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Takahashi T, Wachter F, Alvarez Calderon F, Kapadia M, Qayed M, Keating AK. Umbilical Cord Blood Reduced Relapse but Increased Nonrelapse Mortality Compared to Matched Unrelated Donor Transplantation in Pediatric Acute Myeloid Leukemia With Active Disease: A CIBMTR 2008 to 2017 Analysis of Donor Source and Residual Disease. Transplant Cell Ther 2025; 31:261.e1-261.e15. [PMID: 39938807 DOI: 10.1016/j.jtct.2025.01.889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/23/2024] [Accepted: 01/23/2025] [Indexed: 02/14/2025]
Abstract
Umbilical cord blood (UCB) and matched unrelated donors (MUD) are common alternative donor options in children with high-risk acute myeloid leukemia (AML). Emerging evidence suggests an augmented graft-versus-leukemia (GVL) effect of UCB, but uncertainties persist due to the heterogeneity of the hematopoietic cell transplantation (HCT) characteristics in the previous studies. We reviewed 1148 patients aged ≤18 years with AML, who underwent the first HCT between 2008 to 2017, using a publicly available dataset from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry data. Multivariable analyses evaluated predictors of DFS and other clinical outcomes, factoring in graft source, conditioning regimen, patient age, cytogenetic risk, and HCT year (significance at P < .01). Residual disease status was assessed both as a covariate and as a stratifying factor. Additionally, the differential effects of conditioning regimens were analyzed specifically within the UCB cohort. UCB was used most frequently (33.8%) followed by MUD (29.1%), both of which had comparable DFS and overall survival. In patients with minimal residual disease or not in remission prior to HCT, human-leukocyte antigen (HLA) ≤5/8 matched UCB was associated with lower relapse rates than MUD (hazard risk [HR]: 0.25 and 0.29, P = .005 and .006, respectively) but with increased nonrelapse mortality (HR: 32.8 and 7.5, P = .001 and .012, respectively). Conditioning regimens varies by graft type; total body irradiation (TBI)-based regimens, primarily combined with cyclophosphamide and fludarabine, were more common in the UCB cohort (45% in UCB versus 19% in the other grafts, P < .001). Within the 388 patients received UCB, multivariable analysis demonstrated comparable DFS and OS across variable busulfan- and TBI-based regimens, with no trend of superiority for either approach. In conclusion, highly HLA-mismatched UCB reduced relapse in pediatric AML with higher disease burden but increased nonrelapse mortality, resulting in similar DFS to MUD. Improved supportive care and toxicity mitigation may improve the outcomes of UCB transplant. Overall, UCB should be considered a viable alternative graft source with equally favorable outcomes to MUD. Further research is warranted to refine conditioning regimen, including TBI- and busulfan-based strategies, mitigate toxicity, and improve supportive care to optimize UCB HCT outcomes.
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Affiliation(s)
- Takuto Takahashi
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Franziska Wachter
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Francesca Alvarez Calderon
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Malika Kapadia
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Muna Qayed
- Division of Pediatric Hematology/Oncology, Emory University School of Medicine, Atlanta, Georgia; Children's Healthcare of Atlanta, Atlanta, Georgia
| | - Amy K Keating
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts
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Kruchen A, Fehse B, Müller I. Clinical relevance of feto-maternal microchimerism in (hematopoietic stem cell) transplantation. Semin Immunopathol 2024; 47:4. [PMID: 39644358 PMCID: PMC11625077 DOI: 10.1007/s00281-024-01028-3] [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: 05/20/2024] [Accepted: 11/14/2024] [Indexed: 12/09/2024]
Abstract
Toleration of a semi-allogeneic fetus in the mother's uterus as well as tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) appear to share some immunologic concepts. The existence of microchimeric cells, and the original idea of a bidirectional cell trafficking between mother and child during pregnancy have been known for decades. Today, origins and mechanisms of persistence of microchimeric cells are intensively being elucidated. Both, the translation of the phenomenon of feto-maternal immune tolerance to donor choice or prevention of graft-versus-host disease (GvHD) in HSCT, and the implications of microchimeric cells in and for HSCT are highly intriguing. Yet, differences in detection methods of microchimeric cells, as well as in transplantation protocols impede the comparison of larger cohorts, and limit potential clinical advice. Still, matching of non-inherited maternal antigens (NIMA), which are expressed on maternal microchimeric cells, demonstrated a strong association with decreased risk for the development of acute GvHD in the context of various transplantation strategies. Despite the fact that advances in graft manipulation and immunosuppression ameliorated the safety and outcome after HSCT, NIMA-matching retained a beneficial role in selection of sibling, child, or maternal donors, as well as for cord blood units. Recent findings indicate the existence of a microchimeric stem cell niche, in which only one dominant microchimeric cell population of only one semi-allogeneic origin persists at a time. This implies that studies regarding the impact of (maternal and fetal) microchimerism (MC) on clinical outcome of HSCT should combine analysis of NIMA and direct detection of microchimeric cells from donor and recipient on the verge of HSCT to be efficiently conclusive.
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Affiliation(s)
- Anne Kruchen
- Division of Pediatric Stem Cell Transplantation and Immunology, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Boris Fehse
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
- German Center for Child and Adolescent Health (DZKJ), Hamburg, Germany.
| | - Ingo Müller
- Division of Pediatric Stem Cell Transplantation and Immunology, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
- Research Institute Children's Cancer Center Hamburg, 20246, Hamburg, Germany
- German Center for Child and Adolescent Health (DZKJ), Hamburg, Germany
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Planken S, De Becker A, Kerre T, Schoemans H, Baron F, Graux C, Van Riet I, Lechanteur C, Baudoux E, Schots R, Beguin Y. Feasibility of co-transplantation of umbilical cord blood and third-party mesenchymal stromal cells after (non)myeloablative conditioning in patients with hematological malignancies. Curr Res Transl Med 2024; 72:103466. [PMID: 39213720 DOI: 10.1016/j.retram.2024.103466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/07/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
Umbilical cord blood (UCB) is an alternative source of stem cells for patients lacking a 9/10 or 10/10 HLA identical donor. However, after UCB transplantation, time to engraftment and immune recovery are prolonged, increasing the risk of fatal complications. Mesenchymal stromal cells (MSC) can support hematopoietic engraftment and have immunosuppressive effects. The primary objective of this phase I/II multicenter study was to determine the feasibility and safety of UCB transplantation with co-infusion of third party MSC, as assessed by treatment related mortality (TRM) at day 100. Secondary objectives were engraftment, immune recovery, occurrence of graft versus host disease (GVHD), infections, disease free survival, relapse incidence and overall survival. Eleven patients were grafted according to this protocol. Allogeneic transplantation after co-infusion appears feasible with 18 % TRM at day 100. Engraftment data show a median time of 16 days to neutrophil and 27 days to platelet recovery, which is shorter than what is usually reported after UCB transplantation. Only 1 episode of acute GVHD was reported. In conclusion, MSC and UCB co-transplantation is feasible and might help overcome some of the drawbacks of UCB transplantation.
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Affiliation(s)
- Simon Planken
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium and Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Ann De Becker
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium and Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Tessa Kerre
- UZ Gent, Department of Hematology - SCT Unit, Ghent, Belgium
| | - Hélène Schoemans
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium and Department of Public Health and Primary Care, ACCENT VV, KU Leuven - University of Leuven, Leuven, Belgium
| | - Frédéric Baron
- CHU Sart-Tilman, Department of Hematology, Liège, Belgium
| | - Carlos Graux
- CHU UCL Namur - Godinne, Department of Hematology, Yvoir, Belgium
| | - Ivan Van Riet
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium and Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | | | - Etienne Baudoux
- CHU Sart-Tilman, Laboratory of Cell and Gene Therapy, Liège, Belgium
| | - Rik Schots
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium and Research Group Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Yves Beguin
- CHU Sart-Tilman, Department of Hematology, Liège, Belgium
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Biyun L, Yahui H, Yuanfang L, Xifeng G, Dao W. Risk factors for invasive fungal infections after haematopoietic stem cell transplantation: a systematic review and meta-analysis. Clin Microbiol Infect 2024; 30:601-610. [PMID: 38280518 DOI: 10.1016/j.cmi.2024.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/04/2023] [Accepted: 01/04/2024] [Indexed: 01/29/2024]
Abstract
BACKGROUND Invasive fungal infections (IFIs) are common infectious complications after haematopoietic stem cell transplantation (HSCT), seriously threatening the survival of patients. OBJECTIVES This systematic review aimed to investigate risk factors associated with IFIs following HSCT. METHODS Two authors independently conducted the selection of studies and extraction of data. Risk factors for IFIs, invasive aspergillosis or invasive mould infections and invasive candida infection after HSCT were compiled separately by meta-analysis using RevMan 5.4 and R language 4.1.2. DATA SOURCES Pubmed, EMBASE, Web of Science, and the Cochrane Library until April 2023. STUDY ELIGIBILITY CRITERIA Case-control or cohort studies that assessed risk factors for IFIs among HSCT recipients were included. PARTICIPANTS Patients experiencing HSCT. TEST/S None. REFERENCE STANDARD The IFIs were defined according to the European Organisation for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria, or a similar definition. ASSESSMENT OF RISK OF BIAS A modified version of the Newcastle-Ottawa Scale was used. METHODS OF DATA SYNTHESIS A random-effects model with the Mantel-Haenszel method was used to pool results from primary studies. RESULTS Out of 1637 studies screened, 51 studies involving 109 155 patients were included, with 45 studies providing adequate data for meta-analysis. Identified risk factors for IFIs included prolonged neutropenia, intensified therapy for graft-versus-host disease (GVHD), previous transplantation, previous proven or probable IFI, acute GVHD ≥ grade II, extensive or severe chronic GVHD, use of anti-thymocyte globulin during transplantation, haploidentical transplantation, high-dose glucocorticoids, Epstein-Barr virus infection, cytomegalovirus infection or reactivation, and lower albumin. Conversely, antifungal prophylaxis emerged as the sole preventive factor. For invasive aspergillosis or invasive mould infections, the top risk factors were extensive or severe chronic GVHD, respiratory viral infection, high-dose glucocorticoids, acute GVHD ≥ grade II, and human leukocyte antigen mismatch. Cord blood transplantation was the sole significant risk factor for invasive candidiasis. However, there was likely a high degree of interdependence among various risk factors. DISCUSSION This meta-analysis provides a thorough review of risk factors for IFIs infection after HSCT. The achieved insights can aid in stratifying patients who are at an elevated risk of IFIs and promoting antifungal preventive strategies.
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Affiliation(s)
- Li Biyun
- Department of Pediatric Hematology and Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Han Yahui
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li Yuanfang
- Department of Pediatric Hematology and Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guo Xifeng
- Department of Pediatric Hematology and Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wang Dao
- Department of Pediatric Hematology and Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Ali SR, Ahmad W, Salim A, Durrieu MC, Khan I. Xenogeneic Stem Cell–Induced Cardiac Progenitor Cells Regenerated Infarcted Myocardium in Rat Model. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024; 10:110-125. [DOI: 10.1007/s40883-023-00311-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 05/04/2023] [Accepted: 06/22/2023] [Indexed: 09/11/2024]
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Arora S, Thakkar D, Upasana K, Yadav A, Rastogi N, Sharma PS, Yadav SP. Incidence, Risk Factors, Characteristics, and Outcome of Chronic Graft Versus Host Disease in Children Undergoing Haploidentical Peripheral Blood Stem Cell Transplant With Post-transplant Cyclophosphamide. J Pediatr Hematol Oncol 2024; 46:e44-e50. [PMID: 37983773 DOI: 10.1097/mph.0000000000002786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 10/18/2023] [Indexed: 11/22/2023]
Abstract
AIM Chronic graft versus host disease (cGVHD) is a major cause of morbidity postallogeneic peripheral blood stem cell transplant (PBSCT). There is paucity of literature describing incidence, risk factors, characteristics, and outcome of cGVHD in children undergoing haploidentical PBSCT with post-transplant cyclophosphamide (PTCy). Here, we describe our experience from our center regarding the same. METHODS All children who underwent haploidentical PBSCT with PTCy between January 2016 and December 2021 at our center and survived beyond day+100 post-transplant were included in this retrospective study. Conditioning regimens used were: Thiotepa-Fludarabine-Cyclophosphamide with 2 Gy single fraction total body irradiation, Thiotepa-Busulfan-Fludarabine, Fludarabine-total body irradiation and Fludarabine-Melphalan. Peripheral blood was used as stem cell source in all patients. GVHD prophylaxis was PTCy 50 mg/kg on day +3 and +4, Mycophenolate mofetil and Calcineurin inhibitors. Clinical and laboratory data was electronically retrieved and analyzed based on National Institute of Health Consensus Criteria-2014 at regular intervals. Impact of various patient, donor, and transplant-related factors on development of cGVHD were analyzed. Incidence of relapse, event free survival (EFS) and overall survival (OS) were calculated and compared between cGVHD and no cGVHD groups. Patients with rejection were excluded from risk factor analysis for cGVHD but were considered for survival analysis. RESULTS Fifty-one children included in this study. Median age of transplant of our cohort was 7.5 years with male:female=1.6:1. Eight patients had rejection with autologous recovery. History of acute GVHD (aGVHD) was present in 15/51 (Grade III to IV in 7/51). cGVHD developed in 19/51 patients (mild-9/51, moderate-6/51, and severe-4/51). Skin was the most common organ involved (100%) followed by gastrointestinal tract (47.4%), liver (36.8%), eyes (21%), lungs (21%), mouth (15.7%), and joints (5.2%). Advanced donor age (>30 y) and previous aGVHD were found to be significantly associated with increased risk of developing cGVHD. At last follow-up, complete response and partial response of cGVHD was seen in 6/19 and 4/19 patients, respectively. Overall mortality was 15/51 (cause of mortality was relapse of cancer 8/15, cGVHD-3/15, other 4/15). EFS and OS of full cohort was 55% and 70.6%, respectively. Compared with patients without cGVHD, patients with cGVHD demonstrated a lower relapse (18.2% vs. 40%, P =0.2333), higher EFS (68.4% vs. 53.1%, P =0.283), and higher OS (73.7% vs. 68.8%, P =0.708). CONCLUSION Incidence of cGVHD was high in children undergoing haploidentical PBSCT with PTCy. Other than PBSC graft source; donor age and previous aGVHD were the risks factors for development of cGVHD. Patients with cGVHD had lower incidence of relapse translating into better survival but this difference was not statistically significant.
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Affiliation(s)
- Sunisha Arora
- Pediatric Hematology Oncology and Bone Marrow Transplant Unit, Cancer Institute, Medanta The Medicity Hospital, Gurgaon, Haryana
| | - Dhwanee Thakkar
- Pediatric Hematology Oncology and Bone Marrow Transplant Unit, Cancer Institute, Medanta The Medicity Hospital, Gurgaon, Haryana
| | - Karthik Upasana
- Pediatric Hematology Oncology and Bone Marrow Transplant Unit, Cancer Institute, Medanta The Medicity Hospital, Gurgaon, Haryana
| | - Anjali Yadav
- Pediatric Hematology Oncology and Bone Marrow Transplant Unit, Cancer Institute, Medanta The Medicity Hospital, Gurgaon, Haryana
| | - Neha Rastogi
- Pediatric Hematology Oncology and Bone Marrow Transplant Unit, Cancer Institute, Medanta The Medicity Hospital, Gurgaon, Haryana
| | - Prem S Sharma
- Department of Statistics, University College of Medical Sciences, Delhi, India
| | - Satya P Yadav
- Pediatric Hematology Oncology and Bone Marrow Transplant Unit, Cancer Institute, Medanta The Medicity Hospital, Gurgaon, Haryana
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Broxmeyer HE, Luchsinger LL, Weinberg RS, Jimenez A, Frenet EM, Van't Hof W, Capitano ML, Hillyer CD, Kaplan MH, Cooper S, Ropa J. Insights into highly engraftable hematopoietic cells from 27-year cryopreserved umbilical cord blood. Cell Rep Med 2023; 4:101259. [PMID: 37913777 PMCID: PMC10694620 DOI: 10.1016/j.xcrm.2023.101259] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/02/2023] [Accepted: 10/04/2023] [Indexed: 11/03/2023]
Abstract
Umbilical cord blood transplantation is a life-saving treatment for malignant and non-malignant hematologic disorders. It remains unclear how long cryopreserved units remain functional, and the length of cryopreservation is often used as a criterion to exclude older units. We demonstrate that long-term cryopreserved cord blood retains similar numbers of hematopoietic stem and progenitor cells compared with fresh and recently cryopreserved cord blood units. Long-term cryopreserved units contain highly functional cells, yielding robust engraftment in mouse transplantation models. We also leverage differences between units to examine gene programs associated with better engraftment. Transcriptomic analyses reveal that gene programs associated with lineage determination and oxidative stress are enriched in high engrafting cord blood, revealing potential molecular markers to be used as potency markers for cord blood unit selection regardless of length of cryopreservation. In summary, cord blood units cryopreserved for extended periods retain engrafting potential and can potentially be used for patient treatment.
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Affiliation(s)
- Hal E Broxmeyer
- Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | | | - Alexandra Jimenez
- Comprehensive Cell Solutions, New York Blood Center, New York, NY 10065, USA; National Cord Blood Program, Long Island City, NY 11101, USA
| | - Emeline Masson Frenet
- Comprehensive Cell Solutions, New York Blood Center, New York, NY 10065, USA; National Cord Blood Program, Long Island City, NY 11101, USA
| | | | - Maegan L Capitano
- Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | - Mark H Kaplan
- Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Scott Cooper
- Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - James Ropa
- Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Hurley K, Clow R, Jadhav A, Azzam EI, Wang Y. Mitigation of acute radiation syndrome (ARS) with human umbilical cord blood. Int J Radiat Biol 2023; 100:317-334. [PMID: 37967239 DOI: 10.1080/09553002.2023.2277372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/27/2023] [Indexed: 11/17/2023]
Abstract
PURPOSE The growing concern over potential unintended nuclear accidents or malicious activities involving nuclear/radiological devices cannot be overstated. Exposure to whole-body doses of radiation can result in acute radiation syndrome (ARS), colloquially known as "radiation sickness," which can severely damage various organ systems. Long-term health consequences, such as cancer and cardiovascular disease, can develop many years post-exposure. Identifying effective medical countermeasures and devising a strategic medical plan represents an urgent, unmet need. Various clinical studies have investigated the therapeutic use of umbilical cord blood (UCB) for a range of illnesses, including ARS. The objective of this review is to thoroughly discuss ARS and its sub-syndromes, and to highlight recent findings regarding the use of UCB for radiation injury. UCB, a rich source of stem cells, boasts numerous advantages over other stem cell sources, like bone marrow, owing to its ease of collection and relatively low risk of severe graft-versus-host disease. Preclinical studies suggest that treatment with UCB, and often UCB-derived mesenchymal stromal cells (MSCs), results in improved survival, accelerated hematopoietic recovery, reduced gastrointestinal tract damage, and mitigation of radiation-induced pneumonitis and pulmonary fibrosis. Interestingly, recent evidence suggests that UCB-derived exosomes and their microRNAs (miRNAs) might assist in treating radiation-induced damage, largely by inhibiting fibrotic pathways. CONCLUSION UCB holds substantial potential as a radiation countermeasure, and future research should focus on establishing treatment parameters for ARS victims.
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Affiliation(s)
- Kate Hurley
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
| | - Rachel Clow
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
| | - Ashok Jadhav
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
| | - Edouard I Azzam
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
| | - Yi Wang
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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9
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O'Donnell PV, Jones RJ. The development of post-transplant cyclophosphamide: Half a century of translational team science. Blood Rev 2023; 62:101034. [PMID: 36435690 PMCID: PMC11001251 DOI: 10.1016/j.blre.2022.101034] [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: 05/14/2022] [Revised: 10/19/2022] [Accepted: 11/09/2022] [Indexed: 11/14/2022]
Abstract
Close HLA matching of donors and recipients has been the dogma for successful allogeneic blood or marrow transplantation (alloBMT), to limit the complications of graft-versus-host disease (GVHD). However, many patients in need, especially those within certain ethnic groups such as those of African-Americans and Hispanics, remain unable to find a match even with the increased availability of unrelated donors. Over half a century ago, investigators at Johns Hopkins found that cyclophosphamide's immunosuppressive properties made it the ideal replacement for total body irradiation in alloBMT conditioning regimens. They also found it to be the best chemotherapeutic for preventing GVHD in animal models, but its cytotoxic properties scared them from using it clinically in the high doses successful in animal models. Subsequent work showed that cyclophosphamide spared hematopoietic and other stem cells including memory lymphocytes, prompting re-examination at high doses for GVHD prophylaxis. Animal and extensive human studies demonstrated that high-dose post-transplantation cyclophosphamide (PTCy) effectively and safely limited GVHD such that mismatched transplants are now considered standard-of-care worldwide. The beneficial effects of PTCy on GVHD appears to be independent of donor type, graft source, or conditioning regimen intensity.
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Affiliation(s)
- Paul V O'Donnell
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, United States of America
| | - Richard J Jones
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, John Hopkins University, Baltimore, MD, United States of America.
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Haroun E, Agrawal K, Leibovitch J, Kassab J, Zoghbi M, Dutta D, Lim SH. Chronic graft-versus-host disease in pediatric patients: Differences and challenges. Blood Rev 2023; 60:101054. [PMID: 36805299 DOI: 10.1016/j.blre.2023.101054] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023]
Abstract
Despite the use of high-resolution molecular techniques for tissue typing, chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplant. cGVHD adversely affects the life-expectancy and quality of life. The latter is particularly important and functionally relevant in pediatric patients who have a longer life-expectancy than adults. Current laboratory evidence suggests that there is not any difference in the pathophysiology of cGVHD between adults and pediatric patients. However, there are some clinical features and complications of the disease that are different in pediatric patients. There are also challenges in the development of new therapeutics for this group of patients. In this review, we will discuss the epidemiology, pathophysiology, clinical features and consequences of the disease, and highlight the differences between pediatric and adult patients. We will examine the current treatment options for pediatric patients with moderate to severe cGVHD and discuss the challenges facing therapeutic development for cGVHD in the pediatric population.
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Affiliation(s)
- Elio Haroun
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Kavita Agrawal
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Jennifer Leibovitch
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Joseph Kassab
- Department of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Marianne Zoghbi
- Department of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Dibyendu Dutta
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Seah H Lim
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America,; Sanofi Oncology, Cambridge, MA, United States of America.
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11
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Wang J, Metheny L. Umbilical cord blood derived cellular therapy: advances in clinical development. Front Oncol 2023; 13:1167266. [PMID: 37274288 PMCID: PMC10232824 DOI: 10.3389/fonc.2023.1167266] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/04/2023] [Indexed: 06/06/2023] Open
Abstract
While cord blood (CB) is primarily utilized in allogeneic hematopoietic cell transplantation (HCT), the development of novel cell therapy products from CB is a growing and developing field. Compared to adult blood, CB is characterized by a higher percentage of hematopoietic stem cells (HSCs) and progenitor cells, less mature immune cells that retain a high capacity of proliferation, and stronger immune tolerance that requires less stringent HLA-matching when used in the allogenic setting. Given that CB is an FDA regulated product and along with its unique cellular composition, CB lends itself as a readily available and safe starting material for the development of off-the-shelf cell therapies. Moreover, non-hematologic cells such as mesenchymal stem cell (MSCs) residing in CB or CB tissue also have potential in regenerative medicine and inflammatory and autoimmune conditions. In this review, we will focus on recent clinical development on CB-derived cellular therapies in the field of oncology, including T-cell therapies such as chimeric antigen receptor (CAR) T-cells, regulatory T-cells, and virus-specific T-cells; NK-cell therapies, such as NK cell engagers and CAR NK-cells; CB-HCT and various modifications; as well as applications of MSCs in HCT.
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Saiyin T, Kirkham AM, Bailey AJM, Shorr R, Pineault N, Maganti HB, Allan DS. Clinical Outcomes of Umbilical Cord Blood Transplantation Using Ex Vivo Expansion: A Systematic Review and Meta-Analysis of Controlled Studies. Transplant Cell Ther 2023; 29:129.e1-129.e9. [PMID: 36396108 DOI: 10.1016/j.jtct.2022.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 11/16/2022]
Abstract
Greater use of umbilical cord blood (UCB) for hematopoietic cell transplantation (HCT) is limited by the number of cells in banked units. Ex vivo culture strategies have been increasingly evaluated in controlled studies, but their impact on transplantation-related outcomes remains uncertain owing to the small patient numbers in these studies, necessitating an updated systematic review and meta-analysis. A systematic literature search was conducted using the MEDLINE, Embase, and Cochrane databases to March 18, 2022. Nine cohort-controlled phase I to III trials were identified, and data of 1146 patients undergoing umbilical cord blood transplantation (UCBT) were analyzed (308 ex vivo expanded and 838 unmanipulated controls). Expansion strategies involved cytokine cocktails plus the addition of small molecules (UM171, nicotinamide [NiCord], copper chelation, Notch ligand, or Stem regenin-1 [SR-1]) and coculture with mesenchymal stromal cells in a single-unit transplant strategy (5 studies) or a double-unit transplant strategy with 1 unmanipulated unit (4 studies). The included trials reported a median ex vivo expansion of CD34+ cells from 28-fold to 330-fold. Eight of the 9 studies demonstrated a significantly faster time to initial neutrophil and platelet engraftment using expanded cells compared with controls. Studies using UM171 and NiCord in single-unit UCBT and SR-1 or NiCord double-unit UCBT demonstrated long-term donor chimerism of the expanded unit at 100 days to 36 months post-transplantation in all single-unit recipients and in 35% to 78% of double-unit recipients. Our meta-analysis revealed a lower risk of death at the study endpoint in patients who received ex vivo expanded grafts (odds ratio [OR], .66; 95% confidence interval [CI], .47 to .95; P = .02), while the risk of grade II-IV acute graft-versus-host disease was unchanged (OR, .79; 95% CI, .58 to 1.08; P = .14). This review indicates that UCBT following ex vivo expansion can accelerate initial engraftment. Durable donor chimerism can be achieved after transplanting cord blood units expanded using NiCord, UM171, or SR-1; however, long term outcomes remain unclear. Larger studies with longer-term outcomes are needed to better understand the merits of specific expansion strategies on survival.
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Affiliation(s)
- Tana Saiyin
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Aidan M Kirkham
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Adrian J M Bailey
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Risa Shorr
- Medical Information and Education Services, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Nicolas Pineault
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Innovation and Portfolio Management, Canadian Blood Services, Ottawa, Ontario, Canada
| | - Harinad B Maganti
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Innovation and Portfolio Management, Canadian Blood Services, Ottawa, Ontario, Canada
| | - David S Allan
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Innovation and Portfolio Management, Canadian Blood Services, Ottawa, Ontario, Canada.
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13
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Gudauskaitė G, Kairienė I, Ivaškienė T, Rascon J, Mobasheri A. Therapeutic Perspectives for the Clinical Application of Umbilical Cord Hematopoietic and Mesenchymal Stem Cells: Overcoming Complications Arising After Allogeneic Hematopoietic Stem Cell Transplantation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1409:111-126. [PMID: 35995905 DOI: 10.1007/5584_2022_726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
This review focuses on the therapeutic features of umbilical cord blood (UCB) cells as a source for allogeneic hematopoietic stem cell transplantation (aHSCT) in adult and child populations to treat malignant and nonmalignant hematologic diseases, genetic disorders, or pathologies of the immune system, when standard treatment (e.g., chemotherapy) is not effective or clinically contraindicated. In this article, we summarize the immunological properties and the advantages and disadvantages of using UCB stem cells and discuss a variety of treatment outcomes using different sources of stem cells from different donors both in adults and pediatric population. We also highlight the critical properties (total nucleated cell dose depending on HLA compatibility) of UCB cells that reach better survival rates, reveal the advantages of double versus single cord blood unit transplantation, and present recommendations from the most recent studies. Moreover, we summarize the mechanism of action and potential benefit of mesenchymal umbilical cord cells and indicate the most common posttransplantation complications.
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Affiliation(s)
- Greta Gudauskaitė
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Ignė Kairienė
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Tatjana Ivaškienė
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Jelena Rascon
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Ali Mobasheri
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
- Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland.
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
- World Health Organization Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, Université de Liège, Liège, Belgium.
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14
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Wang J, Sanati F, Firoozmand A, Fu P, Kolk M, Reese-Koc J, de Lima M, Boughan K, Cooper B, Caimi P, Gallogly M, Otegbeye F, Tomlinson B, Metheny L. Phase I study of intra-osseous co-transplantation of a single-unit cord blood and mesenchymal stromal cells with reduced intensity conditioning regimens. Front Oncol 2023; 13:1186532. [PMID: 37207167 PMCID: PMC10191226 DOI: 10.3389/fonc.2023.1186532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/24/2023] [Indexed: 05/21/2023] Open
Abstract
Cord blood (CB) is a valuable graft source for patients undergoing allogeneic hematopoietic cell transplant (HCT) who lack human leukocyte antigen (HLA)-matched donors. However, single-unit CB-HCT is limited by the insufficient cell dose and slow engraftment. To overcome these limitations, we combined a single-unit CB with third-party healthy donors' bone marrow (BM) derived mesenchymal stromal cells (MSCs) to improve engraftment and injected intra-osseously (IO) to enhance homing. In this phase I clinical trial, six patients with high-risk hematologic malignancies were enrolled and received allogeneic HCT using reduced intensity conditioning regimens. The primary objective was to determine the engraftment rate at day 42. The median age of enrolled patients was 68 years, and only one patient was in complete remission at the time of HCT. The median CB total nucleated cell dose was 3.2x107/kg. No serious adverse events were reported. Two patients had early deaths due to persistent disease and multi-drug resistant bacterial infection, respectively. Of the remaining four evaluable patients, all had successful neutrophil engraftment in a median of 17.5 days. No grade 3 or higher acute graft-versus-host disease (GvHD) was observed, and only one patient developed moderate-extensive chronic GvHD. In conclusion, IO co-transplantation of a single-unit CB and MSCs was feasible and resulted in a reasonable engraftment rate in these very high-risk patients.
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Affiliation(s)
- Jiasheng Wang
- Department of Hematology/Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH, United States
- *Correspondence: Jiasheng Wang,
| | - Farhad Sanati
- Department of Hematology/Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH, United States
| | - Amin Firoozmand
- Department of Hematology/Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH, United States
| | - Pingfu Fu
- Case Western Reserve University, Cleveland, OH, United States
| | - Merle Kolk
- Adult Hematologic Malignancies & Stem Cell Transplantation Service, University Hospitals Seidman Cancer Center, Cleveland, OH, United States
| | - Jane Reese-Koc
- Case Western Reserve University, Cleveland, OH, United States
| | - Marcos de Lima
- Division of Hematology, Ohio State University, Columbus, OH, United States
| | - Kirsten Boughan
- Department of Hematology/Oncology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH, United States
| | - Brenda Cooper
- Adult Hematologic Malignancies & Stem Cell Transplantation Service, University Hospitals Seidman Cancer Center, Cleveland, OH, United States
| | - Paolo Caimi
- Blood and Marrow Transplant, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Molly Gallogly
- Adult Hematologic Malignancies & Stem Cell Transplantation Service, University Hospitals Seidman Cancer Center, Cleveland, OH, United States
| | - Folashade Otegbeye
- Clinical Research Division, Fred Hutchison Cancer Center, Seattle, WA, United States
| | - Benjamin Tomlinson
- Adult Hematologic Malignancies & Stem Cell Transplantation Service, University Hospitals Seidman Cancer Center, Cleveland, OH, United States
| | - Leland Metheny
- Adult Hematologic Malignancies & Stem Cell Transplantation Service, University Hospitals Seidman Cancer Center, Cleveland, OH, United States
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Welty NE, Gill SI. Cancer Immunotherapy Beyond Checkpoint Blockade: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2022; 4:563-578. [PMID: 36636439 PMCID: PMC9830230 DOI: 10.1016/j.jaccao.2022.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 12/24/2022] Open
Abstract
Avoidance of immune destruction is recognized as one of the hallmarks of cancer development. Although first predicted as a potential antitumor treatment modality more than 50 years ago, the widespread clinical use of cancer immunotherapies has only recently become a reality. Cancer immunotherapy works by reactivation of a stalled pre-existing immune response or by eliciting a de novo immune response, and its toolkit comprises antibodies, vaccines, cytokines, and cell-based therapies. The treatment paradigm in some malignancies has completely changed over the past 10 to 15 years. Massive efforts in preclinical development have led to a surge of clinical trials testing innovative therapeutic approaches as monotherapy and, increasingly, in combination. Here we provide an overview of approved and emerging antitumor immune therapies, focusing on the rich landscape of therapeutic approaches beyond those that block the canonical PD-1/PD-L1 and CTLA-4 axes and placing them in the context of the latest understanding of tumor immunology.
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Key Words
- BiTE, bispecific T cell engager
- CAR, chimeric antigen receptor
- CRS, cytokine-release syndrome
- FDA, U.S. Food and Drug Administration
- HLA, human leukocyte antigen
- ICI, immune checkpoint inhibitor
- IL, interleukin
- NK, natural killer
- NSCLC, non–small cell lung cancer
- TIL, tumor-infiltrating lymphocyte
- alloHCT, allogeneic hematopoietic stem cell transplantation
- cancer
- immune therapy
- immunotherapy
- innovation
- mAb, monoclonal antibody
- treatment
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Affiliation(s)
- Nathan E. Welty
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania, USA,Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Saar I. Gill
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania, USA,Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA,Address for correspondence: Dr Saar I. Gill, Smilow Center for Translational Research, Room 8-101, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
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Chakrabarty JH, Glover J, Schmidt S, Phan M, Bycko M, Duong Q, Vesely SK, O’Neal C, Robertson C, Davis C, Kratochvil K, Yuen C, Khawandanah M, Selby G, Jassim R, Williams KM. Incidence and risk factors for graft failure in the modern era of cord blood transplantation. Vox Sang 2022; 117:1405-1410. [PMID: 36250288 PMCID: PMC9772075 DOI: 10.1111/vox.13368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 08/02/2022] [Accepted: 09/27/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND OBJECTIVES Graft failure (GF) after cord blood transplant (CBT) has decreased with improved supportive care and cord selection strategies. We aimed to evaluate cord blood selection and factors associated with retransplantation on the incidence of GF, determine risk factors for GF including host antibodies to Kell antigen and evaluate survival after GF. MATERIALS AND METHODS We retrospectively reviewed 84 patients who underwent CBT at the University of Oklahoma between 2000 and 2016 and compared outcomes in patients with/without engraftment by Day 28. The nonengraftment cohort was further divided into patients who underwent retransplantation. Kaplan-Meier curves with log-rank tests were calculated to assess the association between mortality and engraftment. RESULTS Engraftment following CBT was high at 81%, with 52% engrafting by Day 28 and an additional 29% engrafting by a median of 36 days. Retransplantation led to 88% engraftment at a median of 53 days. Overall, 75% of the 40 patients who did not engraft by Day 28 died. Female sex and total nucleated cell count < 3.5/kg were significantly associated with lack of engraftment and higher mortality. Antibodies to Kell fetal antigen were not identified. Retransplantation by Day 28 for primary GF conferred a survival advantage. CONCLUSION This study demonstrates that failure to engraft by 28 days was associated with increased mortality, and risk was mitigated with early retransplantation. Female sex and low total cell dose were associated with increased mortality. Early identification of GF coupled with early retransplantation can reduce mortality in CBT.
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Affiliation(s)
| | - Joshua Glover
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Sara Schmidt
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Minh Phan
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Michele Bycko
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Quyen Duong
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Sara K. Vesely
- Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Caroline O’Neal
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Chelsie Robertson
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Christina Davis
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Kristen Kratochvil
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Carrie Yuen
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Mohamad Khawandanah
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - George Selby
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Rami Jassim
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Kirsten M. Williams
- Aflac Cancer and Blood Disorders, Children’s Healthcare of Atlanta, Emory University, Atlanta GA
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17
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Yao D, Tian Y, Li J, Li B, Lu J, Ling J, Zheng D, Yao Y, Xiao P, Meng L, Hu S. Association between haploidentical hematopoietic stem cell transplantation combined with an umbilical cord blood unit and graft- versus-host disease in pediatric patients with acquired severe aplastic anemia. Ther Adv Hematol 2022; 13:20406207221134409. [PMID: 36324490 PMCID: PMC9619284 DOI: 10.1177/20406207221134409] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 09/30/2022] [Indexed: 11/06/2022] Open
Abstract
Background: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) based on granulocyte colony-stimulating factor plus anti-thymocyte regimens (‘Beijing Protocol’) provides a salvage treatment for patients of acquired severe aplastic anemia (SAA) in China. However, graft-versus-host disease (GVHD) is a major impediment of haplo-HSCT due to human leukocyte antigen disparity. Recently, haplo-HSCT combined with umbilical cord blood (UCB) (haplo-cord HSCT) is performed in clinical trials to potentially reduce the risk of severe GVHD. Nevertheless, studies comparing GVHD in pediatric patients receiving haplo and haplo-cord HSCT for SAA are limited. Objective: The objective of this study was to investigate the impact of UCB co-infusion on GVHD in pediatric patients receiving haplo-HSCT for SAA. Design: We conducted a retrospective study of 91 consecutive SAA children undergoing haploidentical transplantation based on the ‘Beijing Protocol’ with or without co-infusion of UCB in our center. Methods: All patients received uniform non-myeloablative conditioning and GVHD prophylaxis. We compared baseline characteristics and transplant outcomes between the haplo (n = 35) and haplo-cord (n = 56) recipients. Results: All 91 patients achieved hematopoietic recovery from haploidentical donors, with a higher incidence of peri-engraftment syndrome observed with the haplo-cord group as compared with the haplo group (75.0% versus 48.6%, p = 0.029). Notably, the haplo-cord group showed a lower incidence of II–IV acute GVHD (aGVHD) than the haplo group (16.1% versus 42.9%, p = 0.002). Observed incidences of chronic GVHD (cGVHD) and moderate to severe cGVHD in the haplo-cord group were also lower than that in the haplo group (25.6% versus 51.3%, p = 0.019; 16.2% versus 41.3%, p = 0.016, respectively). Haplo-cord HSCT was identified as the only factor associated with a lower incidence of II–IV aGVHD and cGVHD in multivariate analysis. However, no differences were observed between the two groups for infections and survival outcomes. Conclusion: Our data indicated that co-infusion of UCB in ‘Beijing Protocol’-based haplo-HSCT may be effective for reducing the risk of severe GVHD in SAA children.
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Affiliation(s)
| | | | | | | | - Jun Lu
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China,Jiangsu Children’s Hematology & Oncology Center, Suzhou, China,Di Yao is also affiliated to Department of Pediatrics, Hangzhou First People’s Hospital, Hangzhou, China
| | - Jing Ling
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China,Jiangsu Children’s Hematology & Oncology Center, Suzhou, China,Di Yao is also affiliated to Department of Pediatrics, Hangzhou First People’s Hospital, Hangzhou, China
| | - Defei Zheng
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China,Jiangsu Children’s Hematology & Oncology Center, Suzhou, China,Di Yao is also affiliated to Department of Pediatrics, Hangzhou First People’s Hospital, Hangzhou, China
| | - Yanhua Yao
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China,Jiangsu Children’s Hematology & Oncology Center, Suzhou, China,Di Yao is also affiliated to Department of Pediatrics, Hangzhou First People’s Hospital, Hangzhou, China
| | - Peifang Xiao
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China,Jiangsu Children’s Hematology & Oncology Center, Suzhou, China,Di Yao is also affiliated to Department of Pediatrics, Hangzhou First People’s Hospital, Hangzhou, China
| | - Lijun Meng
- Department of Hematology, Children’s Hospital of Soochow University, No. 92 Zhongnan Street, Suzhou 215025, Jiangsu, China,Jiangsu Children’s Hematology & Oncology Center, Suzhou, China
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18
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Crompton K, Godler DE, Ling L, Elwood N, Mechinaud-Heloury F, Soosay Raj T, Hsiao KC, Fleming J, Tiedemann K, Novak I, Fahey M, Wang X, Lee KJ, Colditz PB, Edwards P, Reddihough D. Umbilical Cord Blood Cell Clearance Post-Infusion in Immune-Competent Children with Cerebral Palsy. Cells Tissues Organs 2022; 212:546-553. [PMID: 36261026 DOI: 10.1159/000527612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/13/2022] [Indexed: 11/19/2022] Open
Abstract
Umbilical cord blood cells have therapeutic potential for neurological disorders, through a paracrine mechanism of action. A greater understanding of the safety and immunological effects of allogeneic donor cord blood cells in the context of a healthy recipient immune system, such as in cerebral palsy, is needed. This study aimed to determine how quickly donor cord blood cells were cleared from the circulation in children with cerebral palsy who received a single intravenous infusion of 12/12 human leucocyte antigen (HLA)-matched sibling cord blood cells. Twelve participants with cerebral palsy aged 2-12 years received cord blood cell infusions as part of a phase I trial of umbilical blood infusion for cerebral palsy. Digital droplet PCR analysis of DNA copy number variants specific to donor and recipient was used to assess donor DNA clearance at five timepoints post-infusion, a surrogate measure of cell clearance. Donor cells were cleared by 3 months post-infusion in 11/12 participants. When detected, donor DNA was at a fraction of 0.01-0.31% of total DNA with no signs of graft-versus-host disease in any participant. The donor DNA clearance times provided by this study have important implications for understanding the safety of allogeneic cord blood cell infusion for cerebral palsy and translational tissue engineering or regenerative medicine research in other disorders.
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Affiliation(s)
- Kylie Crompton
- Neurodisability and Rehabilitation, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
- Neurodevelopment and Disability, The Royal Children's Hospital, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - David E Godler
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- Diagnosis and Development, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Ling Ling
- Diagnosis and Development, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Ngaire Elwood
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- Blood Development, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
- The Royal Children's Hospital, Parkville, Victoria, Australia
- BMDI Cord Blood Bank, Parkville, Victoria, Australia
| | | | - Trisha Soosay Raj
- Children's Cancer Centre, The Royal Children's Hospital, Parkville, Victoria, Australia
- Oncology, Queensland Children's Hospital, South Brisbane, Queensland, Australia
| | - Kuang-Chih Hsiao
- Allergy Immunology, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
- Immunology, Starship Children's Hospital, Auckland, New Zealand
- Paediatrics, University of Auckland, Auckland, New Zealand
| | - Jacqueline Fleming
- Children's Cancer Centre, The Royal Children's Hospital, Parkville, Victoria, Australia
| | | | - Iona Novak
- Cerebral Palsy Alliance Research Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Michael Fahey
- Paediatric Neurology, Monash Children's Hospital, Clayton, Victoria, Australia
- Medicine, Monash University, Melbourne, Victoria, Australia
| | - Xiaofang Wang
- Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Katherine J Lee
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Paul B Colditz
- Grantley Stable Neonatal Unit, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
- Perinatal Research Centre, The University of Queensland, Brisbane, Queensland, Australia
| | - Priya Edwards
- Queensland Paediatric Rehabilitation Service, Queensland Children's Hospital, South Brisbane, Queensland, Australia
- Queensland Cerebral Palsy and Rehabilitation Research Centre, The Univeristy of Queensland, Brisbane, Queensland, Australia
| | - Dinah Reddihough
- Neurodisability and Rehabilitation, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
- Neurodevelopment and Disability, The Royal Children's Hospital, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
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19
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Regulatory T cell niche in the bone marrow, a new player in Haematopoietic stem cell transplantation. Blood Rev 2022; 59:101030. [PMID: 36336520 DOI: 10.1016/j.blre.2022.101030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 10/03/2022] [Accepted: 10/26/2022] [Indexed: 11/20/2022]
Abstract
Challenges in haematopoietic stem cell transplantation such as low bone marrow (BM) engraftment, graft versus host disease (GvHD) and the need for long-term immunosuppression could be addressed using T regulatory cells (Tregs) resident in the tissue of interest, in this case, BM Tregs. Controlling the adverse immune response in haematopoietic stem cell transplantation (HSCT) and minimising the associated risks such as infection and secondary cancers due to long-term immunosuppression is a crucial aspect of clinical practice in this field. While systemic immunosuppressive therapy could achieve reasonable GvHD control in most patients, related side effects remain the main limiting factor. Developing more targeted immunosuppressive strategies is an unmet clinical need and is the focus of several ongoing research projects. Tregs are a non-redundant sub-population of CD4+ T cells essential for controlling the immune homeostasis. Tregs are known to be reduced in number and function in autoimmune conditions. There is considerable interest in these cells as cell therapy products since they can be expanded in vitro and infused into patients. These trials have found Treg therapy to be safe, well-tolerated, and with some early signs of efficacy. However, Tregs are a heterogeneous subpopulation of T cells, and several novel subpopulations have been identified in recent years beyond the conventional thymic (tTregs) and peripheral (pTregs). There is increasing evidence for the presence of resident and tissue-specific Tregs. Bone marrow (BM) Tregs are one example of tissue-resident Tregs. BM Tregs are enriched within the marrow, serving a dual function of immunosuppression and maintenance of haematopoietic stem cells (HSCs). HSCs maintenance is achieved through direct suppression of HSCs differentiation, maintaining a proliferating pool of HSCs, and promoting the development of functional stromal cells that support HSCs. In this review, we will touch upon the biology of Tregs, focusing on their development and heterogeneity. We will focus on the BM Tregs from their biology to their therapeutic potential, focusing on their use in HSCT.
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20
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Buder K, Zirngibl M, Bapistella S, Meerpohl JJ, Strahm B, Bassler D, Weitz M. Extracorporeal photopheresis versus standard treatment for acute graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents. Cochrane Database Syst Rev 2022; 9:CD009759. [PMID: 36166494 PMCID: PMC9514720 DOI: 10.1002/14651858.cd009759.pub4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation (HSCT), occurring in 8% to 85% of paediatric recipients. Currently, the therapeutic mainstay for aGvHD is treatment with corticosteroids. However, there is no established standard treatment for steroid-refractory aGvHD. Extracorporeal photopheresis (ECP) is a type of immunomodulatory method amongst different therapeutic options that involves ex vivo collection of peripheral mononuclear cells, exposure to the photoactive agent 8-methoxypsoralen and ultraviolet-A radiation, and reinfusion of these treated blood cells to the patient. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and updated in 2015. OBJECTIVES To evaluate the effectiveness and safety of ECP for the management of aGvHD in children and adolescents after HSCT. SEARCH METHODS We searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE (PubMed) and Embase (Ovid) databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively. SELECTION CRITERIA We sought to include randomised controlled trials (RCTs) comparing ECP with or without standard treatment versus standard treatment alone in children and adolescents with aGvHD after HSCT. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. We resolved disagreement in the selection of trials by consultation with a third review author. MAIN RESULTS We identified no additional studies in the 2021 review update, so there are still no studies that meet the criteria for inclusion in this review. AUTHORS' CONCLUSIONS The efficacy of ECP in the treatment of aGvHD in children and adolescents after HSCT is unknown, and its use should be restricted to within the context of RCTs. Such studies should address a comparison of ECP alone or in combination with standard treatment versus standard treatment alone. The 2021 review update brought about no additions to these conclusions.
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Affiliation(s)
- Kathrin Buder
- Department of General Paediatrics and Haematology/Oncology, University Hospital Tübingen, University Children's Hospital, Tübingen, Germany
| | - Matthias Zirngibl
- Department of General Paediatrics and Haematology/Oncology, University Hospital Tübingen, University Children's Hospital, Tübingen, Germany
| | - Sascha Bapistella
- Department of General Paediatrics and Haematology/Oncology, University Hospital Tübingen, University Children's Hospital, Tübingen, Germany
| | - Joerg J Meerpohl
- Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany
| | - Brigitte Strahm
- Pediatric Hematology and Oncology Centre for Pediatrics and Adolescent Medicine, University Medical School Freiburg, Freiburg, Germany
| | - Dirk Bassler
- Department of Neonatology, University Hospital Zürich, Zürich, Switzerland
| | - Marcus Weitz
- Department of General Paediatrics and Haematology/Oncology, University Hospital Tübingen, University Children's Hospital, Tübingen, Germany
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Verbeek AB, Jansen SA, von Asmuth EG, Lankester AC, Bresters D, Bierings M, Mohseny AB, Lindemans CA, Buddingh EP. Clinical Features, Treatment, and Outcome of Pediatric Steroid Refractory Acute Graft-Versus-Host Disease: A Multicenter Study. Transplant Cell Ther 2022; 28:600.e1-600.e9. [DOI: 10.1016/j.jtct.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 11/17/2022]
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22
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Timofeeva OA, Philogene MC, Zhang QJ. Current donor selection strategies for allogeneic hematopoietic cell transplantation. Hum Immunol 2022; 83:674-686. [PMID: 36038413 DOI: 10.1016/j.humimm.2022.08.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/27/2022]
Abstract
Since the first allogeneic hematopoietic stem cell transplantation (HCT) was performed by Dr. E. Donnall Thomas in 1957, the field has advanced with new stem cell sources, immune suppressive regimens, and transplant protocols. Stem cells may be collected from bone marrow, peripheral or cord blood from an identical twin, a sibling, or a related or unrelated donor, which can be human leukocyte antigen (HLA) matched, mismatched, or haploidentical. Although HLA matching is one of the most important criteria for successful allogeneic HCT (allo-HCT) to minimize graft vs host disease (GVHD), prevent relapse, and improve overall survival, the novel immunosuppressive protocols for GVHD prophylaxis offered improved outcomes in haploidentical HCT (haplo-HCT), expanding donor availability for the majority of HCT candidates. These immunosuppressive protocols are currently being tested with the HLA-matched and mismatched donors to improve HCT outcomes further. In addition, fine-tuning the DPB1 mismatching and discovering the B leader genotype and mismatching may offer further optimization of donor selection and transplant outcomes. While the decision about a donor type largely depends on the patient's characteristics, disease status, and the transplant protocols utilized by an individual transplant center, there are general approaches to donor selection dictated by donor-recipient histocompatibility and the urgency for HCT. This review highlights recent advances in understanding critical factors in donor selection strategies for allo-HCT. It uses clinical vignettes to demonstrate the importance of making timely decisions for HCT candidates.
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Affiliation(s)
- Olga A Timofeeva
- Department of Pathology and Laboratory Medicine, MedStar Georgetown University Hospital, Georgetown University School of Medicine, Georgetown University Medical Center, Washington, DC 20007, United States.
| | - Mary Carmelle Philogene
- Histocompatibility Laboratory Services, American Red Cross, Penn-Jersey Region, Philadelphia, PA 19123, United States.
| | - Qiuheng Jennifer Zhang
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles 90095, United States.
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23
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Umbilical Cord Blood as a Hematopoietic Stem Cell Source in Transplantation for Pediatric Sickle Cell Disease: Current Challenges and Strategies. Transfus Apher Sci 2022; 61:103554. [DOI: 10.1016/j.transci.2022.103554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Buder K, Zirngibl M, Bapistella S, Meerpohl JJ, Strahm B, Bassler D, Weitz M. Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents. Cochrane Database Syst Rev 2022; 6:CD009898. [PMID: 35679154 PMCID: PMC9181448 DOI: 10.1002/14651858.cd009898.pub4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation, occurring in 6% to 65% of the paediatric recipients. Currently, the therapeutic mainstay for cGvHD is treatment with corticosteroids, frequently combined with other immunosuppressive agents in people with steroid-refractory manifestations. There is no established standard treatment for steroid-refractory cGvHD. The therapeutic options for these patients include extracorporeal photopheresis (ECP), an immunomodulatory treatment that involves ex vivo collection of mononuclear cells from peripheral blood, exposure to the photoactive agent 8-methoxypsoralen, ultraviolet radiation and re-infusion of the processed cell product. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and first updated in 2015. OBJECTIVES To evaluate the effectiveness and safety of ECP for the management of cGvHD in children and adolescents after haematopoietic stem cell transplantation. SEARCH METHODS We searched the Cochrane Register of Controlled Trials (CENTRAL) (2021), MEDLINE (PubMed) and Embase databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively. SELECTION CRITERIA We aimed to include randomised controlled trials (RCTs) comparing ECP with or without alternative treatment versus alternative treatment alone in children and adolescents with cGvHD after haematopoietic stem cell transplantation. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. We resolved disagreements in the selection of trials by consultation with a third review author. MAIN RESULTS We found no studies meeting the criteria for inclusion in this 2021 review update. AUTHORS' CONCLUSIONS We could not evaluate the efficacy of ECP in the treatment of cGvHD in children and adolescents after haematopoietic stem cell transplantation since the second review update again found no RCTs. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this population will be challenging due to the limited number of eligible participants, variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical data are made in favour of ECP, recipients should be carefully monitored for beneficial and harmful effects. In addition, efforts should be made to share this information with other clinicians, for example by setting up registries for children and adolescents treated with ECP.
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Affiliation(s)
- Kathrin Buder
- Department of General Paediatrics and Haematology/Oncology, University Hospital Tübingen, University Children's Hospital, Tübingen, Germany
| | - Matthias Zirngibl
- Department of General Paediatrics and Haematology/Oncology, University Hospital Tübingen, University Children's Hospital, Tübingen, Germany
| | - Sascha Bapistella
- Department of General Paediatrics and Haematology/Oncology, University Hospital Tübingen, University Children's Hospital, Tübingen, Germany
| | - Joerg J Meerpohl
- Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany
| | - Brigitte Strahm
- Pediatric Hematology and Oncology Centre for Pediatrics and Adolescent Medicine, University Medical School Freiburg, Freiburg, Germany
| | - Dirk Bassler
- Department of Neonatology, University Hospital Zürich, Zürich, Switzerland
| | - Marcus Weitz
- Department of General Paediatrics and Haematology/Oncology, University Hospital Tübingen, University Children's Hospital, Tübingen, Germany
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Systemic Lupus Erythematosus in a 15-year-old with Graft-versus-Host Disease Following Liver Transplant and Unexpected Full Hematopoietic Engraftment. JAAD Case Rep 2022; 24:4-7. [PMID: 35518274 PMCID: PMC9062762 DOI: 10.1016/j.jdcr.2022.03.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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26
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Wen J, Wang X, Chen L, He Y, Feng X, Li C, Ruan Y, Liu S, Wu X. Encouraging the outcomes of children with beta-thalassaemia major who underwent fresh cord blood transplantation from an HLA-matched sibling donor. Hematology 2022; 27:310-317. [PMID: 35220923 DOI: 10.1080/16078454.2022.2038402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Jianyun Wen
- Department of Pediatrics, Southern Medical University, Guangzhou, People’s Republic of China
| | - Xiaodong Wang
- Department of Hematology & Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China
| | - Libai Chen
- Department of Pediatrics, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yuelin He
- Nanfang-Chunfu Children's Institute of Hematology & Oncology, Dongguan, People’s Republic of China
| | - Xiaoqin Feng
- Department of Pediatrics, Southern Medical University, Guangzhou, People’s Republic of China
| | - Chunfu Li
- Nanfang-Chunfu Children's Institute of Hematology & Oncology, Dongguan, People’s Republic of China
| | - Yongshen Ruan
- Department of Pediatrics, Southern Medical University, Guangzhou, People’s Republic of China
| | - Sixi Liu
- Department of Hematology & Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China
| | - Xuedong Wu
- Department of Pediatrics, Southern Medical University, Guangzhou, People’s Republic of China
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27
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Effect of expansion of human umbilical cord blood CD34 + cells on neurotrophic and angiogenic factor expression and function. Cell Tissue Res 2022; 388:117-132. [PMID: 35106623 PMCID: PMC8976778 DOI: 10.1007/s00441-022-03592-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 01/19/2022] [Indexed: 12/29/2022]
Abstract
The use of CD34 + cell-based therapies has largely been focused on haematological conditions. However, there is increasing evidence that umbilical cord blood (UCB) CD34 + -derived cells have neuroregenerative properties. Due to low cell numbers of CD34 + cells present in UCB, expansion is required to produce sufficient cells for therapeutic purposes, especially in adults or when frequent applications are required. However, it is not known whether expansion of CD34 + cells has an impact on their function and neuroregenerative capacity. We addressed this knowledge gap in this study, via expansion of UCB-derived CD34 + cells using combinations of LDL, UM171 and SR-1 to yield large numbers of cells and then tested their functionality. CD34 + cells expanded for 14 days in media containing UM171 and SR-1 resulted in over 1000-fold expansion. The expanded cells showed an up-regulation of the neurotrophic factor genes BDNF, GDNF, NTF-3 and NTF-4, as well as the angiogenic factors VEGF and ANG. In vitro functionality testing showed that these expanded cells promoted angiogenesis and, in brain glial cells, promoted cell proliferation and reduced production of reactive oxygen species (ROS) during oxidative stress. Collectively, this study showed that our 14-day expansion protocol provided a robust expansion that could produce enough cells for therapeutic purposes. These expanded cells, when tested in in vitro, maintained functionality as demonstrated through promotion of cell proliferation, attenuation of ROS production caused by oxidative stress and promotion of angiogenesis.
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28
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Safety of sibling cord blood cell infusion for children with cerebral palsy. Cytotherapy 2022; 24:931-939. [DOI: 10.1016/j.jcyt.2022.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/11/2022] [Accepted: 01/21/2022] [Indexed: 11/23/2022]
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29
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Jeppesen H, Kielsen K, Siersma V, Lindegaard J, Julian HO, Heegaard S, Sengeløv H, Müller K. Ocular graft-versus-host disease and dry eye disease after paediatric haematopoietic stem cell transplantation - incidence and risk factors. Bone Marrow Transplant 2022; 57:487-498. [PMID: 35042981 DOI: 10.1038/s41409-022-01564-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 12/07/2021] [Accepted: 01/04/2022] [Indexed: 01/28/2023]
Abstract
Ocular graft-versus-host disease (oGVHD) contributes substantially to morbidity after allogeneic haematopoietic stem cell transplantation (HSCT) but is sparsely investigated in children. We assessed incidence and risk factors for oGVHD and dry eye disease (DED) in a nationwide, single-centre study of 484 consecutive children receiving HSCT during the period 1980-2016. Ophthalmological examinations were performed before and annually at least until five years after HSCT. Twenty-five patients had DED before transplantation (5.6%). The cumulative incidence was 1.9% for acute oGVHD, 6.0% for chronic oGVHD, 8.7% for new onset DED, and 12.7% for new onset Corneal Fluorescein Staining (CFS). In adjusted Fine-Gray regression models, the use of Busulfan was a risk factor for developing acute oGVHD (HR 5.01, p = 0.03), and malignant disease was a risk factor for developing CFS (HR 2.00, p = 0.047). Younger recipient age was associated with reduced risk of DED when comparing children aged 0-4 years with 10-16 years (HR 0.33, p = 0.03). These data underscore the need of attention to DED and oGVHD in relation to HSCT leading to our recommendation of performing ophthalmic examinations in all children before HSCT, and after HSCT when needed, in order to secure diagnosis and treatment of these complications.
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Sobkowiak-Sobierajska A, Lindemans C, Sykora T, Wachowiak J, Dalle JH, Bonig H, Gennery A, Lawitschka A. Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan. Front Pediatr 2022; 10:808103. [PMID: 35252060 PMCID: PMC8894895 DOI: 10.3389/fped.2022.808103] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/24/2022] [Indexed: 12/18/2022] Open
Abstract
Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.
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Affiliation(s)
| | - Caroline Lindemans
- Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Pediatric Blood and Bone Marrow Transplantation, Princess Máxima Center, Utrecht, Netherlands
| | - Tomas Sykora
- Department of Pediatric Hematology and Oncology - Haematopoietic Stem Cell Transplantation Unit, National Institute of Children's Diseases and Medical Faculty, Comenius University, Bratislava, Slovakia
| | - Jacek Wachowiak
- Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Poznan, Poland
| | - Jean-Hugues Dalle
- Hematology and Immunology Department, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris and University of Paris, Paris, France
| | - Halvard Bonig
- Goethe University Medical Center, Institute of Transfusion Medicine and Immunohematology, and German Red Cross Blood Center Frankfurt, Frankfurt, Germany
| | - Andrew Gennery
- Medical School, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Anita Lawitschka
- Stem Cell Transplantation Unit, St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria.,St. Anna Children's Cancer Research Institute, Vienna, Austria
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31
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Kurogi H, Takijiri T, Sakumoto M, Isogai M, Takahashi A, Okubo T, Koike T, Yamada T, Nagamura-Inoue T, Sakaki-Yumoto M. Study on the Umbilical Cord-Mesenchymal Stem Cell Manufacturing Using Clinical-Grade Culture Medium. Tissue Eng Part C Methods 2022; 28:23-33. [PMID: 35018815 DOI: 10.1089/ten.tec.2021.0207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapies have been gaining increasing attention owing to their application in various diseases and conditions. In this study, we aimed to identify the optimal condition for industrial-scale MSC manufacturing. MSCs were isolated from umbilical cord (UC) tissues by implementing the explant method (Exp) or a collagenase based-enzymatic digestion method (Col), using a good manufacturing practice-compatible serum-free medium developed in-house. Microarray analysis demonstrated that the gene expression profiles of Exp-MSCs and Col-MSCs did not significantly differ according to the method of isolation or the culture conditions used. The isolated UC-MSCs were then subjected to expansion using conventional static culture (ST) or microcarrier-based culture in stirred-tank bioreactors (MC). Metabolomic and cytokine array analyses were conducted to evaluate the biochemical status of the MSCs. However, no remarkable differences in the metabolic profile and cytokine secretome between ST-MSCs and MC-MSCs were observed. On the contrary, we observed for the first time that the hydrophobic components of ST-MSCs and MC-MSCs were different, which suggested that the cell membrane distribution of fatty acids and lipids was altered in the process of adaptation to shear stress in MC-MSCs. These results establish the flexibility of the isolation and expansion method for UC-MSCs during the manufacturing processes and provide new insights into the minor differences between expansion methods that may exert remarkable effects on MSCs. In conclusion, we demonstrated the feasibility of both Exp-MSCs and Col-MSCs and MC and ST culture methods for scale-up and scale-out of MSC production, as well as the equivalence of these cells. As for the industrialized mass production of MSCs, enzyme-based methods for isolation and cell expansion in a bioreactor were considered to be more suitable. The methods developed, which underwent comprehensive evaluation in this study, may contribute toward the provision of sufficient MSC sources and the establishment of cost-effective MSC therapies. Impact statement Our in-house-developed good manufacturing practice-grade serum-free medium could be used for both isolation (Exp and Col) and expansion (ST and MC) of umbilical cord (UC)-mesenchymal stem/stromal cells (MSCs). Characteristics of the obtained UC-MSCs were widely assessed with regard to gene expression, metabolome, and secretome. Cellular characteristics and efficacy were observed to be equivalently maintained among whichever technique was applied. In addition, our research presents the first evidence that bioreactor and microcarrier-based MSC cultures alter the fatty acid and phospholipid composition of MSCs. These results provide new insights into the differences between expansion methods that may exert remarkable effects on MSCs.
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Affiliation(s)
- Hikari Kurogi
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan.,Rohto Advanced Research Hong Kong Limited, New Territories, Hong Kong
| | - Takashi Takijiri
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Marimu Sakumoto
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Maya Isogai
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Atsuko Takahashi
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Toru Okubo
- Basic Research Development Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Tetsuo Koike
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Tetsumasa Yamada
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masayo Sakaki-Yumoto
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
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Huang K, Luo J. Activated CD4 + T lymphocyte is a potential biomarker for acute graft-vs.-host disease after hematopoietic stem cell transplantation in children with transfusion-dependent β-thalassemia. Front Pediatr 2022; 10:985306. [PMID: 36245740 PMCID: PMC9558818 DOI: 10.3389/fped.2022.985306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Acute graft-vs.-host disease (aGVHD) is still one of the most common and life-threatening complications of allogeneic hematopoietic stem cell transplantation (HSCT). Whether or not the level of activated T lymphocytes rises before the onset of aGVHD is unknown. We explored the possibility of T lymphocytes as biomarkers for early prediction of aGVHD in children with transfusion-dependent β-thalassemia (TDTβ). METHODS We retrospectively analyzed the characteristics of T lymphocyte subsets before and 14 days after HSCT in children with TDTβ who developed aGVHD. Data from 95 children (Age ≤ 14 years) who underwent allogeneic HSCT from January 2020 to December 2021 were collected. Patients were divided into non-aGVHD group (n = 55) and aGVHD group (n = 40), and aGVHD group was divided into two subgroups: grade I aGVHD (n = 16) and grade II-IV aGVHD (n = 24). Receiver operating characteristic curve (ROC) analysis was performed to predict aGVHD. RESULTS Before preconditioning in non-aGVHD and aGVHD groups, there was no significant difference in all lymphocyte subsets and ratio of CD4 + /CD8 + T cells. On day 14 post-transplantation in non-aGVHD and aGVHD groups, the absolute concentrations per μl blood of T cells, CD4 + T cells, CD8 + T cells, activated CD4 + T cell and NK cells, were 69.73 (14.70, 137.77) and 140.36 (65.06, 293.42), 10.00 (2.35, 23.59) and 35.91 (12.41, 68.71), 37.25 (5.82, 84.36) and 89.99 (35.83, 180.81), 0.52 (0.17, 2.20) and 4.08 (0.91, 11.12), 43.86 (15.00, 91.31) and 26.35 (15.19, 49.39), respectively. On day + 14 (14 days post-transplantation), the differences in all cell subsets and the ratio of CD4 + /CD8 + T cells were not statistically significant between grade I aGVHD and grade II-IV aGVHD subgroups. The absolute concentrations of CD8 + T cells in grade I aGVHD were significantly higher than in grade II-IV aGVHD [128.21 (61.11, 258.91) vs. 60.81 (21.59, 176.38), P = 0.057]. AUC of NK cells, CD8 + T cells, T cells, CD4 + T cells, and CD4 + CD25 + T cells were 0.6275, 0.6839, 0.7068, 0.7241, and 0.7589, and cut-off values were 73.75 (97.50, 34.55), 146.90 (37.50, 94.55), 187.30 (45.00, 90.91), 18.95 (70.00, 72.73), and 3.24 (52.50, 87.27), respectively. The AUC of the combined CD4 + CD25 + T cells and CD8 + T cells, CD4 + CD25 + T cells and T cells, CD4 + CD25 + T cells and CD4 + T cells, CD4 + CD25 + T cells and NK cells, respectively, were 0.7500, 0.7598, 0.7750, and 0.8050. CONCLUSION Our findings demonstrate that level of activated CD4 + T cells on day + 14 (post-HSCT) is a valuable biomarker for predicting aGVHD in children with TDTβ and CD8 + T cells could likely be a biomarker for severe aGVHD.
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Affiliation(s)
- Ken Huang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jianming Luo
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Ekram S, Khalid S, Salim A, Khan I. Regulating the fate of stem cells for regenerating the intervertebral disc degeneration. World J Stem Cells 2021; 13:1881-1904. [PMID: 35069988 PMCID: PMC8727226 DOI: 10.4252/wjsc.v13.i12.1881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/12/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden. The etiology of intervertebral disc (IVD) degeneration is complicated, and its mechanism is still not completely understood. Factors such as aging, systemic inflammation, biochemical mediators, toxic environmental factors, physical injuries, and genetic factors are involved in the progression of its pathophysiology. Currently, no therapy for restoring degenerated IVD is available except pain management, reduced physical activities, and surgical intervention. Therefore, it is imperative to establish regenerative medicine-based approaches to heal and repair the injured disc, repopulate the cell types to retain water content, synthesize extracellular matrix, and strengthen the disc to restore normal spine flexion. Cellular therapy has gained attention for IVD management as an alternative therapeutic option. In this review, we present an overview of the anatomical and molecular structure and the surrounding pathophysiology of the IVD. Modern therapeutic approaches, including proteins and growth factors, cellular and gene therapy, and cell fate regulators are reviewed. Similarly, small molecules that modulate the fate of stem cells for their differentiation into chondrocytes and notochordal cell types are highlighted.
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Affiliation(s)
- Sobia Ekram
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Shumaila Khalid
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan.
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34
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Lim YJ, Arbiv OA, Kalbfleisch ME, Klaassen RJ, Fernandez C, Rayar M, Steele M, Lipton JH, Cuvelier G, Pastore YD, Silva M, Brossard J, Michon B, Abish S, Sinha R, Corriveau-Bourque C, Breakey VR, Tole S, Goodyear L, Sung L, Zlateska B, Cada M, Dror Y. Poor Outcome After Hematopoietic Stem Cell Transplantation Of Patients With Unclassified Inherited Bone Marrow Failure Syndromes. Eur J Haematol 2021; 108:278-287. [PMID: 34897809 DOI: 10.1111/ejh.13733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 11/29/2021] [Accepted: 12/01/2021] [Indexed: 11/30/2022]
Abstract
Classification of inherited bone marrow failure syndromes (IBMFSs) according to clinical and genetic diagnoses enables proper adjustment of treatment. Unfortunately, 30% of patients enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) with features suggesting hereditability could not be classified with a specific syndromic diagnosis. We analyzed the outcome of hematopoietic stem cell transplantation (HSCT) in unclassified IBMFSs (uIBMFSs) and the factors associated with outcome. Twenty-two patients with uIBMFSs and 70 patients with classified IBMFSs underwent HSCT. Five-year overall survival of uIBMFS patients after HSCT was inferior to that of patients with classified IBMFSs (56% vs 76.5%). The outcome of patients with uIBMFS who received cord blood was significantly lower than that of patients who received other stem cell sources (14.8% vs 90.9%). Engraftment failure was higher among patients with uIBMFS who received cord blood than those who received bone marrow. None of the following factors was significantly associated with poor survival: transfusion load, transplant indication, the intensity of conditioning regimen, human leukocyte antigen-identical sibling/alternative donor. We suggest that identifying the genetic diagnosis is essential to modulate the transplant procedure including conditioning agents and stem cell sources for better outcome and the standard CBT should be avoided in uIBMFS.
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Affiliation(s)
- Yeon Jung Lim
- The Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology, Department of Paediatrics, University of Toronto.,Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.,Current Affiliation, Department of Pediatrics, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Omri A Arbiv
- The Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology, Department of Paediatrics, University of Toronto.,Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Melanie E Kalbfleisch
- The Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology, Department of Paediatrics, University of Toronto.,Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | | | | | - Meera Rayar
- British Columbia Children's Hospital, Vancouver, British Columbia, Canada
| | | | | | | | | | | | - Josee Brossard
- Centre U Sante de l'Estrie-Fleur, Sherbrooke, Québec, Canada
| | - Bruno Michon
- Centre Hospital University Quebec-Pav CHUL, Sainte-Foy, Québec, Canada
| | - Sharon Abish
- Montreal Children's Hospital, Montreal, Québec, Canada
| | - Roona Sinha
- University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | | | - Vicky R Breakey
- McMaster Children's Hospital/McMaster University Health Sciences Centre, Hamilton, Ontario, Canada
| | - Soumitra Tole
- Children's Hospital, London Health Sciences Centre, London, Ontario, Canada
| | - Lisa Goodyear
- Janeway Child Health Centre, St. John's, Newfoundland, Canada
| | - Lillian Sung
- Child Health and Evaluative Sciences, .The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Bozana Zlateska
- The Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology, Department of Paediatrics, University of Toronto.,Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Michaela Cada
- The Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology, Department of Paediatrics, University of Toronto
| | - Yigal Dror
- The Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology, Department of Paediatrics, University of Toronto.,Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, Canada
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35
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Zhu X, Tang B, Sun Z. Umbilical cord blood transplantation: Still growing and improving. Stem Cells Transl Med 2021; 10 Suppl 2:S62-S74. [PMID: 34724722 PMCID: PMC8560197 DOI: 10.1002/sctm.20-0495] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/05/2021] [Accepted: 03/13/2021] [Indexed: 12/26/2022] Open
Abstract
Umbilical cord blood transplantation (UCBT) has been performed in the clinic for over 30 years. The biological and immunological characteristics of umbilical cord blood (UCB) have been re-recognized in recent years. UCB, previously considered medical waste, is rich in hematopoietic stem cells (HSCs), which are naïve and more energetic and more easily expanded than other stem cells. UCB has been identified as a reliable source of HSCs for allogeneic hematopoietic stem cell transplantation (allo-HSCT). UCBT has several advantages over other methods, including no harm to mothers and donors, an off-the-shelf product for urgent use, less stringent HLA match, lower incidence and severity of chronic graft-vs-host disease (GVHD), and probably a stronger graft-vs-leukemia effect, especially for minimal residual disease-positive patients before transplant. Recent studies have shown that the outcome of UCBT has been improved and is comparable to other types of allo-HSCT. Currently, UCBT is widely used in malignant, nonmalignant, hematological, congenital and metabolic diseases. The number of UCB banks and transplantation procedures increased exponentially before 2013. However, the number of UCBTs increased steadily in Asia and China but decreased in the United States and Europe year-on-year from 2013 to 2019. In this review, we focus on the development of UCBT over the past 30 years, the challenges it faces and the strategies for future improvement, including increasing UCB numbers, cord blood unit selection, conditioning regimens and GVHD prophylaxis for UCBT, and management of complications of UCBT.
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Affiliation(s)
- Xiaoyu Zhu
- Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiPeople's Republic of China
- Blood and Cell Therapy Institute, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiPeople's Republic of China
- Anhui Provincial Key Laboratory of Blood Research and ApplicationsHefeiPeople's Republic of China
| | - Baolin Tang
- Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiPeople's Republic of China
- Blood and Cell Therapy Institute, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiPeople's Republic of China
- Anhui Provincial Key Laboratory of Blood Research and ApplicationsHefeiPeople's Republic of China
| | - Zimin Sun
- Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiPeople's Republic of China
- Blood and Cell Therapy Institute, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiPeople's Republic of China
- Anhui Provincial Key Laboratory of Blood Research and ApplicationsHefeiPeople's Republic of China
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36
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Rafii H, Garnier F, Ruggeri A, Ionescu I, Ballot C, Bensoussan D, Chabannon C, Dazey B, De Vos J, Gautier E, Giraud C, Larghero J, Cras A, Mialou V, Persoons V, Pouthier F, Thibert JB, Dalle JH, Michel G, Kenzey C, Volt F, Rocha V, Bay JO, Rubio MT, Faucher C, Marry E, Gluckman E. Umbilical cord blood transplants facilitated by the French cord blood banks network. On behalf of the Agency of Biomedicine, Eurocord and the French society of bone marrow transplant and cell therapy (SFGM-TC). Bone Marrow Transplant 2021; 56:2497-2509. [PMID: 33990703 PMCID: PMC8120495 DOI: 10.1038/s41409-021-01313-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 03/04/2021] [Accepted: 04/13/2021] [Indexed: 11/18/2022]
Abstract
The public French Cord Blood Banks Network was established in 1999 with the objective of standardizing the practices governing umbilical cord blood (UCB) banking in France. The Network adopted a strategy to optimize its inventory and improve the quality of its banked units based on a quality improvement process using outcome data regularly provided by Eurocord. This study aimed to describe the results, over 10 years, of UCBT facilitated by a national network that used the same criteria of UCB collection and banking and to assess how modifications of banking criteria and unit selection might influence transplant outcomes. Nine hundred and ninety-nine units (593 single-unit and 203 double-unit grafts) were released by the Network to transplant 796 patients with malignant (83%) and non-malignant (17%) diseases. Median cell dose exceeded 3.5 × 107 TNC/kg in 86%. There was a trend to select units more recently collected and with higher cell dose. Neutrophil engraftment was 88.2% (85.7-90.7) and 79.3% (72.6-86.5) respectively for malignant and non-malignant diseases with a trend to faster recovery with higher cell doses. The respective 3-year transplant-related mortality were 31.1% (27.5-35.1) and 34.3% (27.0-43.5). OS was 49% ± 4 in malignant and 62% ± 4 in non-malignant disorders. In multivariate analysis, cell dose was the only unit-related factor associated with outcomes. Our results reflect the benefit on clinical outcomes of the strategy adopted by the Network to bank units with higher cell counts.
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Affiliation(s)
- Hanadi Rafii
- Eurocord, Hopital Saint-Louis, AP-HP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France.
- Monacord, Centre Scientifique de Monaco, Monaco, Monaco.
| | | | - Annalisa Ruggeri
- Eurocord, Hopital Saint-Louis, AP-HP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France
- Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Irina Ionescu
- Agency of Biomedecine, Saint Denis La Plaine, France
| | - Caroline Ballot
- Cell Therapy unit, Etablissement Français du Sang Hauts de France Normandie, site de LILLE - Belfort, Lille, France
| | - Danièle Bensoussan
- Tissue Engineering and Cell Therapy unit, Regional University hospital, Nancy, France
| | - Christian Chabannon
- Paoli-Calmettes Institute, Departement of Cancer Biology, Inserm CBT1409, Marseille, France
| | - Bernard Dazey
- Cell Therapy unit, Etablissement Français du Sang, Bordeaux, France
| | - John De Vos
- Cell Therapy unit, University hospital, Montpellier, France
| | - Eric Gautier
- Cell Therapy unit, Etablissement Français du Sang, Créteil, France
| | - Christine Giraud
- Department of Hematology and Cell Therapy, Etablissement Français du Sang, University hospital, Poitiers, France
| | - Jérome Larghero
- Cell Therapy Unit and Cord Blood Bank, AP-HP, Hôpital Saint Louis, Paris, France
| | - Audrey Cras
- Cell Therapy Unit and Cord Blood Bank, AP-HP, Hôpital Saint Louis, Paris, France
| | - Valérie Mialou
- Cell Therapy unit, Etablissement Français du Sang, hopital E. Herriot, Lyon, France
| | - Virginie Persoons
- Cell Therapy and Tissue Engineering unit, Etablissement Français du Sang, Grenoble, France
| | - Fabienne Pouthier
- Cell and Tissue Engineering unit, Etablissement Francais du Sang, Besançon, France
| | | | - Jean-Hugues Dalle
- Hopital Robert Debré, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Gerard Michel
- Aix-Marseille University and La Timone Children's Hospital, Marseille, France
| | - Chantal Kenzey
- Eurocord, Hopital Saint-Louis, AP-HP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France
- Monacord, Centre Scientifique de Monaco, Monaco, Monaco
| | - Fernanda Volt
- Eurocord, Hopital Saint-Louis, AP-HP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France
- Monacord, Centre Scientifique de Monaco, Monaco, Monaco
| | - Vanderson Rocha
- Eurocord, Hopital Saint-Louis, AP-HP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France
- Department of Hematology, Clinics Hospital, University of São Paulo Medical School, São Paulo, Brazil
| | - Jacques-Olivier Bay
- Department of Hematology and Stem Cell Transplantation, Clermont University, Clermont-Ferrand, France
| | - Marie-Thérèse Rubio
- Department of Hematology and Stem Cell Transplantation, regional university hospital, Nancy, France
| | | | - Evelyne Marry
- Agency of Biomedecine, Saint Denis La Plaine, France
| | - Eliane Gluckman
- Eurocord, Hopital Saint-Louis, AP-HP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France
- Monacord, Centre Scientifique de Monaco, Monaco, Monaco
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Mohd Idris MR, Nordin F, Mahdy ZA, Abd Wahid SF. Gestational Diabetes Mellitus in Pregnancy Increased Erythropoietin Level Affecting Differentiation Potency of Haematopoietic Stem Cell of Umbilical Cord Blood. Front Med (Lausanne) 2021; 8:727179. [PMID: 34490314 PMCID: PMC8416672 DOI: 10.3389/fmed.2021.727179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/29/2021] [Indexed: 11/13/2022] Open
Abstract
Background: The in utero environment has many factors that can support cell differentiation. Cytokines, chemokines and growth factors play big roles in haematopoietic mechanisms. Some diseases like gestational diabetes mellitus (GDM) might affect the environment and haematopoietic stem cell (HSC) quality. The aim of this study is to investigate the adverse effects of GDM on umbilical cord blood (UCB) HSC in terms of differentiation potency including the UCB parameters used for banking and transplantation purposes. Methods: UCB-HSC was collected from 42 GDM and 38 normal pregnancies. UCB-HSC was isolated and further enriched using immuno-magnetic separation beads (MACS). The UCB-HSC were cultured in methylcellulose media to investigate the differentiation potency. The level of erythropoietin (EPO) and insulin in the UCB plasma was measured using enzyme linked immunoassay (ELISA) technique. Result: The UCB parameters; volume, total nucleated count (TNC) and total CD34+ cells were significantly reduced in the GDM group compared to the control group. The number of HSC progenitors' colonies were significantly reduced in the GDM group except for progenitor BFU-E, which was significantly increased (GDM = 94.19 ± 6.21, Control = 73.61 ± 2.73, p = 0.010). This data was associated with higher EPO level in GDM group. However, the insulin level in the GDM group was comparable to the Control group. Conclusion: Our results suggest that the changes in the in utero environment due to abnormalities during pregnancy such as GDM might affect the differentiation potency of UCB-HSC. These findings can be considered as an additional parameter for the inclusion and exclusion criteria for UCB banking, particularly for mothers with GDM.
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Affiliation(s)
- Mohd Razif Mohd Idris
- Cell Therapy Centre, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Zaleha Abdullah Mahdy
- Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - S. Fadilah Abd Wahid
- Cell Therapy Centre, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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38
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Choi JY, Kim H, Baek HJ, Kook H, Lee JM, Kim BK, An HY, Hong KT, Shin HY, Kang HJ. Open-Label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in Pediatric Patients with Steroid-Refractory Sclerotic/Fibrotic Type Chronic Graft-versus-Host Disease. Transplant Cell Ther 2021; 27:925.e1-925.e7. [PMID: 34314892 DOI: 10.1016/j.jtct.2021.07.019] [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: 03/17/2021] [Revised: 07/16/2021] [Accepted: 07/19/2021] [Indexed: 11/25/2022]
Abstract
Steroid-refractory chronic graft-versus-host disease (cGVHD) is associated with high morbidity. To date, there is no standard therapy for patients who fail to respond to steroids. In this nonrandomized, open-label, single-arm, multicenter prospective phase II study, we evaluated the efficacy and safety of imatinib mesylate and mycophenolate mofetil (MMF) to treat sclerotic/fibrotic type cGVHD. The primary endpoint was the overall response rate (ORR) to imatinib mesylate plus MMF in 1 year, and the secondary endpoints included safety, quality of life, discontinuation of steroids, and overall survival (OS) rate. A total of 13 patients were enrolled, with a median age of 10.4 years (range, 5.0 to 20.1 years). All patients received a myeloablative conditioning regimen. Specifically, 6 of these patients had previously experienced acute GVHD. The most frequently affected organs were the eyes, lungs, skin, and liver. There were 2 premature deaths. One patient died of pulmonary infection and progression of cGVHD, and the other patient died from neuroblastoma progression and septic shock. The ORR was 76.9% (10 of 13 patients), and the median steroid dose was decreased from 1.0 mg/kg/day to 0.21 mg/kg/day. One-year OS was 84.6% (n = 13), and common adverse events included elevated liver enzyme and serum creatinine levels and fever. Although our sample size was limited, treatment of cGVHD with imatinib mesylate plus MMF shows promising results with acceptable toxicity.
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Affiliation(s)
- Jung Yoon Choi
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Hyery Kim
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, Republic of Korea
| | - Hee Jo Baek
- Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Hoon Kook
- Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Jae Min Lee
- Department of Pediatrics, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Bo Kyung Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Hong Yul An
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Kyung Taek Hong
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Hee Young Shin
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Hyoung Jin Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea.
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Inflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients. Nat Commun 2021; 12:4137. [PMID: 34230468 PMCID: PMC8260612 DOI: 10.1038/s41467-021-24412-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 06/15/2021] [Indexed: 12/01/2022] Open
Abstract
Unrelated cord blood transplantation (UCBT) is an effective treatment for hematopoietic disorders. However, this attractive approach is frequently accompanied by pre-engraftment syndrome (PES), severe cases of PES are associated with enhanced mortality and morbidity, but the pathogenesis of PES remains unclear. Here we show that GM-CSF produced by cord blood-derived inflammatory monocytes drives PES pathology, and that monocytes are the main source of IL-6 during PES. Further, we report the outcome of a single arm, single-center clinical study of tocilizumab in the treatment of steroid-refractory severe PES patients (www.chictr.org.cn ChiCTR1800015472). The study met the primary outcome measure since none of the patients was nonrelapse death during the 100 days follow-up. The study also met key secondary outcomes measures of neutrophil engraftment and hematopoiesis. These findings offer a therapeutic strategy with which to tackle PES and improve nonrelapse mortality. Pre-engraftment syndrome is a major consideration during clinical application of unrelated cord blood transfusion and monocytes represent a critical cell type in immune-pathogenesis. Here the authors further establish the role of monocytes and GM-CSF in pre-engraftment syndrome and show clinical administration of tocilizumab limits pathology in pre-engraftment syndrome pathology in patients.
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40
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Hansen M, Stahl L, Heider A, Hilger N, Sack U, Kirschner A, Cross M, Fricke S. Reduction of Graft-versus-Host-Disease in NOD.Cg-Prkdc scid Il2rg tm1Wjl/SzJ (NSG) Mice by Cotransplantation of Syngeneic Human Umbilical Cord-Derived Mesenchymal Stromal Cells. Transplant Cell Ther 2021; 27:658.e1-658.e10. [PMID: 33964513 DOI: 10.1016/j.jtct.2021.04.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/16/2021] [Accepted: 04/25/2021] [Indexed: 12/12/2022]
Abstract
Graft-versus-host disease (GVHD) is one of the major complications following hematopoietic stem cell transplantation, which remains the sole curative therapy for many malignant diseases of the hematopoietic system. The immunomodulatory potential of mesenchymal stromal cells (MSCs) to treat GVHD is currently being tested in various preclinical and clinical trials. Because the results of the preclinical and clinical trials on the use of MSCs to treat GVHD have not been consistent, we analyzed the potential beneficial effects of syngeneic versus allogenic treatment, culture expansion of MSCs, and various MSC cell doses and time points of MSC transplantation in a murine GVHD model. We established the murine GVHD model based on the transplantation of umbilical cord blood-derived hematopoietic stem cells (UC-HSCs) and used this model to assess the therapeutic potential of umbilical cord blood-derived MSCs (UC-MSCs). The use of HSC and MSC populations derived from the same donor allowed us to exclude third-party cells and test the UC-HSCs and UC-MSCs in a matched setting. Moreover, we were able to compare various doses, transplantation time points, and the influence of culture expansion of MSCs on the impact of treatment. This resulted in 16 different treatment groups. The most efficient setting for treatment of UC-HSC-induced GVHD reactions was based on the simultaneous administration of 1 × 106 culture-expanded, syngeneically matched UC-MSCs. This therapy effectively reduced the number of CD8+ T cells in the blood, protected the mice from weight loss, and prolonged their survival until the end of observation period. Taken together, our data show beneficial effects of (1) syngeneic over allogeneic UC-HSCs and UC-MSCs, (2) culture-expanded cells over freshly isolated primary cells, (3) simultaneous over sequential administration, and (4) high doses of UC-MSCs. The animal model of GVHD established here is now available for more detailed studies, including a comparative analysis of the efficacy of MSCs derived from alternative sources, such as adipose tissue and bone marrow.
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Affiliation(s)
- Max Hansen
- Vita 34 AG, Leipzig, Germany; Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig, Germany.
| | - Lilly Stahl
- Tcell Tolerance GmbH, Leipzig, Germany; Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | | | - Nadja Hilger
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Ulrich Sack
- Department of Hematology and Cell Therapy, Leipzig University Hospital, Leipzig, Germany
| | - Andreas Kirschner
- Vita 34 AG, Leipzig, Germany; Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Michael Cross
- Department of Hematology and Cell Therapy, Leipzig University Hospital, Leipzig, Germany
| | - Stephan Fricke
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
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41
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Ahn SY, Chang YS, Lee MH, Sung SI, Lee BS, Kim KS, Kim AR, Park WS. Stem cells for bronchopulmonary dysplasia in preterm infants: A randomized controlled phase II trial. Stem Cells Transl Med 2021; 10:1129-1137. [PMID: 33876883 PMCID: PMC8284779 DOI: 10.1002/sctm.20-0330] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 02/05/2021] [Accepted: 02/23/2021] [Indexed: 12/23/2022] Open
Abstract
We previously demonstrated the safety and feasibility of mesenchymal stem cell (MSC) transplantation for bronchopulmonary dysplasia (BPD) in preterm infants in a phase I clinical trial. We thus investigated the therapeutic efficacy of MSCs for BPD in premature infants. A phase II double-blind, randomized, placebo-controlled clinical trial was conducted on preterm infants at 23 to 28 gestational weeks (GW) receiving mechanical ventilator support with respiratory deterioration between postnatal days 5 and 14. Infants were stratified by 23 to 24 GW and 25 to 28 GW and randomly allocated (1:1) to receive stem cells (1 × 107 cells/kg, n = 33) or placebo (n = 33). Although the inflammatory cytokines in the tracheal aspirate fluid were significantly reduced with MSCs, the primary outcome of death or severe/moderate BPD in the control group (18/33, 55%) was not significantly improved with MSC transplantation (17/33, 52%). In the subgroup analysis, the secondary outcome of severe BPD was significantly improved from 53% (8/15) to 19% (3/16) with MSC transplantation in the 23 to 24 GW group but not in the 25 to 28 GW subgroup. In summary, although MSC transplantation might be safe and feasible, this small study was underpowered to detect its therapeutic efficacy in preterm infants at 23 to 28 GW. Accordingly, we are now conducting an additional larger and controlled phase II clinical trial focusing on infants at 23 to 24 GW (NCT03392467). ClinicalTrials.gov identifier: NCT01828957.
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Affiliation(s)
- So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yun Sil Chang
- Department of Pediatrics, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Myung Hee Lee
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea
| | - Se In Sung
- Department of Pediatrics, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Byong Sop Lee
- Department of Pediatrics, Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - Ki Soo Kim
- Department of Pediatrics, Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - Ai-Rhan Kim
- Department of Pediatrics, Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - Won Soon Park
- Department of Pediatrics, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul, South Korea
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Trenker C, Dietrich CF, Klein S, Safai Zadeh E, Sohlbach K, Neubauer A, Burchert A, Görg C. [Potential of ultrasound in allogeneic stem cell transplantation and transplant-related complications]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:336-344. [PMID: 33634439 DOI: 10.1055/a-1374-4192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (HCT) is a complex therapeutic procedure causing significant morbidity and mortality, including the gastrointestinal tract. Early diagnosis and treatment of HCT-associated complications are, therefore, of utmost importance to improve overall HCT outcome. Sonography can be a powerful diagnostic tool and is easily accessible at the bedside of HCT patients. In the hands of a sonography-experienced physician, it allows for instant diagnosis and can also rule out several important transplant-associated complications. Here we review available evidence on the diagnostic and clinical value of ultrasound prior, during and after HCT.
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Affiliation(s)
- Corinna Trenker
- Klinik für Hämatologie, Onkologie und Immunologie, UKGM Marburg und Philipps-Universität Marburg
| | | | - Stefan Klein
- Universitätsklinikum Mannheim, III. Medizinische Klinik
| | | | - Kristina Sohlbach
- Klinik für Hämatologie, Onkologie und Immunologie, UKGM Marburg und Philipps-Universität Marburg
| | - Andreas Neubauer
- Klinik für Hämatologie, Onkologie und Immunologie, UKGM Marburg und Philipps-Universität Marburg
| | - Andreas Burchert
- Klinik für Hämatologie, Onkologie und Immunologie, UKGM Marburg und Philipps-Universität Marburg
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43
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Lei L, Zhang X, Yang X, Su Y, Liu H, Yang H, Wang J, Zou Y, Wang X, Jiao A, Zhang C, Zheng H, Zhang J, Zhang D, Shi L, Zhou X, Sun C, Zhang B. A Genetic Model Reveals Biological Features of Neonatal CD4 Helper Cells Undergone Homeostasis in Mice. Front Cell Dev Biol 2021; 9:659744. [PMID: 33777965 PMCID: PMC7991801 DOI: 10.3389/fcell.2021.659744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 02/22/2021] [Indexed: 11/13/2022] Open
Abstract
CD4+ T cells are essential for regulating effective immune response to pathogens and immune balance. Recent studies have demonstrated the unique features of T cells in neonate mice, such as more sensitive to antigen response and preference toward T helper 2 (Th2) response and regulatory T cells (Tregs) differentiation. However, the biological characteristics of neonatal age-derived CD4+ T cells following homeostasis remain unclear. Here we utilized a lineage tracing model of TCRδ CreER R26 ZsGreen to mark neonatal- and adult-derived CD4+ T cells followed by a combination analysis of activation, proliferation, survival, and differentiation. Our results showed that neonatal CD4+ T cells had higher capacity of activation, proliferation, apoptosis, and differentiation toward Th2 and T helper 17 (Th17) lineages, accompanied by a reduced potential for T helper 1 (Th1), T helper 9 (Th9), and Treg lineages. In contrast, tracked neonatal CD4+ T cells exhibited similar characters of above-mentioned of tracked adult cells in adult mice. Therefore, our data support a natural requirement for CD4+ T cells to acquire fully-equipped functional potentials of adult cells.
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Affiliation(s)
- Lei Lei
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, China.,Xi'an Key Laboratory of Immune Related Diseases, Xi'an, China
| | - Xingzhe Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaofeng Yang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, China.,Xi'an Key Laboratory of Immune Related Diseases, Xi'an, China
| | - Yanhong Su
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Haiyan Liu
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Hang Yang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Jinli Wang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Yujing Zou
- Duke University Medical Center, Durham, NC, United States
| | - Xin Wang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Anjun Jiao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Cangang Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Huiqiang Zheng
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Jiahui Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Dan Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, China.,Xi'an Key Laboratory of Immune Related Diseases, Xi'an, China
| | - Lin Shi
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, China.,Xi'an Key Laboratory of Immune Related Diseases, Xi'an, China
| | - Xiaobo Zhou
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, China.,Xi'an Key Laboratory of Immune Related Diseases, Xi'an, China
| | - Chenming Sun
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, China.,Xi'an Key Laboratory of Immune Related Diseases, Xi'an, China
| | - Baojun Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, China.,Xi'an Key Laboratory of Immune Related Diseases, Xi'an, China
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44
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Kuldanek S, Pasko B, DomBourian M, Annen K. Cellular Therapy in Pediatric Hematologic Malignancies. Clin Lab Med 2021; 41:121-132. [PMID: 33494880 DOI: 10.1016/j.cll.2020.10.008] [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: 12/14/2022]
Abstract
Advances in cellular therapies for pediatric patients have created many opportunities for improved survival with reduced morbidity. This article reviews current cellular therapies in pediatric hematological malignancy, including the most updated practices in hematopoietic stem cell transplant and the use of chimeric antigen receptor (CAR) therapy in T cells. Hematopoietic stem cell transplant has evolved with improvements in chemotherapy regimens, immunosuppression, and donor-matching options. Novel therapies in development which will likely further improve the options for patients are reviewed including Natural Killer, Regulatory T-cells and αβ depletion.
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Affiliation(s)
- Susan Kuldanek
- Hemophilia and Thrombosis Center, Center for Cancer and Blood Disorders, Children's Hospital Colorado, University of Colorado-Anschutz Medical Campus, 13123 East 16th Avenue, Aurora, CO 80045, USA
| | - Bryce Pasko
- Department of Pathology and Laboratory Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA; Department of Pathology, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
| | - Melkon DomBourian
- Main Core Laboratory and Point of Care Testing, Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, 13123 East 16th Avenue, B120, Aurora, CO 80045, USA; Department of Pathology, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
| | - Kyle Annen
- Department of Pathology and Laboratory Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA; Department of Pathology, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.
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45
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CD34T+ Humanized Mouse Model to Study Mucosal HIV-1 Transmission and Prevention. Vaccines (Basel) 2021; 9:vaccines9030198. [PMID: 33673566 PMCID: PMC7997265 DOI: 10.3390/vaccines9030198] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 02/01/2023] Open
Abstract
Humanized mice are critical for HIV-1 research, but humanized mice generated from cord blood are inefficient at mucosal HIV-1 transmission. Most mucosal HIV-1 transmission studies in mice require fetal tissue-engraftment, the use of which is highly restricted or prohibited. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection and also show normal env diversification in vivo despite high viral replication. Moreover, mucosal infection in CD34T+ mice can be prevented by infusion of broadly neutralizing antibodies. CD34T+ mice can be rapidly and easily generated using only cord blood cells and do not require any complicated surgical procedures for the humanization process. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission studies as well as rapid in vivo testing of novel prevention molecules against HIV-1.
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46
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Little AM, Akbarzad-Yousefi A, Anand A, Diaz Burlinson N, Dunn PPJ, Evseeva I, Latham K, Poulton K, Railton D, Vivers S, Wright PA. BSHI guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation. Int J Immunogenet 2021; 48:75-109. [PMID: 33565720 DOI: 10.1111/iji.12527] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/29/2020] [Accepted: 12/31/2020] [Indexed: 01/18/2023]
Abstract
A review of the British Society for Histocompatibility and Immunogenetics (BSHI) Guideline 'HLA matching and donor selection for haematopoietic progenitor cell transplantation' published in 2016 was undertaken by a BSHI appointed writing committee. Literature searches were performed and the data extracted were presented as recommendations according to the GRADE nomenclature.
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Affiliation(s)
- Ann-Margaret Little
- Histocompatibility and Immunogenetics Laboratory, Gartnavel General Hospital, Glasgow, UK.,Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Arash Akbarzad-Yousefi
- Histocompatibility and Immunogenetics Laboratory, NHS Blood and Transplant, Newcastle-Upon-Tyne, UK
| | - Arthi Anand
- Histocompatibility and Immunogenetics Laboratory, North West London Pathology, Hammersmith Hospital, London, UK
| | | | - Paul P J Dunn
- Transplant Laboratory University Hospitals of Leicester, Leicester General Hospital, Leicester, UK.,Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | | | - Katy Latham
- Cellular and Molecular Therapies, NHS Blood and Transplant, Bristol, UK
| | - Kay Poulton
- Transplantation Laboratory, Manchester Royal Infirmary, Manchester, UK
| | - Dawn Railton
- Tissue Typing Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
| | | | - Paul A Wright
- Transplantation Laboratory, Manchester Royal Infirmary, Manchester, UK
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47
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Anwar I, Ashfaq UA, Shokat Z. Therapeutic Potential of Umbilical Cord Stem Cells for Liver Regeneration. Curr Stem Cell Res Ther 2020; 15:219-232. [PMID: 32077830 DOI: 10.2174/1568026620666200220122536] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 07/16/2019] [Accepted: 08/08/2019] [Indexed: 01/18/2023]
Abstract
The liver is a vital organ for life and the only internal organ that is capable of natural regeneration. Although the liver has high regeneration capacity, excessive hepatocyte death can lead to liver failure. Various factors can lead to liver damage including drug abuse, some natural products, alcohol, hepatitis, and autoimmunity. Some models for studying liver injury are APAP-based model, Fas ligand (FasL), D-galactosamine/endotoxin (Gal/ET), Concanavalin A, and carbon tetrachloride-based models. The regeneration of the liver can be carried out using umbilical cord blood stem cells which have various advantages over other stem cell types used in liver transplantation. UCB-derived stem cells lack tumorigenicity, have karyotype stability and high immunomodulatory, low risk of graft versus host disease (GVHD), low risk of transmitting somatic mutations or viral infections, and low immunogenicity. They are readily available and their collection is safe and painless. This review focuses on recent development and modern trends in the use of umbilical cord stem cells for the regeneration of liver fibrosis.
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Affiliation(s)
- Ifrah Anwar
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Usman A Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Zeeshan Shokat
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
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48
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Lin HD, Fong CY, Biswas A, Bongso A. Allogeneic human umbilical cord Wharton's jelly stem cells increase several-fold the expansion of human cord blood CD34+ cells both in vitro and in vivo. Stem Cell Res Ther 2020; 11:527. [PMID: 33298170 PMCID: PMC7724853 DOI: 10.1186/s13287-020-02048-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Background The transplantation of human umbilical cord blood (UCB) CD34+ cells has been successfully used to treat hematological disorders but one major limitation has been the low cell numbers available. Mesenchymal stem cells (MSCs) lying within the bone marrow in vivo behave like a scaffold on which CD34+ cells interact and proliferate. We therefore evaluated the use of allogeneic MSCs from the human UC Wharton’s jelly (hWJSCs) as stromal support for the ex vivo expansion of CD34+ cells. Methods We performed an in-depth evaluation of the primitiveness, migration, adhesion, maturation, mitochondrial behavior, and pathway mechanisms of this platform using conventional assays followed by the evaluation of engraftment potential of the expanded CD34+ cells in an in vivo murine model. Results We demonstrate that hWJSCs and its conditioned medium (hWJSC-CM) support the production of significantly high fold changes of CD34+, CD34+CD133+, CD34+CD90+, CD34+ALDH+, CD34+CD45+, and CD34+CD49f+ cells after 7 days of interaction when compared to controls. In the presence of hWJSCs or hWJSC-CM, the CD34+ cells produced significantly more primitive CFU-GEMM colonies, HoxB4, and HoxA9 gene expression and lower percentages of CD34+CXCR4+ cells. There were also significantly higher N-cadherin+ cell numbers and increased cell migration in transwell migration assays. The CD34+ cells expanded with hWJSCs had significantly lower mitochondrial mass, mitochondrial membrane potential, and oxidative stress. Green Mitotracker-tagged mitochondria from CD34+ cells were observed lying within red CellTracker-tagged hWJSCs under confocal microscopy indicating mitochondrial transfer via tunneling nanotubes. CD34+ cells expanded with hWJSCs and hWJSC-CM showed significantly reduced oxidative phosphorylation (ATP6VIH and NDUFA10) and increased glycolytic (HIF-1a and HK-1) pathway-related gene expression. CD34+ cells expanded with hWJSCs for 7 days showed significant greater CD45+ cell chimerism in the bone marrow of primary and secondary irradiated mice when transplanted intravenously. Conclusions In this report, we confirmed that allogeneic hWJSCs provide an attractive platform for the ex vivo expansion of high fold numbers of UCB CD34+ cells while keeping them primitive. Allogeneic hWJSCs are readily available in abundance from discarded UCs, can be easily frozen in cord blood banks, thawed, and then used as a platform for UCB-HSC expansion if numbers are inadequate.
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Affiliation(s)
- Hao Daniel Lin
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Kent Ridge, 119228, Singapore
| | - Chui-Yee Fong
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Kent Ridge, 119228, Singapore
| | - Arijit Biswas
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Kent Ridge, 119228, Singapore
| | - Ariff Bongso
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Kent Ridge, 119228, Singapore.
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49
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Kanaan SB, Delaney C, Milano F, Scaradavou A, Besien KV, Allen J, Lambert NC, Cousin E, Thur LA, Kahn E, Forsyth AM, Sensoy O, Nelson JL. Cord blood maternal microchimerism following unrelated cord blood transplantation. Bone Marrow Transplant 2020; 56:1090-1098. [PMID: 33257776 PMCID: PMC8119290 DOI: 10.1038/s41409-020-01149-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/28/2020] [Accepted: 11/09/2020] [Indexed: 01/13/2023]
Abstract
Cord blood transplantation (CBT) is associated with low risk of leukemia
relapse. Mechanisms underlying antileukemia benefit of CBT are not well
understood, however a previous study strongly but indirectly implicated cells
from the mother of the cord blood (CB) donor. A fetus acquires a small number of
maternal cells referred to as maternal microchimerism (MMc) and MMc is sometimes
detectable in CB. From a series of 95 patients who underwent double or single
CBT at our center, we obtained or generated HLA-genotyping of CB mothers in 68.
We employed a technique of highly sensitive HLA-specific quantitative-PCR assays
targeting polymorphisms unique to the CB mother to assay CB-MMc in patients
post-CBT. After additional exclusion criteria, CB-MMc was evaluated at multiple
timepoints in 36 patients (529 specimens). CB-MMc was present in 7 (19.4%)
patients in bone marrow, peripheral blood, innate and adaptive immune cell
subsets, and was detected up to 1-year post-CBT. Statistical trends to lower
relapse, mortality, and treatment failure were observed for patients with vs.
without CB-MMc post-CBT. Our study provides proof-of-concept that maternal cells
of the CB graft can be tracked in recipients post-CBT, and underscore the
importance of further investigating CB-MMc in sustained remission from leukemia
following CBT.
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Affiliation(s)
- Sami B Kanaan
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.
| | - Colleen Delaney
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.,Department of Medicine, University of Washington (UW), Seattle, WA, USA
| | - Filippo Milano
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.,Department of Medicine, University of Washington (UW), Seattle, WA, USA
| | - Andromachi Scaradavou
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Koen van Besien
- Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Judy Allen
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA
| | - Nathalie C Lambert
- INSERM UMRs 1097 Arthrites Autoimmunes, Aix Marseille University, Marseille, France
| | - Emma Cousin
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA
| | - Laurel A Thur
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA
| | - Elena Kahn
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA
| | - Alexandra M Forsyth
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA
| | - Oyku Sensoy
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA
| | - J Lee Nelson
- Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.,Department of Medicine, University of Washington (UW), Seattle, WA, USA
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50
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An K, Li B, Luo C, Wang J, Luo C, Chen J. The impact of donor full-length KIR2DS4 in the development of acute and chronic GVHD after unrelated allogeneic HSCT. Pediatr Transplant 2020; 24:e13728. [PMID: 32594584 DOI: 10.1111/petr.13728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 03/05/2020] [Accepted: 04/13/2020] [Indexed: 11/27/2022]
Abstract
BACKGROUND Killer Ig-like receptor 2DS4 (KIR2DS4) is the most prevalent activating killer Ig-like receptor gene. It is divergent and encodes either full-length or deleted allele variants. The studies of donor killer KIR2DS4 in unrelated allogeneic hematopoietic stem cell transplantations were limited. METHODS KIR and HLA genotyping were determined in 75 pairs of Chinese pediatric hematologic malignancy patients. RESULTS Among the 75 donor-recipient pairs, 77.3% (58/75) of the donors were positive for full-length KIR2DS4 and 22.7% (17/75) were negative. Patients who had donors positive for full-length KIR2DS4 had higher cumulative incidence of aGVHD than patients whose donor negative for full-length KIR2DS4 (86.2% versus 76.5%, P = .038). Multivariate analysis showed full-length KIR2DS4 was the significant factor for I-IV aGVHD (HR = 2.166, 95% CI: 1.01-4.26, P = .025). Subgroup analysis showed that AML and CML patients who received donors negative for full-length KIR2DS4 have a higher cumulative incidences of cGVHD (75% vs 62%, P = .008). There were no significant effects of full-length KIR2DS4 on overall survival (P = .13), relapse-free survival (P = .14), CMV reactivation (P = .52), and relapse (HR = 0.38, 95% CI: 0.09-1.6, P = .1875). CONCLUSIONS Our findings indicated a significant correlation of donor full-length KIR2DS4 on aGVHD and cGVHD. These results suggested that combining KIR and HLA genotyping may help make a better sense of transplants in these patients.
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MESH Headings
- Acute Disease
- Adolescent
- Alleles
- Child
- Child, Preschool
- China
- Cytomegalovirus
- Disease-Free Survival
- Female
- Genotype
- Graft vs Host Disease/etiology
- Graft vs Host Disease/immunology
- HLA Antigens/genetics
- Haplotypes
- Hematologic Neoplasms/genetics
- Hematopoietic Stem Cell Transplantation/methods
- Humans
- Incidence
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myelomonocytic, Juvenile/immunology
- Male
- Myelodysplastic Syndromes/immunology
- Neoplasm Recurrence, Local
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology
- Receptors, KIR/genetics
- Recurrence
- Treatment Outcome
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Affiliation(s)
- Kang An
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Benshang Li
- Department of Hematology and Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Changying Luo
- Department of Hematology and Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianmin Wang
- Department of Hematology and Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chengjuan Luo
- Department of Hematology and Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Chen
- Department of Hematology and Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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