RESUMO
[This corrects the article DOI: 10.3389/fphar.2022.828094.].
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Anti-thymocyte globulin (ATG), a polyclonal antibody, is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-vs.-host-disease (GvHD) and graft failure (GF). Overexposure to ATG leads to poor early T-cell recovery, which is associated with viral infections and poor survival. Patients with severe inflammation are at high risk for GF and GvHD, and may have active infections warranting swift T-cell recovery. As ATG exposure may be critical in these patients, individualized dosing combined with therapeutic drug monitoring (TDM) may improve outcomes. We describe the individualized dosing approach, an optimal sampling scheme, the assay to measure the active fraction of ATG, and the workflow to perform TDM. Using a previously published population pharmacokinetic (PK) model, we determine the dose to reach optimal exposures associated with low GvHD and rejection, and at the same time promote T-cell recovery. Based on an optimal sampling scheme, peak and trough samples are taken during the first 3 days of once-daily dosing. The fraction of ATG able to bind to T-cells (active ATG) is analyzed using a bio-assay in which Jurkat cells are co-cultured with patient's plasma and the binding is quantified using flow cytometry. TDM is performed based on these ATG concentrations on the third day of dosing; subsequent doses can be adjusted based on the expected area under the curve. We show that individualized ATG dosing with TDM is feasible. This approach is unique in the setting of antibody treatment and may result in better immune reconstitution post-HCT and subsequently better survival chances.
RESUMO
Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.
Assuntos
Reparo do DNA/genética , Variação Genética , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Antineoplásicos Alquilantes/farmacocinética , Bussulfano/farmacocinética , Criança , Pré-Escolar , Estudos de Coortes , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Testes Genéticos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Heterozigoto , Humanos , Incidência , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Proteínas Supressoras de Tumor/genéticaRESUMO
Umbilical cord blood is the preferred donor cell source for children with Inherited Metabolic disorders undergoing Hematopoietic Cell Transplant (HCT), and its use has been associated with improved "engrafted survival" and higher donor chimerism compared to other cell sources. However, as in other pediatric cord blood transplants for non-malignant disease, immune-mediated cytopenia and primary graft failure limit its use, and the latter remains the commonest cause of death following cord blood transplant for non-malignant disease. We have previously shown an association between immune-mediated cytopenia and graft failure in inherited metabolic diseases suggesting that both immune-mediated cytopenia and graft failure could be mediated by antibodies from the residual recipient B cells. Since rituximab is effective in depletion of B cells and management of refractory immune-mediated cytopenia following HCT, we have added rituximab to the conditioning regimen. We studied 57 patients in 2 centers who received myeloablative conditioning for cord blood transplant in Hurler syndrome, and report a significant improvement in event-free survival with reduced incidence of graft failure and without any evidence of immune-mediated cytopenia in those patients that had received rituximab.
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Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Criança , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Rituximab/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversosRESUMO
The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide (BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE ± 9.0) in the BuCy group, 59.2 % (SE ± 8.1) after BuCyMel, and 66.7 % (SE ± 7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p = 0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p = 0.06). Younger age was a predictor for relapse (p = 0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p < 0.001) was found. In conclusion, LFS after BuCyMel and CloFluBu was comparable, lower LFS was found after BuCy, due to higher relapse incidence. CloFluBu was associated with lower incidence of aGvHD, suggesting lower toxicity with this type of conditioning. This finding is also explained by the impact of Busulfan monitoring.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica , Bussulfano/uso terapêutico , Criança , Ciclofosfamida/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Estudos Retrospectivos , Condicionamento Pré-Transplante , Vidarabina/uso terapêuticoRESUMO
Hematopoietic cell transplantation (HCT) is a curative treatment option for both malignant and nonmalignant diseases. Success of the procedure mainly depends on disease control and treatment-related complications. Pharmacotherapy plays a major role in HCT and significantly impacts the outcomes. Main drug use within HCT includes conditioning, GvHD prophylaxis, and prevention/treatment of infections.Increasing evidence suggests individualized dosing in (pediatric) HCT may improve outcome. Dose individualization may result in a better predictable drug treatment in terms of safety and efficacy, including timely immune reconstitution after HCT and optimal tumor or disease control, which may result in improved survival chances.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Condicionamento Pré-TransplanteAssuntos
Pneumopatias/genética , Linfopenia/genética , Doenças da Imunodeficiência Primária/genética , Proteínas rac de Ligação ao GTP/genética , Adulto , Linfócitos B/imunologia , Progressão da Doença , Proteínas Ativadoras de GTPase/metabolismo , Mutação com Ganho de Função , Doença Enxerto-Hospedeiro/tratamento farmacológico , Guanosina Trifosfato/metabolismo , Transplante de Células-Tronco Hematopoéticas , Heterozigoto , Humanos , Memória Imunológica/imunologia , Imunossupressores/uso terapêutico , Lactente , Pneumopatias/imunologia , Pneumopatias/fisiopatologia , Pneumopatias/cirurgia , Transplante de Pulmão , Linfopenia/imunologia , Masculino , Simulação de Acoplamento Molecular , Neutrófilos , Doenças da Imunodeficiência Primária/imunologia , Doenças da Imunodeficiência Primária/terapia , Recidiva , Infecções Respiratórias/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Proteínas rac de Ligação ao GTP/imunologia , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas rac de Ligação ao GTP/ultraestrutura , Proteína RAC2 de Ligação ao GTPRESUMO
Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m2) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day -9/-12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; P = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; P <001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; P <001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; P = .02; HR, 4.8; 95% CI, 1.2-19; P = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and "renal function" or "therapeutic drug monitoring," to achieve optimal fludarabine exposure might improve survival.
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Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adolescente , Adulto , Causas de Morte , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/efeitos adversos , Agonistas Mieloablativos/farmacocinética , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/farmacocinética , Vidarabina/uso terapêutico , Adulto JovemAssuntos
Linfócitos T CD4-Positivos/citologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia Linfoide/terapia , Leucemia Mieloide/terapia , Doadores não Relacionados , Adolescente , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Estudos de Coortes , Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/mortalidade , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/mortalidade , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
INTRODUCTION: The conditioning regimen used in cord blood transplantation (CBT) may significantly impact the outcomes. Variable pharmacokinetics (PK) of drugs used may further influence outcome. Individualized dosing takes inter-patient differences in PK into account, tailoring drug dose for each individual patient in order to reach optimal exposure. Dose individualization may result in a better predictable regimen in terms of safety and efficacy, including timely T cell reconstitution, which may result in improved survival chances. AREAS COVERED: Conditioning regimens used in CBT varies significantly between and within centres. For busulfan, individualized dosing with therapeutic drug monitoring has resulted in better outcomes. Anti-thymocyte globulin (ATG), used to prevent rejection and GvHD, significantly hampers early T-cell reconstitution (IR). Timely IR is crucial in preventing viral reactivations and relapse. By individudalizing ATG, IR is better predicted and may prevent morbidity and mortality. EXPERT OPINION: Individualization of agents used in the conditioning regimen in CBT has proven its added value. Further fine-tuning, including new drugs and/or comprehensive models for all drugs, may result in better predictable conditioning regimens. A predictable conditioning regimen is also of interest/importance when studying adjuvant therapies, including immunotherapies (e.g. cellular vaccines or engineered T-cell) in a harmonized clinical trial design setting.
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Sangue Fetal/transplante , Doença Enxerto-Hospedeiro/prevenção & controle , Medicina de Precisão/métodos , Condicionamento Pré-Transplante/métodos , Animais , Sangue Fetal/imunologia , Sangue Fetal/metabolismo , Sangue Fetal/fisiologia , Previsões , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Transplante Homólogo/métodos , Resultado do TratamentoRESUMO
We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.
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Resistência a Medicamentos , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Doença Aguda , Adolescente , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Citocinas/sangue , Citocinas/metabolismo , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Imunofenotipagem , Imunossupressores/uso terapêutico , Lactente , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Esteroides/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
The aim of this analysis was to explore the diversity of reduced intensity conditioning (RIC) in paediatric allo-SCT in daily practice across Europe. Data from the European Group for Blood and Marrow Transplantation (EBMT) Promise database from 1994 to 2008 were supplemented by a survey of EBMT centres performing paediatric allo-SCT on the current policy asking for the underlying diseases and for the drug combinations. Records from 161 centres from 30 countries were analysed and 139 various RIC regimens were reported. More centres applied RIC for malignant rather than for non-malignant diseases. In general, fludarabine (FLU)-based regimens predominated except for BU-based regimens in myeloid malignancies and haemoglobinopathies. Treosulfan (TREO) was mainly applied for unspecified malignant diseases and for haemophagocytic diseases. FLU-based regimens revealed the greatest number of different combinations. Correlating the number of regimens with the number of treating centres revealed the lowest variety in FLU and the highest variety in TBI and TREO. FLU/melphalane and FLU/CY were the most frequent combinations. This extreme heterogeneity in RIC may influence both the efficacy and the safety of the procedures, which requires further investigation. Optimization and standardization of RIC is the final goal to provide a platform for future prospective studies.
Assuntos
Bases de Dados Factuais , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Condicionamento Pré-Transplante/métodos , Adolescente , Aloenxertos , Antineoplásicos Alquilantes/administração & dosagem , Bussulfano/administração & dosagem , Bussulfano/análogos & derivados , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Agonistas Mieloablativos/administração & dosagem , Qualidade da Assistência à Saúde , Estudos Retrospectivos , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
UNLABELLED: Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord blood transplantation (CBT), lowering survival rates by approximately 25%. While antiviral treatment ameliorates viremia, complete viral control requires CD8+ T-cell-driven immunity. Mouse studies suggest that cognate antigen-specific CD4+ T-cell licensing of dendritic cells (DCs) is required to generate effective CD8+ T-cell responses. For humans, this was not fully understood. We here show that CD4+ T cells are essential for licensing of human DCs to generate effector and memory CD8+ T-cell immunity against CMV in CBT patients. First, we show in CBT recipients that clonal expansion of CMV-pp65-specific CD4+ T cells precedes the rise in CMV-pp65-specific CD8+ T cells. Second, the elicitation of CMV-pp65-specific CD8+ T cells from rare naive precursors in cord blood requires DC licensing by cognate CMV-pp65-specific CD4+ T cells. Finally, also CD8+ T-cell memory responses require CD4+ T-cell-mediated licensing of DCs in our system, by secretion of gamma interferon (IFN-γ) by pp65-specific CD4+ T cells. Together, these data show that human DCs require licensing by cognate antigen-specific CD4+ T cells to elicit effective CD8+ T-cell-mediated immunity and fight off viral reactivation in CBT patients. IMPORTANCE: Survival rates after stem cell transplantation are lowered by 25% when patients undergo reactivation of cytomegalovirus (CMV) that they harbor. Immune protection against CMV is mostly executed by white blood cells called killer T cells. We here show that for generation of optimally protective killer T-cell responses that respond to CMV, the early elicitation of help from a second branch of CMV-directed T cells, called helper T cells, is required.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Células Dendríticas/imunologia , Ativação Viral , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Interferon gama/metabolismo , Masculino , Fosfoproteínas/imunologia , Proteínas da Matriz Viral/imunologiaRESUMO
This study was aimed at finding predictors of invasive fungal infection (IFI) after pediatric allogeneic hematopoietic SCT (HSCT). All children who received allogeneic HSCT in the Wilhelmina Children's Hospital Utrecht between 2004 and 2012 were included. HSCT data were prospectively collected. Patients were retrospectively classified into high- or low-risk groups for developing IFI using criteria based on available literature. Predictors for the occurrence of IFI were analyzed using Cox regression models. We used logistic regression models to analyze the association between other HSCT-related complications and IFI. Secondary outcomes were overall survival and treatment-related mortality (TRM). Two-hundred nine patients were included in the analysis; median age was 6.6 years. The cumulative incidence of IFI was 12%. In patients classified as 'low risk' (n=75), only 5.3% developed IFI (odds ratio (OR): 0.325; P=0.047). In multivariate analysis, a predictor for the occurrence of IFI was an a priori determined HSCT TRM risk >20% (based on EBMT-risk score). Post-HSCT, the administration of high-dose steroids was associated with IFI (OR: 4.458; P=0.010). Patients who developed IFI showed an increased risk of TRM (OR: 3.773; P=0.004). These results confirm that risk group stratification should guide intensity of monitoring for IFI and use of antifungal prophylaxis.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Micoses/complicações , Micoses/diagnóstico , Adolescente , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Aspergilose/complicações , Candidíase/complicações , Caspofungina , Criança , Pré-Escolar , Equinocandinas/uso terapêutico , Feminino , Fusariose/complicações , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Lactente , Lipopeptídeos , Modelos Logísticos , Masculino , Neutrófilos/citologia , Estudos Prospectivos , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Risco , Resultado do Tratamento , Triazóis/uso terapêutico , Voriconazol , Adulto JovemRESUMO
Hematopoietic SCT (HSCT) is often complicated by viral reactivations. In this retrospective cohort study (January 2004-August 2008), predictors for human herpes virus 6 (HHV6)-reactivation and associations between HHV6-reactivation and clinical outcomes after allogeneic HSCT were studied. HHV6 DNA load in plasma was monitored weekly by quantitative real-time PCR. Associations between the main end point HHV6-reactivation and other end points, that is, acute GVHD (aGVHD) and NRM were analyzed using Cox proportional hazard models. In total, 108 patients receiving either a myeloablative (MA; n=60) or non-myeloablative (NMA; n=48) conditioning regimen were included. Median age was 40 years (range 17-65); median follow-up was 20 months (range 3-36). In 16/60 (27%) patients with MA conditioning regimen, a HHV6 reactivation was observed (mean viral load 50 323 cp/mL) compared with 2/48 (4%) patients with a NMA conditioning regimen with low viral load (mean 1100 cp/mL). In multivariate analysis, MA conditioning was the only predictor for HHV6 reactivation (P=0.02). In addition, HHV6 reactivation was associated with grades 2-4 aGVHD (P<0.001) and NRM (P=0.03). Regular monitoring of HHV6 reactivation after HSCT might be important in MA HSCT patients to enable early initiation of antiviral treatment or to anticipate aGVHD, all of which may improve clinical outcome.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 6/fisiologia , Infecções por Roseolovirus/virologia , Adolescente , Adulto , Idoso , Estudos de Coortes , DNA Viral/sangue , Doença Enxerto-Hospedeiro/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 6/genética , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Ativação Viral/fisiologia , Adulto JovemRESUMO
Hematopoietic stem cell transplantation (HSCT) is frequently complicated by viral reactivations. Early diagnosis of viral reactivations and preemptive therapy relies on frequent viralload monitoring. An easy marker of effective cytotoxicity in lymphopenia is lacking and therefore we studied perforin-expression in CD8+T-cells in children following HSCT. Prospectively, we weekly monitored viral loads and perforin-expression of CD8+T-cells in whole blood by FACS, until 4months after HSCT in children. 27 patients were included (median age 4,3, range 0.3-20,1years) of whom 19 developed viral reactivations. These patients showed higher percentages of perforin-expressing CD8+T-cells (17,2%, range 0-63%) than those without (6,8%; range 0-16%) (p=0.001). The increased percentage of perforin-expressing CD8+T-cells coincided with a decrease in viral load with a median interval between maximum viral load and maximum level of perforin-expression of 0,4weeks (range 0.1-7.1). We conclude that perforin-expression in CD8+T-cells may be a marker for effective antiviral T-cell reconstitution early after HSCT in children.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 6/fisiologia , Perforina/biossíntese , Perforina/sangue , Infecções por Roseolovirus/imunologia , Adolescente , Linfócitos T CD8-Positivos/virologia , Criança , Pré-Escolar , Estudos de Coortes , DNA Viral/química , DNA Viral/genética , Citometria de Fluxo , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/imunologia , Humanos , Imunofenotipagem , Lactente , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Infecções por Roseolovirus/sangue , Infecções por Roseolovirus/virologia , Estatísticas não Paramétricas , Ativação Viral , Adulto JovemRESUMO
In adult patients, regulatory CD4+FOXP3+ T cells are suggested to have a role in the control of allo-reactive disease after hematopoietic SCT (HSCT). We compared CD4+FOXP3+ T-cell reconstitution after unrelated cord blood (UCB), matched unrelated donor (MUD) and matched sibling donor (MSD) HSCT in children, starting as early as 1 week after transplantation, and analyzed the association with allo-reactive disease. A total of 30 children were included who underwent a myeloablative-conditioning regimen followed by UCB (12/30), MUD (7/30) or MSD (11/30) HSCT. These three patient groups showed significant differences in FOXP3+ T-cell reconstitution pattern. Early after UCB and MSD, but not after MUD, HSCT a peak in FOXP3+ T cells was observed. There were significant differences in activation status and Ki67 expression of the FOXP3+ T cells after UCB and MSD, respectively. FOXP3+ T-cell proportions early after HSCT and in the graft were inversely correlated with allo-reactivity. This study indicates that FOXP3 reconstitution after HSCT is dependent on the type of graft used. Furthermore, in children evaluation of FOXP3+ T-cell numbers early after HSCT and in the graft may be used to judge the risk of developing allo-reactivity after HSCT.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Irmãos , Doadores não Relacionados , Adolescente , Adulto , Linfócitos T CD4-Positivos/patologia , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica/imunologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Antígeno Ki-67/imunologia , Masculino , Transplante HomólogoRESUMO
Early human herpesvirus 6 (HHV6) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with poor survival. We characterized HHV6 immuneresponses in HSCT patients during lymphopenia. Prospectively, HHV6 DNA-load was measured weekly by realtime-PCR. Numbers of IFNγ-producing HHV6-T-cells were retrospectively determined by enzyme-linked immunospot assay 2 months after HSCT. HHV6-specific T-cell proliferative capacity was analyzed with a newly developed assay using antigen-presenting autologous HHV6-infected PBMC. Fifty-six patients were included (median age 4.6 years; range 0.2-21.2 years). HHV6-reactivation occurred in 29/56 (52%) patients with a median time of 14 (range 1-41) days after HSCT. The median number of IFN-γ producing HHV6-specific T-cells at 2 months and the HHV6-specific CD8+ T-cell proliferative capacity at 6 months after HSCT was increased after HHV6-reactivation compared to non-reactivating patients (P=0.006 and p=0.019). In conclusion, HHV6-specific immuneresponses can be initiated during lymphopenia early after HSCT, which implicates a potential window for development of HHV6-specific (immuno)therapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Herpesvirus Humano 6/imunologia , Infecções por Roseolovirus/imunologia , Infecções por Roseolovirus/virologia , Células-Tronco/imunologia , Adolescente , Adulto , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/virologia , Linfócitos T CD8-Positivos/virologia , Proliferação de Células , Criança , Pré-Escolar , Estudos de Coortes , DNA Viral/genética , DNA Viral/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 6/genética , Humanos , Lactente , Interferon gama/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Linfopenia/imunologia , Linfopenia/virologia , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Infecções por Roseolovirus/genética , Ativação Viral/genética , Ativação Viral/imunologia , Adulto JovemRESUMO
Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1-23) years and underwent HSCT at a median of 3.6 (1.3-23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1-12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.