RESUMO
Umbilical cord blood (UCB) is a rich source of beneficial stem and progenitor cells with known angiogenic, neuroregenerative and immune-modulatory properties. Preclinical studies have highlighted the benefit of UCB for a broad range of conditions including haematological conditions, metabolic disorders and neurological conditions, however clinical translation of UCB therapies is lacking. One barrier for clinical translation is inadequate cell numbers in some samples meaning that often a therapeutic dose cannot be achieved. This is particularly important when treating adults or when administering repeat doses of cells. To overcome this, UCB cell expansion is being explored to increase cell numbers. The current focus of UCB cell expansion is CD34+ haematopoietic stem cells (HSCs) for which the main application is treatment of haematological conditions. Currently there are 36 registered clinical trials that are examining the efficacy of expanded UCB cells with 31 of these being for haematological malignancies. Early data from these trials suggest that expanded UCB cells are a safe and feasible treatment option and show greater engraftment potential than unexpanded UCB. Outside of the haematology research space, expanded UCB has been trialled as a therapy in only two preclinical studies, one for spinal cord injury and one for hind limb ischemia. Proteomic analysis of expanded UCB cells in these studies showed that the cells were neuroprotective, anti-inflammatory and angiogenic. These findings are also supported by in vitro studies where expanded UCB CD34+ cells showed increased gene expression of neurotrophic and angiogenic factors compared to unexpanded CD34+ cells. Preclinical evidence demonstrates that unexpanded CD34+ cells are a promising therapy for neurological conditions where they have been shown to improve multiple indices of injury in rodent models of stroke, Parkinson's disease and neonatal hypoxic ischemic brain injury. This review will highlight the current application of expanded UCB derived HSCs in transplant medicine, and also explore the potential use of expanded HSCs as a therapy for neurological conditions. It is proposed that expanded UCB derived CD34+ cells are an appropriate cellular therapy for a range of neurological conditions in children and adults.
Assuntos
Sangue Fetal , Células-Tronco Hematopoéticas , Humanos , Sangue Fetal/citologia , Animais , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Antígenos CD34/metabolismoRESUMO
Background: Researchers are focusing on cellular therapy for chronic obstructive pulmonary disease (COPD) using mesenchymal stem cells (MSCs), with human bone marrow-derived MSCs (hBM-MSCs) leading the way. However, BM-MSCs may not be as optimal as therapeutic cells owing to their low growth potential, invasive harvesting, and high expression of aging-related genes with poor differentiation potential. Consequently, umbilical cord-derived MSCs (hUC-MSCs), which have many excellent features as allogeneic heterologous stem cells, have received considerable attention. Allogeneic and heterologous hUC-MSCs appear to be promising owing to their excellent therapeutic properties. However, MSCs cannot remain in the lungs for long periods after intravenous infusion. Objective: To develop designer hUC-MSCs (dUC-MSCs), which are novel therapeutic cells with modified cell-adhesion properties, to aid COPD treatment. Methods: dUC-MSCs were cultured on type-I collagen gels and laminin 411, which are extracellular matrices. Mouse models of elastase-induced COPD were treated with hUC-MSCs. Biochemical analysis of the lungs of treated and control animals was performed. Results: Increased efficiency of vascular induction was found with dUC-MSCs transplanted into COPD mouse models compared with that observed with transplanted hUC-MSCs cultured on plates. The transplanted dUC-MSCs inhibited apoptosis by downregulating pro-inflammatory cytokine production, enhancing adhesion of the extracellular matrix to alveolar tissue via integrin ß1, promoting the polarity of M2 macrophages, and contributing to the repair of collapsed alveolar walls by forming smooth muscle fibers. dUC-MSCs inhibited osteoclastogenesis in COPD-induced osteoporosis. hUC-MSCs are a promising cell source and have many advantages over BM-MSCs and adipose tissue-derived MSCs. Conclusion: We developed novel designer cells that may be involved in anti-inflammatory, homeostatic, injury repair, and disease resistance processes. dUC-MSCs repair and regenerate the alveolar wall by enhancing adhesion to the damaged site. Therefore, they can contribute to the treatment of COPD and systemic diseases such as osteoporosis.
Assuntos
Modelos Animais de Doenças , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Doença Pulmonar Obstrutiva Crônica , Regeneração , Animais , Camundongos , Células-Tronco Mesenquimais/metabolismo , Humanos , Doença Pulmonar Obstrutiva Crônica/terapia , Alvéolos Pulmonares , Cordão Umbilical/citologia , Células Cultivadas , Diferenciação Celular , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Camundongos Endogâmicos C57BL , MasculinoRESUMO
INTRODUCTION: Lung injuries, such as bronchopulmonary dysplasia (BPD), remain a major complication of preterm birth, with limited therapeutic options. One potential emerging therapy is umbilical cord blood (UCB)-derived therapy. OBJECTIVES: To systematically assess the safety and efficacy of UCB-derived therapy for preterm lung injury in preclinical and clinical studies. METHODS: A systematic search of MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO International Trials Registry Platform was performed. A meta-analysis was conducted with Review Manager (5.4.1) using a random effects model. Data was expressed as standardized mean difference (SMD) for preclinical data and pooled relative risk (RR) for clinical data, with 95% confidence intervals (CI). Potential effect modifiers were investigated via subgroup analysis. Certainty of evidence was assessed using the GRADE system. RESULTS: Twenty-three preclinical studies and six clinical studies met eligibility criteria. Statistically significant improvements were seen across several preclinical outcomes, including alveolarization (SMD, 1.32, 95%CI [0.99, 1.65]), angiogenesis (SMD, 1.53, 95%CI [0.87, 2.18]), and anti-inflammatory cytokines (SMD, 1.68, 95%CI [1.03, 2.34]). In clinical studies, 103 preterm infants have received UCB-derived therapy for preterm lung injury and no significant difference was observed in the development of BPD (RR, 0.93, 95%CI [0.73, 1.18]). Across both preclinical and clinical studies, administration of UCB-derived therapy appeared safe. Certainty of evidence was assessed as "low." CONCLUSIONS: Administration of UCB-derived therapy was associated with statistically significant improvements across several lung injury markers in preclinical studies. Early clinical studies demonstrated the administration of UCB-derived therapy as safe and feasible but lacked data regarding efficacy.
Assuntos
Sangue Fetal , Humanos , Sangue Fetal/citologia , Displasia Broncopulmonar/terapia , Recém-Nascido , Recém-Nascido Prematuro , Lesão Pulmonar/terapia , Animais , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodosRESUMO
BACKGROUND: Umbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury. METHODS: Preterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; n = 5) or 15 min ex utero high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; n = 7) or allogeneic term-derived UCB cells (24.5 ± 5.0 million cells/kg; VENT + UCB; n = 7). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNFα and/or IFNγ; 10 ng/mL; n = 3/group) for 16 h then supernatant and cells collected for protein and mRNA assessments respectively. RESULTS: In VENT + UCB lambs, systemic IFNγ levels increased and by 24 h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of OCLN and CLDN1 compared to SHAM. In vitro, MNCs subjected to TNFα and/or IFNγ displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 & IL-10) and growth factor (BDNF & VEGF) gene and protein expression compared to controls. CONCLUSIONS: UCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.
Assuntos
Volume de Ventilação Pulmonar , Animais , Ovinos , Feminino , Humanos , Volume de Ventilação Pulmonar/fisiologia , Sangue Fetal/citologia , Gravidez , Citocinas/metabolismo , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Respiração Artificial/métodos , Respiração Artificial/efeitos adversos , Animais Recém-NascidosRESUMO
BACKGROUND: To investigate the effect and underlying mechanism of umbilical cord blood-mononuclear cells (UCB-MNCs) in treating knee osteoarthritis (KOA) in rabbits. METHODS: A rabbit KOA model was prepared by anterior cruciate ligament transection (ACLT). Fifty New Zealand white rabbits were randomly divided into the control group, model group, sodium hyaluronate (SH) group, platelet-rich plasma (PRP) group and UCB-MNC group. Knee injections were performed once a week for five consecutive weeks. The gross view of the knee joint, morphology of knee cartilage and structural changes in the knee joint were observed on CT scans, and graded by the Lequesne MG behavioral score and the Mankin score. TNF-α and IL-1ß levels in the synovial fluid of the knee were measured by the enzyme-linked immunosorbent assay (ELISA). Expression levels of MMP-13 and COL-II in the knee cartilage were detected by Western blotting and qRT-PCR. RESULTS: The Lequesne MG behavioral score and the Mankin score were significantly higher in the model group than those in the control group (P < 0.05). Rabbits in the SH, PRP and UCB-MNC groups had sequentially lower scores than those in the model group. Imaging features of KOA were more pronounced in the model group than in the remaining groups. CB-MNC significantly relieved KOA, compared to SH and PRP. Significantly higher levels of TNF-α and IL-1ß in the synovial fluid of the knee, and up-regulated MMP-13 and down-regulated COL-II in the knee cartilage were detected in the model group than in the control group. These changes were significantly reversed by the treatment with SH, PRP and UCB-MNCs, especially UCB-MNCs. CONCLUSION: Injections of UCB-MNCs into knees protect the articular cartilage and hinder the progression of KOA in rabbits by improving the local microenvironment at knee joints.
Assuntos
Osteoartrite do Joelho , Animais , Coelhos , Osteoartrite do Joelho/terapia , Osteoartrite do Joelho/patologia , Sangue Fetal , Modelos Animais de Doenças , Masculino , Leucócitos Mononucleares/transplante , Leucócitos Mononucleares/metabolismo , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Líquido Sinovial/metabolismo , Plasma Rico em Plaquetas , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Distribuição AleatóriaRESUMO
BACKGROUND AND AIMS: Umbilical cord blood transplantation (UCBT) has emerged as a promising treatment option for patients with acute leukemia needing hematopoietic stem cell transplantation. Both single (sUCBT) and double cord blood units (dUCBT) demonstrate potential benefits, but studies comparing their effectiveness have shown mixed results. This meta-analysis aimed to determine the comparative safety and efficacy of sUCBT versus dUCBT in acute leukemia patients. METHODS: Electronic databases were systematically examined to identify relevant studies comparing single vs double UCBT published until November 2023. Nine studies involving 3864 acute leukemia patients undergoing UCBT were included. Outcomes analyzed were acute graft-versus-host disease (GVHD), chronic GVHD, relapse, non-relapse mortality, leukemia-free survival and overall survival. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model. RESULTS: The risk of Grade II-IV acute GVHD (RR 1.55, 95% CI 1.19-2.03) and Grade III-IV acute GVHD (RR 1.25, 95% CI 1.07-1.46) were significantly higher with dUCBT. Relapse risk was lower with dUCBT (RR 0.57, 95% CI 0.38-0.88) while overall survival favored sUCBT (RR 1.25, 95% CI 1.06-1.46). No significant differences were observed for chronic GVHD, non-relapse mortality or leukemia-free survival. CONCLUSION: Both single and double UCBT have potential as effective treatments for acute leukemia. The choice of treatment should consider various factors, including the risk of GVHD, relapse, and mortality. More research, especially randomized trials, is needed to provide definitive guidance on the optimal use of single and double unit UCBT in patients with acute leukemia.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Humanos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Leucemia/terapia , Leucemia/mortalidade , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidade , Doença AgudaRESUMO
BACKGROUND: Interleukin-2 (IL-2) is one of the most important cytokines that regulate the activation and proliferation of T cells and natural killer cells. The production of IL-2 may be affected by polymorphisms in the promoter region of the IL-2 gene (rs2069762). In allogeneic hematopoietic cell transplantation (HCT) from adult donors, rs2069762 has been associated with the incidence of acute and chronic graft-versus-host disease (GVHD). However, the impacts of IL-2 polymorphism on cord blood transplantation (CBT) outcomes remain unclear. OBJECTIVE: The objective of this study was to assess the impact of IL-2 polymorphism rs2069762 on transplant outcomes, such as hematopoietic recovery, GVHD, overall survival, relapse, and non-relapse mortality (NRM) after CBT. STUDY DESIGN: We conducted a retrospective analysis of data from adult patients who underwent single-unit CBT at our institution from November 2005 to March 2023 for whom DNA samples from recipients and donors were available. IL-2 genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs2069762. RESULTS: A total of 143 recipient and donor pairs were included in this study. The proportion of recipient IL-2 polymorphism rs2069762 was 48 % (n = 69) for AA, 42 % (n = 60) for CA, and 10 % (n = 14) for CC. The proportion of donor IL-2 polymorphism rs2069762 was 43 % (n = 61) for AA, 48 % (n = 69) for CA, and 9 % (n = 13) for CC. In the multivariate analysis, the use of an rs2069762 CA + CC donor was associated with lower neutrophil recovery compared to an rs2069762 AA donor (hazard ratio [HR], 0.66; 95 % confidence interval [CI], 0.50-0.88; P = 0.004). Furthermore, recipients of rs2069762 CA + CC were associated with higher NRM compared to recipients of rs2069762 AA (HR, 2.32; 95 % CI, 1.01-5.34; P = 0.047). Serum IL-2 levels at 8 weeks were significantly higher in rs2069762 CA + CC recipients compared to those with rs2069762 AA recipients (P = 0.014). CONCLUSION: Our data showed that donor IL-2 polymorphism affects neutrophil recovery and recipient IL-2 polymorphism affects NRM in adults undergoing single-unit CBT. The polymorphism of IL-2 rs2069762 in recipients and donors might be associated with the clinical outcomes of single-unit CBT.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Interleucina-2 , Polimorfismo de Nucleotídeo Único , Humanos , Interleucina-2/genética , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Estudos Retrospectivos , Adulto Jovem , Resultado do Tratamento , Genótipo , Idoso , Adolescente , Transplante de Células-Tronco Hematopoéticas/métodosRESUMO
We retrospectively evaluated the incidence, factors, and clinical outcomes of the discontinuation of immunosuppressive treatment (IST) after single-unit unrelated cord blood transplantation (CBT) in adults receiving cyclosporine-based graft-versus-host disease (GVHD) prophylaxis at our institute. Among the 309 patients who achieved engraftment, 247 were able to discontinue IST with a median follow-up of 121 months for survivors. The cumulative incidence of the discontinuation of IST was 46.2% at 180 days, 72.8% at 2 years, and 79.3% at 5 years post-CBT. In the multivariate analysis, discontinuation of IST after CBT was significantly associated with the requirement for steroid therapy (hazard ratio [HR]: 0.46; P < 0.001) and the recent calendar year of CBT (HR: 1.79; P < 0.001). In the conditional landmark analysis at 180 days, discontinuation of IST was not associated with the development of extensive chronic GVHD (HR: 1.00; P = 0.989), non-relapse mortality (HR: 0.49; P = 0.122), relapse (HR: 1.46; P = 0.388), or overall survival (HR: 1.91; P = 0.065). Our data showed that successful discontinuation of IST is common after single-unit CBT in adults. Discontinuation of IST did not affect subsequent outcomes, suggesting that discontinuation of IST is both feasible and safe in adults undergoing single-unit CBT.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Imunossupressores , Humanos , Adulto , Feminino , Masculino , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Pessoa de Meia-Idade , Imunossupressores/uso terapêutico , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/prevenção & controle , Adolescente , Estudos de Viabilidade , Adulto Jovem , Idoso , Ciclosporina/uso terapêuticoRESUMO
Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency (CID) and explore prognostic risk factors. Methods: In this retrospective cohort study, clinical characteristics, laboratory tests and prognosis of 73 CID children who underwent allogeneic hematopoietic stem cell transplantation from February 2014 to April 2022 in the Children's Hospital of Fudan University were analyzed. Based on the subtypes of diseases, all patients were divided into severe combined immunodeficiency disease (SCID) group and other CID group. Based on the types of donors, all patients were divided into matched sibling donor group, matched unrelated donor group, unrelated cord blood group, and haploidentical donor group. Kaplan-Meier method and Log-Rank test were used to analyze the survival data. Cox regression was used to analyze prognostic factors. Results: Among the 73 patients, there were 61 (84%) males and 12 (16%) females. Fifty-five (75%) patients were SCID, and 18 (25%) patients were other CID. Donor source included 2 (3%) matched sibling donors (MSD), 3 (4%) matched unrelated donors (MUD), 64 (88%) unrelated cord blood (UCB), and 4 (5%) haploidentical donors. The age at transplant was 10.7 (5.9, 27.5) months, and the follow-up time was 36.2 (2.5, 62.9) months. The 3-year overall survival rate of 73 patients with CID was (67±6) %. No significant difference was found in the 3-year overall survival rates between patients with SCID (55 cases) and other CID (18 cases) ((64±7) % vs. (78±10) %, χ2=1.31, P=0.252). And no significant difference was found in the 3-year overall survival rates among patients who received MSD or MUD (5 cases), UCB (64 cases), and haploidentical donor (4 cases) transplant (100% vs. (66±6)% vs. (50±25) %, χ2=2.30, P=0.317). Cox regression analysis showed that the medical history of sepsis (HR=2.55, 95%CI 1.05-6.20, P=0.039) and hypoalbuminemia at transplant (HR=2.96, 95%CI 1.14-7.68, P=0.026) were independent risk factors for the prognosis of allogeneic hematopoietic stem cell transplantation in pediatric patients with CID. Conclusions: Allogeneic hematopoietic stem cell transplantation is an effective treatment for CID. The medical history of sepsis and hypoalbuminemia at transplant were risk factors for prognosis. Enhancing infection prevention and nutritional intervention before transplant can improve patient prognosis.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Masculino , Feminino , Lactente , Prognóstico , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/mortalidade , Pré-Escolar , Criança , Fatores de Risco , Taxa de Sobrevida , Doadores não Relacionados , Resultado do Tratamento , Irmãos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Estimativa de Kaplan-Meier , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodosRESUMO
This study aimed to investigate the kinetics of immune recovery following umbilical cord blood transplantation (UCBT) in adults who received a myeloablative conditioning (MAC) regimen and antithymocyte globulin (ATG). While the immune recovery kinetics has been extensively studied in pediatric UCBT recipients, limited data exist for adults. We conducted a comprehensive analysis of 221 consecutive adult patients who underwent UCBT with MAC and ATG at a single institution. Our objective was to evaluate the influence of patient, disease, and transplant factors, along with acute graft-versus-host disease (aGVHD), on immune reconstitution and overall survival. Our findings confirm a delayed recovery of T cells, while B and NK cell reconstitution exhibited rapid progress, with NK cell counts reaching normal levels within 3 months post-transplantation and B cells within 6 months. Within CD3+ T cells, CD8+ T cells also experienced a delayed recovery (12 months), but to a lesser extent compared to CD4+ T cells (18 months). Delayed immune recovery of T-cell subsets was associated with the development of aGVHD grade II-IV, older age, CMV negativity, and a female donor. Patients with lymphoproliferative diseases showed slower NK cell recovery. Our study demonstrates that adult patients undergoing MAC with ATG and receiving a single unit UCBT for hematologic malignancies experienced rapid reconstitution of NK and B cells. However, T cell recovery, particularly CD4+ T cells, was significantly delayed. To enhance T cell recovery, it may be crucial to consider UCB units with higher cellularity and optimize ATG doses in conditioning.
Assuntos
Soro Antilinfocitário , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Reconstituição Imune , Condicionamento Pré-Transplante , Humanos , Condicionamento Pré-Transplante/métodos , Feminino , Neoplasias Hematológicas/terapia , Masculino , Adulto , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Soro Antilinfocitário/uso terapêutico , Pessoa de Meia-Idade , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Idoso , Adulto Jovem , Adolescente , Células Matadoras Naturais/imunologia , Agonistas Mieloablativos/uso terapêuticoRESUMO
To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).
Assuntos
Antivirais , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Citomegalovirus , Citomegalovirus , Quinazolinas , Ativação Viral , Humanos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Masculino , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/etiologia , Feminino , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Adulto , Estudos Retrospectivos , Adolescente , Pessoa de Meia-Idade , Criança , Ativação Viral/efeitos dos fármacos , Antivirais/uso terapêutico , Quinazolinas/uso terapêutico , Quinazolinas/farmacologia , Pré-Escolar , Farmacorresistência Viral , Adulto Jovem , Lactente , Idoso , AcetatosRESUMO
Real data confirm an excellent toxicity profile and effectiveness of letermovir prophylaxis with decreased cytomegalovirus reactivation and resistance in umbilical cord blood transplantation for both paediatric and adult patients. Commentary on: Yan et al. Letermovir prophylaxis reduced cytomegalovirus reactivation and resistance post umbilical cord blood transplantation. Br J Haematol 2024;204:2378-2389.
Assuntos
Antivirais , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Citomegalovirus , Citomegalovirus , Humanos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/fisiologia , Antivirais/uso terapêutico , Quinazolinas/uso terapêutico , Adulto , Ativação Viral , AcetatosRESUMO
PURPOSE OF REVIEW: Here, we review classic and emerging uses of umbilical cord blood and highlight strategies to improve its utility, focusing on selection of the appropriate units and cell types for the intended applications. RECENT LITERATURE: Recent studies have shown advancements in cord blood cell utility in a variety of cellular therapies and have made strides in elucidating manners to select the best units for therapy and target new ways to improve the various cell subpopulations for their respective applications. SUMMARY: Umbilical cord blood is a proven source of cells for hematopoietic cell transplantation and research and is an important potential source for additional cellular therapies. However, cord blood utility is limited by low "doses" of potent cells that can be obtained from individual units, a limitation that is specific to cord blood as a donor source. In addition to traditional CD34 + progenitor cells, cord blood lymphocytes are being pursued as therapeutic entities with their own unique properties and characteristics. Thus, selection of ideal units depends on the intended therapeutic entity and target, and identification of differential potency parameters is critical to drive effective banking strategies accommodating successful clinical use of cord blood in broader cell therapy settings.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Sangue Fetal , Humanos , Sangue Fetal/citologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismoRESUMO
Current treatments for schizophrenia (SCZ) remain largely ineffective in one-third of patients. Recent studies using stem cell therapy show a close relationship between stem cell immunomodulatory function and neuroinflammation in SCZ. To better investigate the efficacy of stem cell therapy for SCZ, human umbilical cord blood mesenchymal stem cells (hUC-MSC) with powerful immunomodulatory effects were administered to rats via the tail vein (once a week for 5 consecutive weeks starting from the weaning period) using a maternal immune activation (MIA) rodent model. Open field, PPI, Western blotting, Q-PCR, and immunofluorescence were used to assess the biological effects of repeated tail vein injections of hUC-MSC in offspring rats following the MIA model of SCZ. The results indicated that offspring of MIA rats exhibited schizophrenia-like (SCZ-like) anxiety behavior, with observed microglial activation triggering neuroinflammation. Furthermore, levels of IBA1, HMGB1, and PSD95 were significantly up-regulated, while SYP was significantly down-regulated. It is suggested that hUCB-MSCs may act through HMGB1, Iba1, PSD95, and related pathway molecules to alleviate neuroinflammation and repair synaptic damage by regulating the activity state of microglia. Consequently, this could improve the abnormal behavior observed in MIA offspring rats.
Assuntos
Ansiedade , Modelos Animais de Doenças , Proteína HMGB1 , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Microglia , Ratos Sprague-Dawley , Esquizofrenia , Animais , Ratos , Esquizofrenia/terapia , Esquizofrenia/induzido quimicamente , Transplante de Células-Tronco Mesenquimais/métodos , Humanos , Feminino , Ansiedade/terapia , Proteína HMGB1/metabolismo , Gravidez , Proteína 4 Homóloga a Disks-Large/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas dos Microfilamentos/metabolismo , Masculino , Sangue Fetal/citologia , Doenças Neuroinflamatórias , Sinaptofisina/metabolismo , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Efeitos Tardios da Exposição Pré-NatalRESUMO
BACKGROUND: Graft-versus-host disease (GvHD) and rejection are main limitations of cord blood transplantation (CBT), more so in patients with severe inflammation or previous rejections. While rigorous T-cell depletion with antithymocyte globulin (ATG) is needed to prevent GvHD and rejection, overexposure to ATG leads to slow T-cell recovery after transplantation, especially in CBT. OBJECTIVE: To evaluate high-dose, upfront ATG with individualized dosing and therapeutic drug monitoring (TDM) in pediatric CBT for patients at high risk for GvHD and rejection. STUDY DESIGN: Heavily inflamed patients and patients with a recent history of rejection were eligible for individualized high-dose ATG with real-time TDM. The ATG dosing scheme was adjusted to target a post-CBT exposure of <10 AU*day/mL, while achieving a pre-CBT exposure of 60-120 AU*day/mL; exposure levels previously defined for optimal efficacy and safety in terms of reduced GvHD and rejection, respectively. Main outcomes of interest included efficacy (target exposure attainment) and safety (incidence of GvHD and rejection). Other outcomes of interest included T-cell recovery and survival. RESULTS: Twenty-one patients were included ranging from 2 months to 18 years old, receiving an actual median cumulative dose of ATG of 13.3 mg/kg (range 6-30 mg/kg) starting at a median 15 days (range 12-17) prior to CBT. Dosing was adjusted in 14 patients (increased in 3 and decreased in 11 patients). Eighteen (86%) and 19 (91%) patients reached the target pre-CBT and post-CBT exposure, respectively. Cumulative incidence for acute GvHD was 34% (95% CI 23-45) and 5% (95% CI 0-10%) for grade 2-4 and grade 3-4, respectively; cumulative incidence of rejection was 9% (95% CI 2-16%). Overall survival was 75% (95% CI 65-85%). CONCLUSION: Individualized high-dose ATG with TDM is feasible and safe for patients with hyperinflammation in a CBT setting. We observe high target ATG exposure attainment, good immune reconstitution (despite very high doses of ATG) and acceptable rates of GvHD and rejection.
Assuntos
Soro Antilinfocitário , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Monitoramento de Medicamentos , Doença Enxerto-Hospedeiro , Humanos , Soro Antilinfocitário/administração & dosagem , Soro Antilinfocitário/uso terapêutico , Criança , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Masculino , Feminino , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Adolescente , Pré-Escolar , Monitoramento de Medicamentos/métodos , Lactente , Rejeição de Enxerto/tratamento farmacológico , Linfócitos T/imunologia , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagemRESUMO
To evaluate the co-transplantation efficacy of umbilical cord mesenchymal stem cells (UC-MSCs) and peripheral blood stem cells (PBSCs) as a novel approach for refractory or relapsed severe aplastic anemia (R/R SAA) in children and adolescents, thirty-two children and adolescents diagnosed with R/R SAA underwent a retrospective chart review. The patients were categorized into two groups based on the source of PBSCs: the matched sibling donor (MSD) group and the unrelated donor (UD) group. No adverse events related to UC-MSC infusion occurred in any of the patients. The median time for neutrophil engraftment was 13 days (range: 10-23 days), and for platelets, it was 15 days (range: 11-28 days). Acute GVHD of Grade I-II and moderate chronic GVHD were observed in 21.8 and 12.5% of cases, respectively. No statistically significant differences were found between the MSD and UD groups in terms of engraftment, GVHD, and complications, including infection and hemorrhagic cystitis. The median follow-up time was 38.6 months (range: 1.4-140.8 months). As of October 31, 2021, five patients had succumbed, while 27 (84.4%) survived. The 5-year OS rate showed no statistically significant difference between the MSD and UD groups (84.8 ± 10.0 vs. 82.4 ± 9.2%, p = 0.674). In conclusion, the application of UC-MSCs in the treatment of R/R SAA in PBSC transplantation is reliable and safe, they had no graft rejection, low incidence of severe GVHD which may have been contributed by the co-infusion of MSC.
Assuntos
Anemia Aplástica , Transplante de Células-Tronco Mesenquimais , Humanos , Anemia Aplástica/terapia , Anemia Aplástica/mortalidade , Criança , Adolescente , Masculino , Feminino , Pré-Escolar , Transplante de Células-Tronco Mesenquimais/métodos , Estudos Retrospectivos , Transplante de Células-Tronco de Sangue Periférico/métodos , Recidiva , Doença Enxerto-Hospedeiro , Lactente , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodosRESUMO
Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. A predictive model for neutrophil recovery after single-unit CBT was developed by using a machine learning method, which can handle large and complex datasets, allowing for the analysis of massive amounts of information to uncover patterns and make accurate predictions. Japanese registry data, the largest real-world dataset of CBT, was selected as the data source. Ninety-eight variables with observed values for >80% of the subjects known at the time of CBT were selected. Model building was performed with a competing risk regression model with lasso penalty. Prediction accuracy of the models was evaluated by calculating the area under the receiver operating characteristic curve (AUC) using a test dataset. The primary outcome was neutrophil recovery at day (D) 28, with recovery at D14 and D42 analyzed as secondary outcomes. The final cord blood engraftment prediction (CBEP) models included 2991 single-unit CBT recipients with acute leukemia. The median AUC of a D28-CBEP lasso regression model run 100 times was .74, and those for D14 and D42 were .88 and .68, respectively. The predictivity of the D28-CBEP model was higher than that of 4 different legacy models constructed separately. A highly predictive model for neutrophil recovery by 28 days after CBT was constructed using machine learning techniques; however, identification of significant risk factors was insufficient for outcome prediction for an individual patient, which is necessary for improving therapeutic outcomes. Notably, the prediction accuracy for post-transplantation D14, D28, and D42 decreased, and the model became more complex with more associated factors with increased time after transplantation.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Neutrófilos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Aprendizado de MáquinaRESUMO
Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia Mielomonocítica Crônica , Humanos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia Mielomonocítica Crônica/terapia , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Estudos Retrospectivos , Idoso , Taxa de SobrevidaRESUMO
To assess the benefits of HLA-haploidentical haematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) relative to those of umbilical cord blood (UCB) transplantation in acute lymphoblastic leukaemia (ALL), we analysed 1999 patients (PTCy-haplo, 330; UCB, 1669), using the nationwide Japanese registry. PTCy-haplo was associated with a significantly higher relapse rate, but lower non-relapse mortality, which results in overall survival and disease-free survival, comparable to those of UCB. Among patients in CR1, PTCy-haplo showed a significantly higher survival than UCB regardless of the CD34+ cell dose. Our findings provide valuable insights into the donor selection algorithm in allogeneic HSCT for adult patients with ALL.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Ciclofosfamida , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Masculino , Adulto , Transplante de Células-Tronco Hematopoéticas/métodos , Pessoa de Meia-Idade , Adolescente , Indução de Remissão , Transplante Haploidêntico/métodos , Adulto Jovem , IdosoRESUMO
The number of umbilical cord blood transplantation (U-CBT) procedures has been growing annually, but little research has been done on long-term immune recovery after U-CBT. Infection risk is high in U-CBT recipients, and this can be partially attributed to immature immunocompetent cells in umbilical cord blood. In this study, we analyzed lymphocyte subset (LST) number to determine the long-term recovery timeline. We included 36 U-CBT and 10 unrelated bone marrow transplantation (U-BMT) recipients who survived more than 2 years after transplantation, and followed them for up to 10 years post-transplant. Recovery kinetics in the early phase post-transplant was different for each LST. Recovery of CD19+ B cells was faster after U-CBT than after U-BMT in the first 5 years after transplantation. Although CD4+ T cells increased in the first several months after U-CBT, long-term cell count recovery was impaired in approximately 20% of patients. Thus, although the LST recovery pattern after U-CBT was unique, LST number recovery was statistically comparable between U-CBT and U-BMT past 5 years post-transplantation.