fan
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yi Jin
- Department of Pharmacy, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213000, China
| | - Huimin Lu
- Department of Outpatient and Emergency, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
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Raoufi A, Soleimani Samarkhazan H, Nouri S, Khaksari MN, Abbasi Sourki P, Sargazi Aval O, Baradaran B, Aghaei M. Macrophages in graft-versus-host disease (GVHD): dual roles as therapeutic tools and targets. Clin Exp Med 2025; 25:73. [PMID: 40048037 PMCID: PMC11885342 DOI: 10.1007/s10238-025-01588-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/03/2025] [Indexed: 03/09/2025]
Abstract
Graft-versus-host disease remains one of the most formidable barriers to the complete success of hematopoietic stem cell transplantation that has emerged as the curative approach for many hematopoietic malignancies because it affects quality of life and overall survival. Macrophages are among the important members of the immune system, which perform dual roles in GVHD as both therapeutic tools and targets. This review epitomizes the multifunctional role of macrophages in the pathophysiology of both acute and chronic GVHD. Macrophages play an important role in the early phase of GVHD because of their recruitment and infiltration into target organs. Furthermore, they polarize into two functionally different phenotypes, including M1 and M2. In the case of acute GVHD, most macrophages express the M1 phenotype characterized by the production of pro-inflammatory cytokines that contribute to tissue damage. In contrast, in chronic GVHD, macrophages tend toward the M2 phenotype associated with the repair of tissues and fibrosis. A critical balance among these phenotypes is central to the course and severity of GVHD. Further interactions of macrophages with other lymphocytes such as T cells, B cells, and fibroblast further determine the course of GVHD. Macrophage interaction associated with alloreactive T cells promotes inflammation. This is therefore important in inducing injuries of tissues during acute GVHD. Interaction of macrophages, B cell, fibroblast, and CD4+ T cells promotes fibrosis during chronic GVHD and, hence, the subsequent dysfunction of organs. These are some insights, while several challenges remain. First, the impact of the dominant cytokines in GVHD on the polarization of macrophages is incompletely characterized and sometimes controversial. Second, the development of targeted therapies able to modulate macrophage function without systemic side effects remains an area of ongoing investigation. Future directions involve the exploration of macrophage-targeted therapies, including small molecules, antibodies, and nanotechnology, which modulate macrophage behavior and improve patient outcomes. This underlines the fact that a profound understanding of the dual role of macrophages in GVHD is essential for developing new and more effective therapeutic strategies. Targeting macrophages might represent one avenue for decreasing the incidence and severity of GVHD and improving the success and safety of HSCT.
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Affiliation(s)
- Atieh Raoufi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan University of Medical Science, Zanjan, Iran
| | - Hamed Soleimani Samarkhazan
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Nouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Navid Khaksari
- Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Abbasi Sourki
- Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Omolbanin Sargazi Aval
- Department of Hematology, Faculty of Allied Medical Sciences, Zabol University of Medical Sciences, Zabol, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran.
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Ma Y, Chen J, Fan Z, Shi J, Li G, Li X, Wang T, Xu N, Liu J, Li Z, Li H, Zhang X, Lin D, Song W, Liu Q, Huang W, Chen X, Xiang AP. Dynamic forecasting module for chronic graft-versus-host disease progression based on a disease-associated subpopulation of B cells: a multicenter prospective study. EBioMedicine 2025; 113:105587. [PMID: 39946832 PMCID: PMC11872411 DOI: 10.1016/j.ebiom.2025.105587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Predicting chronic graft-versus-host disease (cGVHD) progression has been challenging due to its dynamic nature and the lack of reliable real-time monitoring tools, necessitating substantial investments of time and financial resources for effective management. Consequently, identifying appropriate immune cell subsets or molecules as prognostic or predictive biomarkers for cGVHD is essential. METHODS Building on the pivotal role of B-cell homeostasis in cGVHD progression, we integrated spectral flow cytometry with advanced machine learning algorithms to systematically analyze the relationship between B cells and cGVHD progression. Leveraging the identification of a distinct B-cell subpopulation, we developed cGPS (cGVHD Progress Score), a user-friendly tool based on marker distribution. To validate cGPS, we conducted both retrospective and prospective multi-center studies involving 91 patients (25 non-GVHD and 66 cGVHD cases). FINDINGS We identified a distinct B-cell subpopulation characterized by CD27+CD86+CD20-, which can precisely distinguish cGVHD. Leveraging this discovery, we developed cGPS. The retrospective study highlighted the predictive power of cGPS, achieving an impressive area under the curve (AUC) of 0.98 for identifying non-GVHD patients prone to cGVHD and 0.88 for predicting disease progression in cGVHD patients. Notably, the prospective study highlighted cGPS's effectiveness, as it accurately predicted all instances of cGVHD development or progression within an average of three-month observation window. INTERPRETATION These findings validate cGPS as a highly effective and dynamic B cell-based tool for monitoring cGVHD progression, offering a crucial solution for prognosis and prediction of treatment effectiveness. The multicenter approach applied to both retrospective and prospective studies strengthen the reliability and adaptability of our findings. We are confident that cGPS is a highly competitive tool with great potential for clinical application. FUNDING This work was supported by grants from the National Key Research and Development Program of China, Stem Cell and Translational Research (2022YFA1105000, 2022YFA1104100); the National Natural Science Foundation of China (82430050, 32130046, 82270230, 81970109); Key Research and Development Program of Guangdong Province (2023B1111050006); Guangdong Basic and Applied Basic Research Foundation (2023B1515020119); Key Scientific and Technological Program of Guangzhou City (2023B01J1002); Pioneering talents project of Guangzhou Development Zone (2021-L029); the Shenzhen Science and Technology Program (KJZD20230923114504008).
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Affiliation(s)
- Yuanchen Ma
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Jieying Chen
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Zhiping Fan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jiahao Shi
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Gang Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Xiaobo Li
- Core Facility of Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Tao Wang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Na Xu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jialing Liu
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Zhishan Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Heshe Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Xiaoran Zhang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Dongjun Lin
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Wu Song
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Weijun Huang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; Department of Histoembryology and Cell Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China; Department of Histoembryology and Cell Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
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Hayashi T, Nakashima Y, Takeda S, Nishimoto M, Okamura H, Takakuwa T, Kuno M, Makuuchi Y, Ido K, Sakatoku K, Horiuchi M, Koh H, Nakamae M, Hino M, Nakamae H. Posttransplantation cyclophosphamide mediates effective reconstitution of memory B cells after allogeneic hematopoietic cell transplantation. Eur J Haematol 2024; 113:651-663. [PMID: 39072897 DOI: 10.1111/ejh.14280] [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: 03/20/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 07/30/2024]
Abstract
OBJECTIVES Impaired B-cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT) contributes to the pathogenesis of chronic graft-versus-host disease (cGVHD). Therefore, methods to consistently achieve effective B cell lymphogenesis are required. We assessed the long-term effects of posttransplantation cyclophosphamide (PTCy) use on immune reconstitution in clinical settings, an emerging strategy to suppress allogeneic immunological inflammation early after allo-HCT and prevent subsequent GVHD. METHODS We comprehensively analyzed peripheral immune cell subsets and measured serum immunoglobulin G (IgG) or cytokine levels in 39 patients who survived for >1 year after allo-HCT. RESULTS The absolute counts of B1 and IgM memory B cells were significantly lower in patients with severe cGVHD than in those without. The absolute count and percentage (among total CD19+ B cells) of switched memory B cells and serum IgG levels were significantly higher in patients transplanted with PTCy than in those transplanted with conventional GVHD prophylaxis. Interestingly, increased percentages of switched memory B cells and serum IgG levels were observed only in patients transplanted with PTCy and not in those transplanted with umbilical cord blood. CONCLUSIONS PTCy administration can mediate favorable memory B-cell reconstitution long after allo-HCT and may therefore suppress cGVHD.
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Affiliation(s)
- Tetsuya Hayashi
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Nakashima
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shinichi Takeda
- Department of Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
| | - Mitsutaka Nishimoto
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hiroshi Okamura
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Teruhito Takakuwa
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masatomo Kuno
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yosuke Makuuchi
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kentaro Ido
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
- Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kazuki Sakatoku
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Mirei Horiuchi
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hideo Koh
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Preventive Medicine and Environmental Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Mika Nakamae
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
- Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masayuki Hino
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
- Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hirohisa Nakamae
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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[Chinese expert consensus on the diagnosis and treatment of chronic graft-versus-host disease (2024)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:713-726. [PMID: 39307718 PMCID: PMC11535560 DOI: 10.3760/cma.j.cn121090-20240611-00217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Indexed: 12/06/2024]
Abstract
Chronic graft-versus-host disease (cGVHD) is a common and severe complication following allogeneic hematopoietic stem cell transplantation, which significantly impacts patients' survival and quality of life. In recent years, notable progress has been made in the diagnosis, prevention, and treatment of cGVHD, driven by the emergence of novel therapies such as targeted drugs and the advancement of clinical research. This consensus, based on the latest developments in cGVHD research and growing data from evidence-based medicine, has been revised and updated from the "Chinese consensus on the diagnosis and management of chronic graft-versus-host disease (2021)" to better guide clinical practice.
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[Chinese expert consensus on ocular chronic graft-versus-host disease (2023)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2023; 44:449-457. [PMID: 37550199 PMCID: PMC10450544 DOI: 10.3760/cma.j.issn.0253-2727.2023.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Indexed: 08/09/2023]
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Song Y, Wang B, Wang W, Shi Q. Regulatory effect of orexin system on various diseases through mTOR signaling pathway. Trends Endocrinol Metab 2023; 34:292-302. [PMID: 36934048 DOI: 10.1016/j.tem.2023.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/19/2023] [Accepted: 02/21/2023] [Indexed: 03/18/2023]
Abstract
Orexin (OX)A and OXB are a pair of neuropeptides secreted by orexin-producing neurons in the lateral hypothalamus. The orexin system can regulate many physiological processes through these two receptor pathways, such as feeding behavior, sleep/wake state, energy homeostasis, reward, and the coordination of emotion. Mammalian target of rapamycin (mTOR) can coordinate upstream signals with downstream effectors, thereby regulating fundamental cellular processes and also plays an essential role in the signaling network downstream of the orexin system. In turn, the orexin system can activate mTOR. Here, we review the association of the orexin system with the mTOR signaling pathway mainly by discussing that drugs in various diseases exert their effects on the orexin system, indirectly affecting the mTOR signaling pathway.
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Affiliation(s)
- Ying Song
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, China.
| | - Beibei Wang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Wenjun Wang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Qiwen Shi
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, China
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Miklos DB, Abu Zaid M, Cooney JP, Albring JC, Flowers M, Skarbnik AP, Yakoub-Agha I, Ko BS, Bruno B, Waller EK, Yared J, Sohn SK, Bulabois CE, Teshima T, Jacobsohn D, Greinix H, Mokatrin A, Lee Y, Wahlstrom JT, Styles L, Socie G. Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study. J Clin Oncol 2023; 41:1876-1887. [PMID: 36608310 PMCID: PMC10082299 DOI: 10.1200/jco.22.00509] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
PURPOSE To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD). METHODS Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety. RESULTS Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients. CONCLUSION There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.
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Affiliation(s)
| | - Mohammad Abu Zaid
- Melvin and Bren Simon Cancer Center (IUSCC), Indiana University, Indianapolis, IN
| | - Julian P Cooney
- Fiona Stanley Hospital, Murdoch, Australia.,University of Western Australia, Crawley, Australia
| | | | - Mary Flowers
- Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Alan P Skarbnik
- John Theurer Cancer Center, Hackensack, NJ.,Novant Health Cancer Institute, Charlotte, NC
| | | | - Bor-Sheng Ko
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Hematological Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Benedetto Bruno
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | | | - Jean Yared
- University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD
| | - Sang Kyun Sohn
- Kyungpook National University Hospital, Daegu, South Korea
| | | | | | | | | | - Ahmad Mokatrin
- Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
| | - Yihua Lee
- Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
| | | | - Lori Styles
- Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
| | - Gerard Socie
- AP-HP, Hopital St Louis and University of Paris, Paris, France
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9
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Cheng X, Huang R, Huang S, Fan W, Yuan R, Wang X, Zhang X. Recent advances in ocular graft-versus-host disease. Front Immunol 2023; 14:1092108. [PMID: 36761771 PMCID: PMC9905686 DOI: 10.3389/fimmu.2023.1092108] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/10/2023] [Indexed: 01/26/2023] Open
Abstract
Ocular graft-versus-host-disease (GVHD) remains a significant clinical complication after allogeneic hematopoietic stem cell transplantation. Impaired visual function, pain, and other symptoms severely affect affected individuals' quality of life. However, the diagnosis of and therapy for ocular GVHD involve a multidisciplinary approach and remain challenging for both hematologists and ophthalmologists, as there are no unified international criteria. Through an exploration of the complex pathogenesis of ocular GVHD, this review comprehensively summarizes the pathogenic mechanism, related tear biomarkers, and clinical characteristics of this disease. Novel therapies based on the mechanisms are also discussed to provide insights into the ocular GVHD treatment.
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Affiliation(s)
- Xianjing Cheng
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China.,School of Medicine, Chongqing University, Chongqing, China
| | - Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Shiqin Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Wei Fan
- Department of Ophthalmology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Rongdi Yuan
- Department of Ophthalmology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China.,School of Medicine, Chongqing University, Chongqing, China.,Jinfeng Laboratory, Chongqing, China
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10
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Kong X, Wu X, Wang B, Zeng D, Cassady K, Nasri U, Zheng M, Wu A, Qin H, Tsai W, Salhotra A, Nakamura R, Martin PJ, Zeng D. Trafficking between clonally related peripheral T-helper cells and tissue-resident T-helper cells in chronic GVHD. Blood 2022; 140:2740-2753. [PMID: 36084473 PMCID: PMC9935547 DOI: 10.1182/blood.2022016581] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 08/29/2022] [Accepted: 08/29/2022] [Indexed: 12/30/2022] Open
Abstract
Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi peripheral T-helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. We show that in patients with cGVHD, expansion of Tph cells among blood CD4+ T cells was associated with cGVHD severity. These cells augmented memory B-cell differentiation and production of immunoglobulin G via interleukin 21 (IL-21). Tph cell expansion was also observed in a murine model of cGVHD. This Tph cell expansion in the blood is associated with the expansion of pathogenic tissue-resident T-helper (Trh) cells that form lymphoid aggregates surrounded by collagen in graft-versus-host disease (GVHD) target tissues. Adoptive transfer experiments showed that Trh cells from GVHD target tissues give rise to Tph cells in the blood, and conversely, Tph cells from the blood give rise to Trh cells in GVHD target tissues. Tph cells in the blood and Trh cells in GVHD target tissues had highly overlapping T-cell receptor α and β repertoires. Deficiency of IL-21R, B-cell lymphoma 6 (BCL6), or T-bet in donor T cells markedly reduced the proportions of Tph cells in the blood and Trh cells in GVHD target tissues and reduced T-B interaction in the lymphoid aggregates. These results indicate that clonally related pathogenic Tph cells and Trh cells traffic between the blood and cGVHD target tissues, and that IL-21R-BCL6 signaling and T-bet are required for the development and expansion of Tph and Trh cells in the pathogenesis of cGVHD.
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Affiliation(s)
- Xiaohui Kong
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, 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
| | - Xiwei Wu
- Department of Integrative Genomics Core, The Beckman Research Institute of City of Hope, Duarte, CA
| | - Bixin Wang
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, 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, Fujian Medical University Union Hospital, Fuzhou, China
| | - Deye Zeng
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, 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
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Kaniel Cassady
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, 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
| | - Ubaydah Nasri
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, 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
| | - Moqian Zheng
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, 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
| | - Alyssa Wu
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, 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
| | - Hanjun Qin
- Department of Integrative Genomics Core, The Beckman Research Institute of City of Hope, Duarte, CA
| | - Weimin Tsai
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Amandeep Salhotra
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Ryotaro Nakamura
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | | | - Defu Zeng
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, 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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11
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Møller DL, Kielsen K, Nielsen CH, Sengeløv H, Pedersen AE, Ryder LP, Müller K. Thymic stromal lymphopoietin levels after allogeneic hematopoietic stem cell transplantation. Immunopharmacol Immunotoxicol 2022; 44:1004-1012. [PMID: 35899395 DOI: 10.1080/08923973.2022.2102989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Thymic stromal lymphopoietin (TSLP) is an immunoregulatory, Th2-polarizing cytokine produced by epithelial cells. We hypothesized that TSLP affects immune reconstitution after hematopoietic stem cell transplantation (HSCT) leading to increased alloreactivity. METHODS We measured plasma TSLP by ELISA in 38 patients and assessed the immune reconstitution by flow cytometry. RESULTS TSLP levels rose after initiation of the conditioning to peak at day +21 after HSCT (p = .03), where TSLP levels correlated with counts of neutrophils (rho = 0.36, p = .04), monocytes (rho = 0.58, p = .006), and lymphocytes (rho = 0.59, p = .02). Overall absolute TSLP levels were not associated with acute or chronic graft-vs-host disease (a/cGvHD). However, patients mounting a sustained increase in TSLP levels at day +90 had a higher risk of cGvHD compared to patients who had returned to pre-conditioning levels at that stage (cumulative incidence: 77% vs. 38%, p = .01). CONCLUSION In conclusion, this study suggests a role of TSLP in immune reconstitution and alloreactivity post-HSCT. lymphopoietin (TSLP) is an immunoregulatory, Th2-polarizing cytokine produced by epithelial cells. We hypothesized that TSLP affects immune reconstitution after hematopoietic stem cell transplantation (HSCT) leading to increased alloreactivity. We measured plasma TSLP by ELISA in 38 patients and assessed the immune reconstitution by flow cytometry.
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Affiliation(s)
- Dina Leth Møller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Katrine Kielsen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Claus Henrik Nielsen
- Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Henrik Sengeløv
- Department of Hematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | | | - Lars Peter Ryder
- The Tissue Typing Laboratory, Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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12
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Zhang MY, Zhao P, Zhang Y, Wang JS. Efficacy and safety of ruxolitinib for steroid-refractory graft-versus-host disease: Systematic review and meta-analysis of randomised and non-randomised studies. PLoS One 2022; 17:e0271979. [PMID: 35905125 PMCID: PMC9337651 DOI: 10.1371/journal.pone.0271979] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 07/11/2022] [Indexed: 11/18/2022] Open
Abstract
Background Hematopoietic stem cell transplantation (HSCT) for haematological disorders. Graft-versus-host disease (GVHD), a cause of morbidity and mortality is treated with corticosteroids. However, patients with steroid-refractory GVHD after HSCT have a poor prognosis. Ruxolitinib, a selective Janus kinase inhibitor, is a novel treatment strategy for steroid-refractory GVHD. Objectives To assess the efficacy of ruxolitinib for the treatment of steroid-refractory GVHD and analyse its adverse effects. Study design Meta-analysis. Search methods Randomised controlled trials (RCTs) and non-RCTs of ruxolitinib-based therapy in patients with steroid-refractory GVHD were found in the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of Science in March 2021. Outcomes included overall response rate, survival, and adverse effects. The Methodological Index for Non-randomised Studies (MINORS) and the Cochrane collaboration risk-of-bias tool were used to assess methodological quality. Funnel plots, Egger’s test, and the trim and fill method were used to assess publication bias. Results In total, 1470 studies were identified; 19 studies (17 non-RCTs, 2 RCTs) involving 1358 patients met our inclusion criteria. Survival rates at the longest follow-up in non-RCTs, were 57.5% (95% CI 46.9–67.4) and 80.3% (95% CI 69.7–87.9) for acute GVHD (aGVHD) and chronic GVHD (cGVHD), respectively. In non-RCTs, the overall response was 74.9% (95% CI 66.6–81.8, I2 = 49%) in aGVHD and 73.1% (95% CI 62.5–81.6, I2 = 49%) in cGVHD. In aGVHD, the response rates were gastrointestinal, 61.4–90.2%; skin, 52.5–80.6%; and liver, 41.8–71.8%. In cGVHD, the response rates were gastrointestinal, 30.1–70.4%; skin, 30.1–84.4%; lung, 27.0–83.0%; and mouth 3.5–98.1%. In addition, a lower aGVHD grade and moderate cGVHD were associated with a better clinical response. Common adverse events were cytopenia and infectious complications. Conclusions Our systematic review and meta-analysis indicated that ruxolitinib therapy could be a potentially effective and safe treatment for patients with steroid-refractory GVHD.
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Affiliation(s)
- Meng-yun Zhang
- School of Clinical Medicine, Guizhou Medical University, Guiyang, GuiZhou Province, China
| | - Peng Zhao
- Department of Haematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, GuiZhou Province, China
| | - Yan Zhang
- Department of Haematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, GuiZhou Province, China
- * E-mail: (YZ); (JW)
| | - Ji-shi Wang
- Department of Haematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, GuiZhou Province, China
- * E-mail: (YZ); (JW)
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13
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Xu Z, Chu M. Advances in Immunosuppressive Agents Based on Signal Pathway. Front Pharmacol 2022; 13:917162. [PMID: 35694243 PMCID: PMC9178660 DOI: 10.3389/fphar.2022.917162] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/02/2022] [Indexed: 12/13/2022] Open
Abstract
Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.
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Affiliation(s)
- Zhiqing Xu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Pharmacology, Jilin University, Changchun, China
| | - Ming Chu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
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14
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Adoptive transfer of ex vivo expanded regulatory T-cells improves immune cell engraftment and therapy-refractory chronic GvHD. Mol Ther 2022; 30:2298-2314. [PMID: 35240319 DOI: 10.1016/j.ymthe.2022.02.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 01/09/2022] [Accepted: 02/25/2022] [Indexed: 11/22/2022] Open
Abstract
Graft-versus-Host-Disease (GvHD) is still the major non-relapse, life-limiting complication following hematopoietic stem cell transplantation. Modern pharmacologic immunosuppression is often insufficient and associated with significant side effects. Novel treatment strategies now include adoptive transfer of ex vivo expanded regulatory T-cells (Tregs), but their efficacy in chronic GvHD is unknown. We treated three children suffering from severe, therapy-refractory GvHD with polyclonally expanded Tregs generated from the original stem cell donor. Third-line maintenance immunosuppression was tapered to Cyclosporin A and low-dose steroids shortly before cell transfer. Regular follow-up included assessment of the subjective and objective clinical development, safety parameters and in-depth immune monitoring. All patients showed marked clinical improvement with substantially reduced GvHD activity. Laboratory follow-up showed a significant enhancement of the immunologic engraftment including lymphocytes and dendritic cells. Monitoring the fate of Tregs by next generation sequencing demonstrated clonal expansion. In summary, adoptive transfer of Tregs was well tolerated and able to modulate an established undesired T-cell mediated allo-response. Although no signs of overimmunosuppression were detectable, treatment of patients with invasive opportunistic infections should be undertaken with caution. Further controlled studies, are necessary to confirm these encouraging effects and eventually pave the way for adoptive Treg therapy in chronic GvHD.
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15
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Inamoto Y, Zeiser R, Chan GCF. Novel Treatment for Graft-versus-Host Disease. BLOOD CELL THERAPY 2021; 4:101-109. [PMID: 36714067 PMCID: PMC9847314 DOI: 10.31547/bct-2021-022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 10/16/2021] [Indexed: 02/01/2023]
Abstract
Allogeneic hematopoietic cell transplantation is a curative therapy for a variety of hematological diseases, but its success is hampered by acute and chronic graft-versus-host disease (GvHD). In the last five years, multiple novel therapeutic approaches for GvHD have entered the arena. The National Institutes of Health consensus criteria for chronic GvHD have set standards for designing and reporting clinical trials, and preclinical experiments of chronic GvHD have revealed the central roles of regulatory T cells, B-cell signaling, Th17 cells, Tc17 cells, follicular helper T cells, follicular regulatory T cells, and fibrosis-promoting factors. These scientific efforts and the resulting clinical studies led to the approval of ibrutinib, belumosudil and ruxolitinib for the treatment of refractory chronic GvHD. Recently, large randomized phase III trials showed that ruxolitinib was superior to the best available therapy for glucocorticoid-refractory acute GvHD (REACH2 trial) and glucocorticoid-refractory chronic GvHD (REACH3 trial). Furthermore, novel regenerative approaches, including IL-22, R-spondin, and glucogon-like peptide-2, and cellular therapies, such as the transfer of mesenchymal stem cells and regulatory T cells, are under intensive investigation. GvHD prevention using abatacept, dipeptidyl peptidase 4 inhibition, and post-transplant cyclophosphamide are also promising strategies that require further evaluation. In this article, we summarize the emerging knowledge of acute GvHD, chronic GvHD, and preclinical and clinical data of mesenchymal stem cells as GvHD therapy. In the next five years, basic and clinical studies will further advance the field, and dramatic changes in GvHD management will be encountered.
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Affiliation(s)
- Yoshihiro Inamoto
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Godfrey Chi-Fung Chan
- Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong,Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital,Department of Paediatrics and Adolescent Medicine, HKU-Shenzhen Hospital
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16
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Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung. Bone Marrow Transplant 2021; 56:2291-2294. [PMID: 34108671 DOI: 10.1038/s41409-021-01335-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/26/2021] [Accepted: 05/05/2021] [Indexed: 02/05/2023]
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17
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Shakshouk H, Tkaczyk ER, Cowen EW, El-Azhary RA, Hashmi SK, Kenderian SJ, Lehman JS. Methods to Assess Disease Activity and Severity in Cutaneous Chronic Graft-versus-Host Disease: A Critical Literature Review. Transplant Cell Ther 2021; 27:738-746. [PMID: 34107339 DOI: 10.1016/j.jtct.2021.05.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/28/2021] [Accepted: 05/31/2021] [Indexed: 12/26/2022]
Abstract
Chronic graft-versus-host disease (cGVHD), a potentially debilitating complication of hematopoietic cell transplantation, confers increased risk for mortality. Whereas treatment decisions rely on an accurate assessment of disease activity/severity, validated methods of assessing cutaneous cGVHD activity/severity appear to be limited. In this study, we aimed to identify and evaluate current data on the assessment of disease activity/severity in cutaneous cGVHD. Using modified PRISMA methods, we performed a critical literature review for relevant articles. Our literature search identified 1741 articles, of which 1635 were excluded as duplicates or failure to meet inclusion criteria. Of the included studies (n = 106), 39 (37%) addressed clinical and/or histopathologic parameters, 53 (50%) addressed serologic parameters, 8 (7.5%) addressed imaging parameters, and 6 (5.5%) addressed computer-based technologies. The only formally validated metric of disease activity/severity assessment in cutaneous cGVHD is the National Institutes of Health consensus scoring system, which is founded on clinical assessment alone. The lack of an objective marker for cGVHD necessitates further studies. An evaluation of the potential contributions of serologic, imaging, and/or computer-based technologies is warranted.
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Affiliation(s)
- Hadir Shakshouk
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota; Department of Dermatology, Andrology and Venerology, Alexandria University, Alexandria, Egypt
| | - Eric R Tkaczyk
- Dermatology and Research Services, Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN; Department of Dermatology, Vanderbilt University Medical Center, Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Edward W Cowen
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland
| | | | - Shahrukh K Hashmi
- Division of Hematology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, Sheikh Shakhbout Medical City, Abu Dhabi, UAE
| | | | - Julia S Lehman
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota.
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18
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[Chinese consensus on the diagnosis and management of chronic graft-versus-host disease (2021)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:265-275. [PMID: 33979969 PMCID: PMC8120129 DOI: 10.3760/cma.j.issn.0253-2727.2021.04.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Indexed: 12/02/2022]
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19
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Stokes J, Molina MS, Hoffman EA, Simpson RJ, Katsanis E. Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation. Cancers (Basel) 2021; 13:1702. [PMID: 33916711 PMCID: PMC8038415 DOI: 10.3390/cancers13071702] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/25/2021] [Accepted: 04/01/2021] [Indexed: 12/22/2022] Open
Abstract
Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.
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Affiliation(s)
- Jessica Stokes
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
| | - Megan S. Molina
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
- Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA
| | - Emely A. Hoffman
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
| | - Richard J. Simpson
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
- Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA
- Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85721, USA
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
| | - Emmanuel Katsanis
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
- Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- Department of Medicine, University of Arizona, Tucson, AZ 85721, USA
- Department of Pathology, University of Arizona, Tucson, AZ 85721, USA
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20
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Hong C, Jin R, Dai X, Gao X. Functional Contributions of Antigen Presenting Cells in Chronic Graft-Versus-Host Disease. Front Immunol 2021; 12:614183. [PMID: 33717098 PMCID: PMC7943746 DOI: 10.3389/fimmu.2021.614183] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/11/2021] [Indexed: 12/27/2022] Open
Abstract
Chronic graft-versus-host disease (cGVHD) is one of the most common reasons of late non-relapse morbidity and mortality of patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). While acute GVHD is considered driven by a pathogenic T cell dominant mechanism, the pathogenesis of cGVHD is much complicated and involves participation of a variety of immune cells other than pathogenic T cells. Existing studies have revealed that antigen presenting cells (APCs) play crucial roles in the pathophysiology of cGVHD. APCs could not only present auto- and alloantigens to prime and activate pathogenic T cells, but also directly mediate the pathogenesis of cGVHD via multiple mechanisms including infiltration into tissues/organs, production of inflammatory cytokines as well as auto- and alloantibodies. The studies of this field have led to several therapies targeting different APCs with promising results. This review will focus on the important roles of APCs and their contributions in the pathophysiology of cGVHD after allo-HSCT.
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Affiliation(s)
- Chao Hong
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Rong Jin
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Xiaoqiu Dai
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Xiaoming Gao
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
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21
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Cuthbertson P, Geraghty NJ, Adhikary SR, Casolin S, Watson D, Sluyter R. P2X7 receptor antagonism increases regulatory T cells and reduces clinical and histological graft-versus-host disease in a humanised mouse model. Clin Sci (Lond) 2021; 135:495-513. [PMID: 33463682 DOI: 10.1042/cs20201352] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 02/06/2023]
Abstract
Graft-versus-host disease (GVHD) is a severe inflammatory response arising from allogeneic haematopoietic stem cell transplantation. Previous studies revealed that antagonism of the P2X7 receptor with Brilliant Blue G (BBG) reduced liver GVHD but did not alter clinical GVHD in a humanised mouse model. Therefore, the present study aimed to trial a modified injection regime using more frequent dosing of BBG to improve outcomes in this model of GVHD. NOD-scid IL2Rγnull (NSG) mice were injected intraperitoneally (i.p.) with 10 × 106 human peripheral blood mononuclear cells (hPBMCs) (day 0), then daily with BBG (50 mg/kg) or saline (days 0-10). BBG significantly reduced clinical score, mortality and histological GVHD compared with saline treatment (endpoint). BBG significantly increased proportions of human regulatory T cells (Tregs) and human B cells and reduced serum human interferon-γ compared with saline treatment prior to development of clinical GVHD (day 21). To confirm the therapeutic benefit of P2X7 antagonism, NSG mice were injected i.p. with 10 × 106 hPBMCs (day 0), then daily with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) (300 mg/kg) or saline (days 0-10). PPADS increased human Treg proportions compared with saline treatment (day 21), but potential clinical benefits were confounded by increased weight loss with this antagonist. To investigate the role of P2X7 antagonism on Treg survival, hPBMCs were cultured in reduced serum conditions to promote cell death. BBG increased proportions of Tregs (and B cells) compared with saline under these conditions. In conclusion, P2X7 antagonism reduces clinical and histological GVHD in a humanised mouse model corresponding to an increase in human Tregs.
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Affiliation(s)
- Peter Cuthbertson
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Nicholas J Geraghty
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Sam R Adhikary
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Sienna Casolin
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Debbie Watson
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Ronald Sluyter
- Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
- Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
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22
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Lertkovit O, Anurathapan U, Hongeng S, Thokanit NS, Pakakasama S. Chronic graft-versus-host disease in children and adolescents with thalassemia after hematopoietic stem cell transplantation. Int J Hematol 2021; 113:556-565. [PMID: 33385291 DOI: 10.1007/s12185-020-03055-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/27/2022]
Abstract
Data on chronic graft-versus-host disease (cGVHD) in patients with thalassemia after hematopoietic stem cell transplantation (HSCT) have not been specifically explored. The present study aimed to determine the incidence and clinical manifestations of cGVHD in children and adolescents with thalassemia who underwent HSCT and to compare healthcare utilization and medical cost between patients with and without cGVHD. We retrospectively analyzed the presentations, treatments, and outcomes of historical cGVHD (Seattle criteria), post-transplant admissions and direct medical cost for HSCT patients (n = 66). We used the 2014 NIH consensus criteria to reclassify the diagnosis of cGVHD (NIH cGVHD). Among 28 historical cGVHD patients, 13 (46.4%) fulfilled the NIH criteria. Reasons why the NIH criteria were unmet were reclassification as late acute GVHD and presence of distinctive signs without confirmatory tests. At 2 years after HSCT, the cumulative incidence of NIH cGVHD was 21.67% (95% CI, 12.31-32.74%). Lung cGVHD was associated with inferior survival with a hazard ratio of 13.6 (95% CI, 1.42-131.48). Patients with historical cGVHD had significantly increased frequency of inpatient admissions and medical cost. In conclusion, cGVHD was common in children with thalassemia receiving HSCT. Patients with cGVHD required prolonged immunosuppressive treatment and incurred high medical expenses.
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Affiliation(s)
- Oranooj Lertkovit
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Usanarat Anurathapan
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Suradej Hongeng
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nintita Sripaiboonkit Thokanit
- Ramathibodi Comprehensive Cancer Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Samart Pakakasama
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
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23
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Saidu NEB, Bonini C, Dickinson A, Grce M, Inngjerdingen M, Koehl U, Toubert A, Zeiser R, Galimberti S. New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions. Front Immunol 2020; 11:578314. [PMID: 33162993 PMCID: PMC7583636 DOI: 10.3389/fimmu.2020.578314] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/18/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions.
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Affiliation(s)
- Nathaniel Edward Bennett Saidu
- Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
- Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Chiara Bonini
- Experimental Hematology Unit, San Raffaele Scientific Institute, Milano, Italy
| | - Anne Dickinson
- Haematological Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Magdalena Grce
- Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Marit Inngjerdingen
- Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Ulrike Koehl
- Faculty of Medicine, Institute of Clinical Immunology, University Leipzig and Fraunhofer IZI, Leipzig, Germany
| | - Antoine Toubert
- Université de Paris, Institut de Recherche Saint Louis, EMiLy, Inserm U1160, Paris, France
- Laboratoire d'Immunologie et d`Histocompatibilité, AP-HP, Hopital Saint-Louis, Paris, France
| | - Robert Zeiser
- Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Faculty of Medicine, Freiburg, Germany
| | - Sara Galimberti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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24
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Zhu W, Feng YM, Chen T, Yao H, Quan Y, Rao J, Gao L, Zhang C, Liu Y, Gao L, Kong PY, Zhang X. [The clinical observation of sirolimus combined with calcineurin inhibitors for steroid-resistant/steroid-dependent extensive cGVHD]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2020; 41:716-722. [PMID: 33113602 PMCID: PMC7595869 DOI: 10.3760/cma.j.issn.0253-2727.2020.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Indexed: 11/05/2022]
Abstract
Objective: To observe the efficacy and safety of sirolimus combined with calcineurin inhibitor (CNI) in the treatment of glucocorticoid resistant/dependent extensive chronic graft-versus-host disease (cGVHD) . Methods: A total of 27 patients with steroid-resistant/steroid-dependent extensive cGVHD from November 2015 to January 2019 were enrolled and given sirolimus capsules combined with cyclosporine or tacrolimus to observe the clinical efficacy and adverse events. Results: The median duration of medication was 14.2 months and the mean duration was 16.7 months. The median follow-up time was 20.1 months (12.9-46.1 months) . Following the 6-month follow-up, 3 cases achieved complete response (CR) and 12 cases partial response (PR) . The overall response rate (ORR) was 55.6% ; for progression-free survival (PFS) , PFS-6 reached 88.9% (24/27) , and for overall survival (OS) , OS-6 was 100% . At the 1-year follow-up, there were 5 cases of CR and 11 cases of PR, ORR was 59.3% , PFS-12 reached 62.9% (17/27) , and OS-12 was 100% . The subgroup analysis found that the program was more effective for cGVHD in male donors and the target organ analysis had an advantage in the treatment of oral cavity, skin, and liver rejection. Adverse events were observed: hyperlipidemia 11.1% , oral ulcer 7.4% , fungal infection 11.1% , liver injury 3.7% , renal insufficiency 0, and no new CMV and EB viremia. Conclusion: Sirolimus combined with calcineurin inhibitors is effective in treating steroid-resistant/steroid-dependent extensive cGVHD, especially because adverse reactions (renal toxicity, CMV, EBV infection) are low in number, which is suitable for long-term treatment of cGVHD.
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Affiliation(s)
- W Zhu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - Y M Feng
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - T Chen
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - H Yao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - Y Quan
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - J Rao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - L Gao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - C Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - Y Liu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - L Gao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - P Y Kong
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
| | - X Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China
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25
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Hong YQ, Wan B, Li XF. Macrophage regulation of graft- vs-host disease. World J Clin Cases 2020; 8:1793-1805. [PMID: 32518770 PMCID: PMC7262718 DOI: 10.12998/wjcc.v8.i10.1793] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 02/05/2023] Open
Abstract
Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy, but graft-vs-host disease (GVHD) has limited the survival quality and overall survival of hematopoietic stem cell transplantation. Understanding of the immune cells’ reaction in pathophysiology of GVHD has improved, but a review on the role of macrophages in GVHD is still absent. Studies have observed that macrophage infiltration is associated with GVHD occurrence and development. In this review, we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD, focusing on the macrophage recruitment and infiltration, macrophage polarization, macrophage secretion, and especially interaction of macrophages with other immune cells. We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD. Based on distinguishing pathology of acute and chronic GVHD, macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD. However, the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization. In addition, interaction of macrophages with alloreactive T cells plays an important role in acute GVHD. Meanwhile, the interaction among macrophages, B cells, fibroblasts, and CD4+ T cells participates in chronic GVHD development.
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Affiliation(s)
- Ya-Qun Hong
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
| | - Bo Wan
- Faculty of Life Sciences and Medicine, King’s College London, London WC1N 3BG, United Kingdom
| | - Xiao-Fan Li
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
- INSERM U1160, Hospital Saint Louis, Université Paris Diderot, Paris 94430, France
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26
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Yehudai-Ofir D, Henig I, Zuckerman T. Aberrant B cells, autoimmunity and the benefit of targeting B cells in chronic graft-versus-host disease. Autoimmun Rev 2020; 19:102493. [DOI: 10.1016/j.autrev.2020.102493] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 10/24/2019] [Indexed: 01/09/2023]
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27
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Feng Y, Xiao Y, Yan H, Wang P, Zhu W, Cassady K, Zou Z, Wang K, Chen T, Quan Y, Wang Z, Yang S, Wang R, Li X, Gao L, Zhang C, Liu Y, Kong P, Gao L, Zhang X. Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study. Front Med (Lausanne) 2020; 7:110. [PMID: 32296709 PMCID: PMC7136762 DOI: 10.3389/fmed.2020.00110] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 03/10/2020] [Indexed: 02/05/2023] Open
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disease which arises due to self-destruction of circulating platelets. Failure to respond or maintain a response to first-line treatment can lead to refractory/relapsed (R/R) ITP. The mechanism remains complicated and lacks a standard clinical treatment. Sirolimus (SRL) is a mammalian target of rapamycin (mTOR) inhibitor that has been demonstrated to inhibit lymphocyte activity, indicating potential for SRL in treatment of ITP. Activation of the mTOR pathway in autoimmune diseases suggests that SRL might be a useful agent for treating ITP. Accordingly, we initiated an open-label, prospective clinical trial using SRL for patients with R/R ITP (ChiCTR-ONC-17012126). The trial enrolled 86 patients, each dosed with 2-4 mg/day of SRL. By the third month, 40% of patients (34 of 86) achieved complete remission (CR) and 45% of patients (39 of 86) achieved partial remission (PR), whereby establishing an overall response rate (ORR) of 85%. By 6 months of treatment, 41% of patients (32 of 78) achieved CR and 29% of patients (23 of 78) achieved PR, establishing an ORR of 70% without serious side effects. After 12 months follow-up, the ORR remained at 65%. We also found that SRL treatment exhibited higher efficacy in achieving CR in ITP patients who were younger than 40 years old or steroid dependent by univariate analysis. Importantly, in patients who responded, SRL treatment was associated with a reduction in the percentage of Th2, Th17 cells, and increase in the percentage of M-MDSCs and Tregs, indicating that SRL may reestablish peripheral tolerance. Taken together, Sirolimus demonstrated efficacy as a second-line agent for R/R ITP.
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Affiliation(s)
- Yimei Feng
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Yunshuo Xiao
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Hongju Yan
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Ping Wang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Wen Zhu
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Kaniel Cassady
- Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, United States
| | - Zhongmin Zou
- Department of Chemical Defense, School of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Kaifa Wang
- School of Mathematics and Statistics, Southwest University, Chongqing, China
| | - Ting Chen
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Yao Quan
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Zheng Wang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Shijie Yang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Rui Wang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Xiaoping Li
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Lei Gao
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Cheng Zhang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Yao Liu
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Peiyan Kong
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Li Gao
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
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28
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Yoshida H, Koike M, Tada Y, Nakata K, Hino A, Fuji S, Masaie H, Oka C, Higeno A, Idota A, Yamasaki T, Ishikawa J. Different Immune Reconstitution between Cord Blood and Unrelated Bone Marrow Transplantation with Relation to Chronic Graft-versus-Host Disease. Int J Hematol Oncol Stem Cell Res 2020; 14:1-10. [PMID: 32337009 PMCID: PMC7167606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Background: Advances of allogeneic hematopoietic cell transplantation (allo-HCT) have brought long-term survival to the patients with hematologic malignancies. Chronic graft-versus-host disease (GVHD) is one of major problems for the long- term survivors after allo-HCT. Dysregulation of immune reconstitution has been reported to be involved in the pathogenesis of chronic GVHD. Differences of immune reconstitution between cord blood transplantation (CBT) and unrelated bone marrow transplantation (UBMT) remain unclear in long-term survivors. We investigated immune reconstitution in patients surviving for more than 2 years after CBT (n=21) or UBMT (n=20) without relapse of underlying disease. Materials and Methods: Using flow cytometric analysis of peripheral blood, we investigated immune reconstitution of T cells, B cells, and NK cells between CBT and UBMT patients. We collected clinical data regarding allo-HCT and examined the relation of immune reconstitution to the development of chronic GVHD. Results: Between CBT and UBMT patients, we found significant differences in absolute cell number of CD8+ as well as CD19+ cell and CD4/CD8 ratio even more than 2 years after allo-HCT. Among UBMT patients, absolute cell number of naive CD4+ cell was significantly lower in patients with chronic GVHD. In addition, we found significant differences in absolute cell number of CD19+ cell, especially naive B cell between patients with and without chronic GVHD in both CBT and UBMT patients. Conclusion: These results suggest that differences of immune recovery between CBT and UBMT patients may exist even in patients surviving for more than 2 years and might be related to the development of chronic GVHD.
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Affiliation(s)
- Hitoshi Yoshida
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan
| | - Midori Koike
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan
| | - Yuma Tada
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan
| | - Keiichi Nakata
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan
| | - Akihisa Hino
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan
| | - Shigeo Fuji
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan
| | - Hiroaki Masaie
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan
| | - Chihiro Oka
- Department of Laboratory, Osaka International Cancer Institute, Osaka, Japan
| | - Akemi Higeno
- Department of Laboratory, Osaka International Cancer Institute, Osaka, Japan
| | - Atsushi Idota
- Department of Laboratory, Osaka International Cancer Institute, Osaka, Japan
| | - Tomoyuki Yamasaki
- Department of Laboratory, Osaka International Cancer Institute, Osaka, Japan
| | - Jun Ishikawa
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan
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29
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Alves da Costa T, Lang J, Torres RM, Pelanda R. The development of human immune system mice and their use to study tolerance and autoimmunity. J Transl Autoimmun 2019; 2:100021. [PMID: 32743507 PMCID: PMC7388352 DOI: 10.1016/j.jtauto.2019.100021] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 11/04/2019] [Indexed: 12/26/2022] Open
Abstract
Autoimmune diseases evolve from complex interactions between the immune system and self-antigens and involve several genetic attributes, environmental triggers and diverse cell types. Research using experimental mouse models has contributed key knowledge on the mechanisms that underlie these diseases in humans, but differences between the mouse and human immune systems can and, at times, do undermine the translational significance of these findings. The use of human immune system (HIS) mice enables the utility of mouse models with greater relevance for human diseases. As the name conveys, these mice are reconstituted with mature human immune cells transferred directly from peripheral blood or via transplantation of human hematopoietic stem cells that nucleate the generation of a complex human immune system. The function of the human immune system in HIS mice has improved over the years with the stepwise development of better models. HIS mice exhibit key benefits of the murine animal model, such as small size, robust and rapid reproduction and ease of experimental manipulation. Importantly, HIS mice also provide an applicable in vivo setting that permit the investigation of the physiological and pathological functions of the human immune system and its response to novel treatments. With the gaining popularity of HIS mice in the last decade, the potential of this model has been exploited for research in basic science, infectious diseases, cancer, and autoimmunity. In this review we focus on the use of HIS mice in autoimmune studies to stimulate further development of these valuable models.
Human immune system (HIS) mice bear components of the human immune system. HIS mice engraft with human blood or hematopoietic stem cells, and sometimes thymus. HIS mice are used to investigate development and function of the human immune system. Immunological tolerance and autoimmune responses can be studied in HIS mice. HIS models of autoimmunity vary in complexity and in ability to represent disease.
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Affiliation(s)
- Thiago Alves da Costa
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Julie Lang
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Raul M. Torres
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Biomedical Research, National Jewish Health, Denver, CO, 80206, USA
| | - Roberta Pelanda
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Biomedical Research, National Jewish Health, Denver, CO, 80206, USA
- Corresponding author. University of Colorado School of Medicine, 12800 East 19th Avenue Mail Stop 8333, Aurora, CO, 80045-2508, USA.
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Abstract
Introduction: Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplantation (HSCT); therefore, the prevention of GVHD is important for a successful treatment. Tacrolimus (Tac), a calcineurin inhibitor, has been widely used for the prophylaxis of GVHD in HSCT recipients. Areas covered: This review introduces phase II/III of clinical trials related with Tac's roles in the prevention of GVHD in HSCT. Furthermore, we discuss the normal ranges of Tac concentrations, pharmacogenetics, and drug interactions of Tac, as well as its side effects in adult HSCT recipients. Expert opinion: A series of studies has established the efficacy and safety of Tac alone or in combination with other agents in HSCT. However, successful administration of Tac is complicated by its narrow therapeutic window, inter-patient pharmacokinetic variability, and a spectrum of undesirable side effects. It is necessary to maintain concentrations of Tac within the desired ranges for GVHD prophylaxis. Moreover, various factors contribute to significant variability in Tac pharmacokinetics, including drug interactions and genomic variation.
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Affiliation(s)
- Yuan Gao
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Soochow University , Suzhou , China
| | - Jingjing Ma
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Soochow University , Suzhou , China
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31
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Progress of cGVHD pathogenesis from the perspective of B cells. BLOOD SCIENCE 2019; 1:84-87. [PMID: 35402796 PMCID: PMC8974942 DOI: 10.1097/bs9.0000000000000021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 07/19/2019] [Indexed: 11/26/2022] Open
Abstract
An increasing number of physicians realize that chronic graft-versus-host disease (cGVHD) is not just dominated by T cells and that B cells also play a vital role in cGVHD development. It has been reported that altered B cell subsets, aberrant B cell signaling pathways, antibody deposition, and abnormal T-B interactions can be observed in many cGVHD patients. Studies of B cells in cGVHD development are now mainly focused on B cell subsets and GC destruction. These two aspects describe the process of B cell evolution in cGVHD patients and are associated with some original treatments. In this review, we summarize recent literature and discuss mechanisms and novel ideas of therapeutic strategies regarding the two aspects mentioned above.
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Lu D, Ma T, Zhou X, Jiang Y, Han Y, Li H. B Lymphocytes Are the Target of Mesenchymal Stem Cells Immunoregulatory Effect in a Murine Graft-versus-Host Disease Model. Cell Transplant 2019; 28:1279-1288. [PMID: 31257911 PMCID: PMC6767898 DOI: 10.1177/0963689719860127] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
There is growing clinical interest in the utilization of mesenchymal stem cells (MSCs) in the management of acute graft-versus-host disease (aGvHD), yet the effect of major histocompatibility complexes (MHCs) on B lymphocytes in this process has been less well documented. Working in an MHC fully mismatched murine aGvHD model, we found that MSC co-transfer significantly prolonged the survival time of the recipients. More interestingly, analysis on immunophenotypic profiles of posttransplant splenocytes showed that surface expression of CD69 (an early activation marker) and CD86 (a costimulatory molecule) was suppressed predominantly on donor derived B lymphocytes by MSC infusion. Additionally, mRNA level of interleukin-4, a potent B lymphocyte stimulator, was strikingly reduced from MSC-treated mice, while interleukin-10, the regulatory B lymphocytes inductor, was increased; these may underlie the lesser activation of B lymphocytes. In consistence, depletion of B lymphocytes in the transfusion inoculum further prolonged the survival time of aGvHD mice regardless of MSC administration. Therefore, B lymphocytes played an important role in the development of aGvHD, and they are targets in MSC-regulated immune response cascade in vivo. This study may provide a mechanistic clue for the treatment of human clinical aGvHD.
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Affiliation(s)
- Di Lu
- Department of Plastic and Reconstructive Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, China.,Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, China.,Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Beijing, China
| | - Tian Ma
- Department of Plastic and Reconstructive Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - XiangBin Zhou
- Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, China.,Department of Stomatology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - YanMing Jiang
- Department of Ophthalmology, Rocket Force General Hospital, Beijing, China
| | - Yan Han
- Department of Plastic and Reconstructive Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Hong Li
- Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, China.,Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Beijing, China
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