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1.
Artigo em Inglês | MEDLINE | ID: mdl-33273414

RESUMO

Hepatitis-associated aplastic anemia (HAAA) has been reported in 23% to 33% of patients who received orthotopic liver transplantation (LT) for acute liver disease of unknown origin (nonviral hepatitis). In this situation, hematopoietic stem cell transplantation (HSCT) might be a curative option. Here the authors report on 6 patients who received HSCT after LT for nonviral HAAA hepatitis. The outcomes were interpreted in the context of recently reported immune suppressive therapy (IST) outcomes in 8 patients with HAAA and to HSCT outcomes in patients with HAAA who recovered from hepatitis without undergoing LT. All patients transplanted by using HLA-identical sibling donors (3 out of 6) were alive and had normal liver function and hematopoiesis without graft versus host disease. Both patients receiving bone marrow from a matched unrelated donor (MUD) experienced extensive graft versus host disease that was fatal for one patient. Thereby, the authors conclude that HSCT can be considered as a first-choice treatment for this category of patients when HLA-identical donors are available. When no HLA-identical donor is available, IST should be applied as HSCT with other donor sources might be reserved for IST nonresponders or poor responders.

2.
J Clin Immunol ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33070266

RESUMO

PURPOSE: While neonatal bloodspot screening (NBS) for severe combined immunodeficiency (SCID) has been introduced more than a decade ago, implementation in NBS programs remains challenging in many countries. Even if high-quality test methods and follow-up care are available, public uptake and parental acceptance are not guaranteed. The aim of this study was to describe the parental perspective on NBS for SCID in the context of an implementation pilot. Psychosocial aspects have never been studied before for NBS for SCID and are important for societal acceptance, a major criterion when introducing new disorders in NBS programs. METHODS: To evaluate the perspective of parents, interviews were conducted with parents of newborns with abnormal SCID screening results (N = 17). In addition, questionnaires about NBS for SCID were sent to 2000 parents of healthy newborns who either participated or declined participation in the SONNET-study that screened 140,593 newborns for SCID. RESULTS: Support for NBS for SCID was expressed by the majority of parents in questionnaires from both a public health perspective and a personal perspective. Parents emphasized the emotional impact of an abnormal screening result in interviews. (Long-term) stress and anxiety can be experienced during and after referral indicating the importance of uniform follow-up protocols and adequate information provision. CONCLUSION: The perspective of parents has led to several recommendations for NBS programs that are considering screening for SCID or other disorders. A close partnership of NBS programs' stakeholders, immunologists, geneticists, and pediatricians-immunologists in different countries is required for moving towards universal SCID screening for all infants.

4.
J Immunol ; 205(3): 864-871, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32591399

RESUMO

The introduction of single-cell platforms inspired the development of high-dimensional single-cell analysis tools to comprehensively characterize the underlying cellular heterogeneity. Flow cytometry data are traditionally analyzed by (subjective) gating of subpopulations on two-dimensional plots. However, the increasing number of parameters measured by conventional and spectral flow cytometry reinforces the need to apply many of the recently developed tools for single-cell analysis on flow cytometry data, as well. However, the myriads of analysis options offered by the continuously released novel packages can be overwhelming to the immunologist with limited computational background. In this article, we explain the main concepts of such analyses and provide a detailed workflow to illustrate their implications and additional prerequisites when applied on flow cytometry data. Moreover, we provide readily applicable R code covering transformation, normalization, dimensionality reduction, clustering, and pseudotime analysis that can serve as a template for future analyses. We demonstrate the merit of our workflow by reanalyzing a public human dataset. Compared with standard gating, the results of our workflow provide new insights in cellular subsets, alternative classifications, and hypothetical trajectories. Taken together, we present a well-documented workflow, which utilizes existing high-dimensional single-cell analysis tools to reveal cellular heterogeneity and intercellular relationships in flow cytometry data.

5.
Blood Adv ; 4(9): 1998-2010, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32384542

RESUMO

Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation-approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti-T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.

6.
Bone Marrow Transplant ; 55(11): 2071-2076, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32404975

RESUMO

The new coronavirus SARS-CoV-2 has rapidly spread over the world causing the disease by WHO called COVID-19. This pandemic poses unprecedented stress on the health care system including programs performing allogeneic and autologous hematopoietic cell transplantation (HCT) and cellular therapy such as with CAR T cells. Risk factors for severe disease include age and predisposing conditions such as cancer. The true impact on stem cell transplant and CAR T-cell recipients in unknown. The European Society for Blood and Marrow Transplantation (EBMT) has therefore developed recommendations for transplant programs and physicians caring for these patients. These guidelines were developed by experts from the Infectious Diseases Working Party and have been endorsed by EBMT's scientific council and board. This work intends to provide guidelines for transplant centers, management of transplant candidates and recipients, and donor issues until the COVID-19 pandemic has passed.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Assistência à Saúde/normas , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Controle de Infecções/normas , Pandemias , Pneumonia Viral , Acreditação/organização & administração , Aloenxertos , Técnicas de Laboratório Clínico , Continuidade da Assistência ao Paciente , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecção Hospitalar/prevenção & controle , Europa (Continente) , Pessoal de Saúde , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Hospedeiro Imunocomprometido , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Transmissão de Doença Infecciosa do Profissional para o Paciente/prevenção & controle , Visita a Consultório Médico , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Utilização de Procedimentos e Técnicas , Telemedicina , Doadores de Tecidos , Transplantados , Transplante Autólogo , Visitas a Pacientes
7.
Pediatr Blood Cancer ; 67(5): e28229, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134215

RESUMO

BACKGROUND: In pediatric hematopoietic stem cell transplantation (HSCT), the end-of-life (EOL) phase and the loss of the child is often characterized by a sudden deterioration of the child following a period of intensive curative treatment. This demands a fast transition for parents. Therefore, an understanding of the parents' perspective on decision-making in such a complex situation is needed. This study aims to gain insight in parental experiences in EOL decision-making in allogeneic pediatric HSCT. METHODS: A qualitative descriptive study was performed among parents of eight families. Data were thematically analyzed. RESULTS: All parents were aware of their child's deterioration. Six families were confronted with a rapid deterioration, while two families experienced a gradual realization that their child would not survive. Parental EOL decision-making in pediatric HSCT shows a reflective perspective on the meaning of parenthood in EOL decision-making. Two central themes were identified: "survival-oriented decision-making" and "struggling with doubts in hindsight." Six subthemes within the first theme described the parents' goal of doing everything to achieve survival. DISCUSSION: Parents experienced EOL decision-making mainly as a process guided by health care professionals (HCPs) based on the child's condition and treatment possibilities. The decision-making is characterized by following opportunities and focusing on hope for cure. In hindsight parents experienced doubts about treatment steps and their child's suffering. HCPs can strengthen the parental role by an early integration of palliative care, providing timely support to parents in the process of imminent loss. Advance care planning can be used to support communication processes, defining preferences for future care.


Assuntos
Tomada de Decisões , Transplante de Células-Tronco Hematopoéticas , Cuidados Paliativos , Pais , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino
8.
Bone Marrow Transplant ; 55(10): 1946-1954, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32157246

RESUMO

We report the results of an analysis of unrelated allogeneic hematopoietic stem cell transplantations (HSCT) in 71 patients with sickle cell disease (SCD) transplanted in EBMT centers between 2005 and 2017. Median age was 9.3 years; graft type was bone marrow in 79% and peripheral blood in 21%. Recipient-donor HLA match at high resolution typing was 10/10 in 31, 9/10 in 20, and 8/10 in 4 patients; the other patients had intermediate resolution typing. The most frequent conditioning regimens were fludarabine-thiotepa-treosulfan (64%) or busulfan-cyclophosphamide (12%). Cumulative incidence of neutrophil engraftment was 92%; platelet engraftment was 90%. Eleven patients (15%) experienced graft failure. Grade II-IV acute graft-vs.-host disease (GvHD) was 23%; 3-year chronic GvHD was 23%. Three-year overall survival (OS) was 88 ± 4%. GRFS was 62 ± 6%. HLA matching was the most significant risk factor for OS: 3-year OS was 96 ± 4% in 10/10 group vs. 75 ± 10% in 9-8/10 (p = 0.042); GRFS was 69 ± 9% vs. 50 ± 12% (p = 0.114), respectively. In conclusion, unrelated donor HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor, preferably in the context of clinical trials. Using a 10/10 HLA-matched unrelated donor yields better survival indicating that HLA matching is an important donor selection factor in this nonmalignant disease.

9.
Hematol Oncol Stem Cell Ther ; 13(2): 61-65, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32202242

RESUMO

Antithymocyte globulin (ATG) is a widely accepted part of the conditioning regimen applied in the setting of hematopoietic stem cell transplantation (HSCT) to prevent graft rejection and graft-versus-host disease. Although weight-based dosing of ATG has been introduced to optimize ATG dosing, substantial variance in clearance of active ATG, the actual lymphocyte binding component, remains a challenge. Therefore, further research regarding ATG pharmacokinetics and pharmacodynamics in different HSCT settings and in patients with different types of underlying diseases is required.


Assuntos
Anemia Falciforme/terapia , Soro Antilinfocitário/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Transplante Haploidêntico/métodos , Animais , Soro Antilinfocitário/farmacologia , Europa (Continente) , Feminino , Alemanha , História do Século XXI , Humanos , Masculino
10.
Bone Marrow Transplant ; 55(8): 1604-1613, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32066864

RESUMO

Hematopoietic-cell transplantation (HCT) is widely used for acquired and congenital disorders of the hematopoietic system. Number of transplants performed in Europe and associated countries continues to rise with 47,468 HCT in 42,901 patients [19,630 allogeneic (41%) and 27,838 autologous (59%)] reported by 701 centers in 50 countries in 2018. Main indications were myeloid malignancies 10,679 (25%; 97% allogeneic), lymphoid malignancies 27,318 (64%; 20% allogeneic), solid tumors 1625 (4%; 2.9% allogeneic), and nonmalignant disorders 3063 (7%; 81% allogeneic). This year's analysis focuses on cellular therapies with the marked growth in CAR T-cell therapies from 151 in 2017 to 301 patients reported in 2018. Other cellular therapy numbers show less significant changes. Important trends in HCT include a 49% increase in allogeneic HCT for chronic phase CML (although transplant numbers remain low) and a 24% increase in aplastic anemia. In autologous HCT, there is an ongoing increase in autoimmune diseases (by 19%), predominantly due to activity in multiple sclerosis. This annual report reflects current activity and highlights important trends, useful for health care planning.

12.
Gene Ther ; 27(5): 209-225, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31900423

RESUMO

Enhancing the intracellular delivery and performance of RNA-guided CRISPR-Cas9 nucleases (RGNs) remains in demand. Here, we show that nuclear translocation of commonly used Streptococcus pyogenes Cas9 (SpCas9) proteins is suboptimal. Hence, we generated eCas9.4NLS by endowing the high-specificity eSpCas9(1.1) nuclease (eCas9.2NLS) with additional nuclear localization signals (NLSs). We demonstrate that eCas9.4NLS coupled to prototypic or optimized guide RNAs achieves efficient targeted DNA cleavage and probe the performance of SpCas9 proteins with different NLS compositions at target sequences embedded in heterochromatin versus euchromatin. Moreover, after adenoviral vector (AdV)-mediated transfer of SpCas9 expression units, unbiased quantitative immunofluorescence microscopy revealed 2.3-fold higher eCas9.4NLS nuclear enrichment levels than those observed for high-specificity eCas9.2NLS. This improved nuclear translocation yielded in turn robust gene editing after nonhomologous end joining repair of targeted double-stranded DNA breaks. In particular, AdV delivery of eCas9.4NLS into muscle progenitor cells resulted in significantly higher editing frequencies at defective DMD alleles causing Duchenne muscular dystrophy (DMD) than those achieved by AdVs encoding the parental, eCas9.2NLS, protein. In conclusion, this work provides a strong rationale for integrating viral vector and optimized gene-editing technologies to bring about enhanced RGN delivery and performance.

13.
Fetal Diagn Ther ; 47(2): 123-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31261154

RESUMO

OBJECTIVE: The aim of this study was to evaluate the differences in leukocyte counts at birth between donors and recipients with twin-twin transfusion syndrome (TTTS) or twin anemia-polycythemia sequence (TAPS). METHODS: We performed a retrospective cohort study in monochorionic twin pairs with TTTS or TAPS. TTTS and TAPS cases treated with fetoscopic laser surgery were excluded. Primary outcome was the difference in leukocyte levels at birth between donor and recipient twins and the presence of leukopenia (defined as leukocyte count <4 × 109/L). Secondary outcomes included early-onset sepsis, necrotizing enterocolitis, use of antibiotics during admission, and neonatal mortality. RESULTS: We included 99 twins pairs, of which 61 twin pairs were affected by TAPS and 38 twin pairs by TTTS. The mean leukocyte count at birth in donors and recipients was 7.5 × 109/L versus 7.4 × 109/L (p = 0.936), respectively. Leukopenia was significantly more common in donor twins compared to recipient twins (7.1% [7/99] vs. 0% [0/99], p = 0.016). Of the 7 donors with leukopenia, 6 were affected by TAPS and 1 by TTTS. Overall, donors were more often affected by early-onset sepsis than recipients, 23.7% (23/97) versus 13% (13.7/95) (p = 0.049), respectively. CONCLUSIONS: Leukocyte counts at birth in twins with TTTS or TAPS are similar between donors and recipients, but TAPS donors are at an increased risk of leukopenia. Overall, TTTS and TAPS donors seem to be at an increased risk of early-onset neonatal sepsis compared to recipient twins.


Assuntos
Anemia/sangue , Transfusão Feto-Fetal/sangue , Policitemia/sangue , Gêmeos Monozigóticos , Anemia/complicações , Anemia/diagnóstico , Anemia/mortalidade , Biomarcadores/sangue , Feminino , Transfusão Feto-Fetal/complicações , Transfusão Feto-Fetal/diagnóstico , Transfusão Feto-Fetal/mortalidade , Humanos , Lactente , Recém-Nascido , Contagem de Leucócitos , Leucopenia/etiologia , Sepse Neonatal/etiologia , Policitemia/complicações , Policitemia/diagnóstico , Valor Preditivo dos Testes , Gravidez , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
14.
Front Immunol ; 10: 2680, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849931

RESUMO

B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Appropriate signaling via this pre-BCR complex is followed by rearrangement of the Ig light chain genes, resulting in the formation, and selection of functional BCR molecules. Consecutive production, expression, and functional selection of the pre-BCR and BCR complexes guide the BCP differentiation process that coincides with corresponding immunophenotypic changes. We studied BCP differentiation in human BM samples from healthy controls and patients with a known genetic defect in V(D)J recombination or pre-BCR signaling to unravel normal immunophenotypic changes and to determine the effect of differentiation blocks caused by the specific genetic defects. Accordingly, we designed a 10-color antibody panel to study human BCP development in BM by flow cytometry, which allows identification of classical preB-I, preB-II, and mature B-cells as defined via BCR-related markers with further characterization by additional markers. We observed heterogeneous phenotypes associated with more than one B-cell maturation pathway, particularly for the preB-I and preB-II stages in which V(D)J recombination takes place, with asynchronous marker expression patterns. Next Generation Sequencing of complete IGH gene rearrangements in sorted BCP subsets unraveled their rearrangement status, indicating that BCP differentiation does not follow a single linear pathway. In conclusion, B-cell development in human BM is not a linear process, but a rather complex network of parallel pathways dictated by V(D)J-recombination-driven checkpoints and pre-BCR/BCR mediated-signaling occurring during B-cell production and selection. It can also be described as asynchronous, because precursor B-cells do not differentiate as full population between the different stages, but rather transit as a continuum, which seems influenced (in part) by V-D-J recombination-driven checkpoints.


Assuntos
Diferenciação Celular/genética , Diferenciação Celular/imunologia , Síndromes de Imunodeficiência/imunologia , Células Precursoras de Linfócitos B/imunologia , Criança , Feminino , Citometria de Fluxo/métodos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Síndromes de Imunodeficiência/genética , Masculino , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Recombinação V(D)J/genética , Recombinação V(D)J/imunologia
15.
Clin Pharmacokinet ; 58(12): 1609-1620, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31131436

RESUMO

BACKGROUND AND OBJECTIVE: Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing. METHODS: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers. RESULTS: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance. CONCLUSION: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.


Assuntos
Alemtuzumab/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Modelos Biológicos , Adolescente , Alemtuzumab/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Masculino , Medicina de Precisão , Estudos Prospectivos , Distribuição Tecidual , Adulto Jovem
16.
Front Immunol ; 10: 782, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031769

RESUMO

B cell reconstitution after hematopoietic stem cell transplantation (HSCT) is variable and influenced by different patient, donor, and treatment related factors. In this review we describe B cell reconstitution after pediatric allogeneic HST, including the kinetics of reconstitution of the different B cell subsets and the development of the B cell repertoire, and discuss the influencing factors. Observational studies show important roles for stem cell source, conditioning regimen, and graft vs. host disease in B cell reconstitution. In addition, B cell recovery can play an important role in post-transplant infections and vaccine responses to encapsulated bacteria, such as pneumococcus. A substantial number of patients experience impaired B cell function and/or dependency on Ig substitution after allogeneic HSCT. The underlying mechanisms are largely unresolved. The integrated aspects of B cell recovery after HSCT, especially BCR repertoire reconstitution, are awaiting further investigation using modern techniques in order to gain more insight into B cell reconstitution and to develop strategies to improve humoral immunity after allogeneic HSCT.


Assuntos
Linfócitos B/imunologia , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Fatores Etários , Linfócitos B/metabolismo , Pré-Escolar , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Infecções/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Vacinação , Vacinas/administração & dosagem , Vacinas/imunologia
17.
Bone Marrow Transplant ; 54(10): 1525-1552, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30953028

RESUMO

This is the seventh special EBMT report on the indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders. Our aim is to provide general guidance on transplant indications according to prevailing clinical practice in EBMT countries and centres. In order to inform patient decisions, these recommendations must be considered together with the risk of the disease, the risk of the transplant procedure and the results of non-transplant strategies. In over two decades since the first report, the EBMT indications manuscripts have incorporated changes in transplant practice coming from scientific and technical developments in the field. In this same period, the establishment of JACIE accreditation has promoted high quality and led to improved outcomes of patient and donor care and laboratory performance in transplantation and cellular therapy. An updated report with operating definitions, revised indications and an additional set of data with overall survival at 1 year and non-relapse mortality at day 100 after transplant in the commonest standard-of-care indications is presented. Additional efforts are currently underway to enable EBMT member centres to benchmark their risk-adapted outcomes as part of the Registry upgrade Project 2020 against national and/or international outcome data.


Assuntos
Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Doenças do Sistema Imunitário/terapia , Neoplasias/terapia , Condicionamento Pré-Transplante/métodos , Europa (Continente) , História do Século XXI , Humanos
18.
Front Immunol ; 10: 315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30894854

RESUMO

Anti-thymocyte globulin (ATG) is a lymphocyte depleting agent applied in hematopoietic stem cell transplantation (HSCT) to prevent rejection and Graft-vs.-Host Disease (GvHD). In this study, we compared two rabbit ATG products, ATG-Genzyme (ATG-GENZ), and ATG-Fresenius (ATG-FRES), with respect to dosing, clearance of the active lymphocyte binding component, post-HSCT immune reconstitution and clinical outcome. Fifty-eigth pediatric acute leukemia patients (n = 42 ATG-GENZ, n = 16 ATG-FRES), who received a non-depleted bone marrow or peripheral blood stem cell graft from an unrelated donor were included. ATG-GENZ was given at a dosage of 6-10 mg/kg; ATG-FRES at 45-60 mg/kg. The active component of ATG from both products was cleared at different rates. Within the ATG-FRES dose range no differences were found in clearance of active ATG or T-cell re-appearance. However, the high dosage of ATG-GENZ (10 mg/kg), in contrast to the low dosage (6-8 mg/kg), correlated with prolonged persistence of active ATG and delayed T-cell reconstitution. Occurrence of serious acute GvHD (grade III-IV) was highest in the ATG-GENZ-low dosage group. These results imply that dosing of ATG-GENZ is more critical than dosing of ATG-FRES due to the difference in clearance of active ATG. This should be taken into account when designing clinical protocols.


Assuntos
Soro Antilinfocitário/imunologia , Doença Enxerto-Hospedeiro/imunologia , Linfócitos T/imunologia , Animais , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/imunologia , Depleção Linfocítica/métodos , Coelhos , Células-Tronco/imunologia , Condicionamento Pré-Transplante/métodos , Doadores não Relacionados
19.
Sci Rep ; 9(1): 5247, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30918307

RESUMO

During pregnancy, maternal T cells can enter the foetus, leading to maternal-foetal chimerism. This phenomenon may affect how leukaemia patients respond to transplantation therapy using stem cells from cord blood (CB). It has been proposed that maternal T cells, primed to inherited paternal HLAs, are present in CB transplants and help to suppress leukaemic relapse. Several studies have reported evidence for the presence of maternal T cells in most CBs at sufficiently high numbers to lend credence to this idea. We here aimed to functionally characterise maternal T cells from CB. To our surprise, we could not isolate viable maternal cells from CB even after using state-of-the-art enrichment techniques that allow detection of viable cells in heterologous populations at frequencies that were several orders of magnitude lower than reported frequencies of maternal T cells in CB. In support of these results, we could only detect maternal DNA in a minority of samples and at insufficient amounts for reliable quantification through a sensitive PCR-based assay to measure In/Del polymorphisms. We conclude that maternal microchimerism is far less prominent than reported, at least in our cohort of CBs, and discuss possible explanations and implications.


Assuntos
Sangue Fetal/metabolismo , Células Cultivadas , Feminino , Citometria de Fluxo , Antígenos HLA/metabolismo , Humanos , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Gravidez , Linfócitos T/metabolismo , Temperatura
20.
Biol Blood Marrow Transplant ; 25(6): 1164-1171, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30731251

RESUMO

Bloodstream infections and graft-versus-host disease are common complications after hematopoietic stem cell transplantation (HSCT) procedures, associated with the gut microbiota that acts as a reservoir for opportunistic pathogens. Selective gut decontamination (SGD) and total gut decontamination (TGD) during HSCT have been associated with a decreased risk of developing these complications after transplantation. However, because studies have shown conflicting results, the use of these treatments remains subject of debate. In addition, their impact on the gut microbiota is not well studied. The aim of this study was to elucidate the dynamics of the microbiota during and after TGD and to compare these with the dynamics of SGD. In this prospective, observational, single-center study fecal samples were longitudinally collected from 19 children eligible for allogenic HSCT (TGD, n=12; SGD, n=7), weekly during hospital admission and monthly after discharge. In addition, fecal samples were collected from 3 family stem cell donors. Fecal microbiota structure of patients and donors was determined by 16S rRNA gene amplicon sequencing. Microbiota richness and diversity markedly decreased during SGD and TGD and gradually increased after cessation of decontamination treatment. During SGD, gut microbiota composition was relatively stable and dominated by Bacteroides, whereas it showed high inter- and intraindividual variation and low Bacteroides abundance during TGD. In some children TGD allowed the genera Enterococcus and Streptococcus to thrive during treatment. A gut microbiota dominated by Bacteroides was associated with increased predicted activity of several metabolic processes. Comparing the microbiota of recipients and their donors indicated that receiving an SCT did not alter the patient's microbiota to become more similar to that of its donor. Overall, our findings indicate that SGD and TGD affect gut microbiota structure in a treatment-specific manner. Whether these treatments affect clinical outcomes via interference with the gut microbiota needs to be further elucidated.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/métodos , Microbiota/efeitos dos fármacos , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Descontaminação , Feminino , Humanos , Masculino , Estudos Prospectivos
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