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1.
Mol Ther ; 32(1): 44-58, 2024 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-37952085

RESUMEN

Hematopoietic stem cell transplantation (HSCT) is the only approved treatment for presymptomatic infantile globoid cell leukodystrophy (GLD [Krabbe disease]). However, correction of disease is not complete, and outcomes remain poor. Herein we evaluated HSCT, intravenous (IV) adeno-associated virus rh10 vector (AAVrh10) gene therapy, and combination HSCT + IV AAVrh10 in the canine model of GLD. While HSCT alone resulted in no increase in survival as compared with untreated GLD dogs (∼16 weeks of age), combination HSCT + IV AAVrh10 at a dose of 4E13 genome copies (gc)/kg resulted in delayed disease progression and increased survival beyond 1 year of age. A 5-fold increase in AAVrh10 dose to 2E14 gc/kg, in combination with HSCT, normalized neurological dysfunction up to 2 years of age. IV AAVrh10 alone resulted in an average survival to 41.2 weeks of age. In the peripheral nervous system, IV AAVrh10 alone or in addition to HSCT normalized nerve conduction velocity, improved ultrastructure, and normalized GALC enzyme activity and psychosine concentration. In the central nervous system, only combination therapy at the highest dose was able to restore galactosylceramidase activity and psychosine concentrations to within the normal range. These data have now guided clinical translation of systemic AAV gene therapy as an addition to HSCT (NCT04693598, NCT05739643).


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucodistrofia de Células Globoides , Perros , Animales , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Galactosilceramidasa/genética , Psicosina , Trasplante de Células Madre Hematopoyéticas/métodos , Terapia Genética/métodos , Modelos Animales de Enfermedad
2.
J Allergy Clin Immunol ; 151(2): 547-555.e5, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36456360

RESUMEN

BACKGROUND: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. OBJECTIVE: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. METHODS: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. RESULTS: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). CONCLUSIONS: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.


Asunto(s)
Inmunodeficiencia Combinada Grave , Recién Nacido , Humanos , Lactante , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Estudios Retrospectivos , Estudios Prospectivos , Proteínas de Homeodominio/genética
3.
Blood ; 137(13): 1719-1730, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33150395

RESUMEN

Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in galactocerebrosidase. The only effective treatment is hematopoietic stem cell transplantation (HSCT). Approximately 85% of Krabbe disease cases are the infantile subtypes, among which ∼20% are late infantile. Prior studies have demonstrated that HSCT is effective for early-infantile patients (0-6 months of age) who undergo transplantation while asymptomatic, compared with those receiving transplants while symptomatic. However, no studies evaluated the efficacy of HSCT for late-infantile patients (6-36 months). In this prospective, longitudinal study, patients were evaluated at a single site according to a standardized protocol. Survival analysis was performed using the Kaplan-Meier method. Differences between groups were estimated using mixed regression models to account for within-person repeated measures. Nineteen late-infantile patients underwent HSCT (March 1997 to January 2020). Compared with untreated patients, transplant recipients had a longer survival probability and improved cognitive and language function. Gross and fine motor development were most affected, with variable results. Asymptomatic patients benefitted the most from transplantation, with normal to near-normal development in all domains and some gross motor delays. Among symptomatic patients, those with disease onset at >12 months of age had better cognitive outcomes than untreated patients. Those with disease onset at ≤12 months were comparable to untreated patients. We found that HSCT prolonged the lifespan and improved the functional abilities of late-infantile patients with Krabbe disease, particularly those who underwent transplantation before onset of symptoms. In addition, our findings support prior literature that reclassifies late-infantile Krabbe disease to be symptom onset at 12 to 36 months of age.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucodistrofia de Células Globoides/terapia , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Preescolar , Cognición , Femenino , Humanos , Lactante , Recién Nacido , Desarrollo del Lenguaje , Leucodistrofia de Células Globoides/fisiopatología , Estudios Longitudinales , Masculino , Resultado del Tratamiento
4.
Cytotherapy ; 25(10): 1091-1100, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37422745

RESUMEN

BACKGROUND AIMS: The γδ T-cells (GDT) are a subpopulation of lymphocytes expressing a distinct T-cell receptor coded by the TRG and TRD genes. GDTs may have immunoregulatory function after stem cell transplantation (SCT), but the relationship between GDT clonality and acute graft-versus-host disease (aGVHD) is not known. METHODS: We prospectively studied spectratype complex complexity of TCR Vγ (γ) and TCR Vδ (δ) pre-SCT and at approximately day 100 and day 180 post-SCT in a cohort of immunocompetent children receiving allogeneic umbilical cord blood SCT for nonmalignant diseases, with identical reduced-intensity conditioning and aGVHD prophylaxis. RESULTS: We studied 13 children undergoing SCT at a median age of 0.9 years (total range 0.4-16.6). In those with grade 0-1 aGVHD (N = 10), the spectratype complexity of most γ and δ genes was not significantly different from baseline at day 100 or day 180 post-SCT, and there was balanced expression of genes at the γ and δ loci. In those with grade 3 aGVHD (N = 3), spectratype complexity was significantly below baseline at day 100 and day 180, and there was relative overexpression of δ2. CD3+ cell counts were also lower in participants with grade 3 aGVHD. CONCLUSIONS: Recovery of a polyclonal GDT repertoire is an early part of immunological recovery after SCT. γ and δ gene expression is balanced in young children before and after SCT. Severe aGVHD is associated with GDT oligoclonality post-SCT and with skewed expression of δ2, which has not been previously reported. This association may reflect aGVHD therapy or aGVHD-associated immune dysregulation. Further studies of GDT clonality during the early post-SCT period may establish whether abnormal GDT spectratype precedes the clinical manifestations of aGVHD.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Niño , Preescolar , Lactante , Adolescente , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Trasplante Homólogo , Enfermedad Injerto contra Huésped/genética , Receptores de Antígenos de Linfocitos T , Enfermedad Aguda
5.
Blood ; 133(18): 1977-1988, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-30723080

RESUMEN

Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67 phox , activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)-bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.


Asunto(s)
Síndromes de Inmunodeficiencia/genética , Proteínas de Unión al GTP rac/genética , Adolescente , Adulto , Animales , Preescolar , Citoesqueleto/patología , Femenino , Mutación con Ganancia de Función , Humanos , Lactante , Recién Nacido , Linfopenia/genética , Ratones , Ratones Endogámicos C57BL , Linaje , Proteínas de Unión al GTP rac/inmunología , Proteína RCA2 de Unión a GTP
6.
Cytotherapy ; 22(3): 149-157, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32089448

RESUMEN

Forkhead box P3 (FOXP3)+ regulatory T cell (Treg) reconstitution after unrelated donor umbilical cord blood transplantation in chemotherapy-naïve children is incompletely characterized. We studied 21 children with nonmalignant diseases receiving an identical alemtuzumab-containing regimen. We hypothesized that Treg recovery may be perturbed in patients not only by acute graft-versus-host disease (aGVHD) but also by viremia. Tregs and their memory and naïve subsets were serially monitored for proliferation and apoptosis along with conventional T cells (Tcon). A "reconstitution index" (RI) was calculated relative to pretransplantation values for each parameter. At 3 months post-UCBT, the RI of Tregs was faster compared with other immune components tested and was most rapid in patients free of aGVHD and viremia. There were significantly fewer Tregs in patients experiencing grade I-II aGVHD and/or viremia, leading to an imbalance between Tregs-Tcon ratios. Central and effector memory Tregs were most affected at this time point when they dominated in the circulation. Impaired Treg proliferation without increased apoptosis accounted for the reduced Treg-Tcon ratio. In patients affected with grade II aGVHD and viremia, the overall reduction in circulating Treg pool were associated with a more oligoclonal T-cell receptor ß repertoire. Taken together, aGVHD and viremia can lead to defective Treg expansion homeostasis.


Asunto(s)
Alemtuzumab/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Linfocitos T Reguladores/inmunología , Acondicionamiento Pretrasplante , Viremia/inmunología , Adolescente , Proliferación Celular , Niño , Preescolar , Femenino , Homeostasis , Humanos , Lactante , Subgrupos Linfocitarios/inmunología , Masculino , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Subgrupos de Linfocitos T/inmunología , Viremia/patología
7.
Pediatr Transplant ; 23(2): e13358, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30687992

RESUMEN

Aerosolized ribavirin has been used in pediatric immunocompromised patients to treat acute respiratory viral infections, but oral ribavirin may be a less expensive alternative that allows for outpatient therapy. Oral ribavirin has compared favorably to aerosolized ribavirin in adult studies, but data on safety are lacking in pediatric populations. Four cases are described in which oral ribavirin was used to treat viral respiratory infections in recipients of allogeneic hematopoietic stem cell transplants at a Children's Hospital, demonstrating safety and feasibility.


Asunto(s)
Alemtuzumab/efectos adversos , Antivirales/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/efectos adversos , Infecciones por Paramyxoviridae/tratamiento farmacológico , Ribavirina/administración & dosificación , Acondicionamiento Pretrasplante/efectos adversos , Administración Oral , Alemtuzumab/uso terapéutico , Antivirales/uso terapéutico , Niño , Quimioterapia Combinada , Humanos , Huésped Inmunocomprometido , Inmunosupresores/uso terapéutico , Lactante , Masculino , Infecciones por Paramyxoviridae/inmunología , Ribavirina/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Adulto Joven
8.
Pediatr Blood Cancer ; 64(4)2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27873442

RESUMEN

We describe the safety and feasibility of a forced deflation pulmonary function test (dPFT) in infants and young children. Fifty-two dPFT studies were performed in 26 patients (median age, 1.4 years). Forced vital capacity (FVC) and forced expiratory flow (FEF75 ) were normal in all except one case, but respiratory system compliance (Crs) was reduced in 24% patients. There were no significant differences in pre-blood and marrow transplantation FVC, FEF75 , and Crs between those patients who did and those who did not have posttransplant pulmonary complications. A larger study is needed to determine the prevalence and significance of PFT abnormalities in this age group.


Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Volumen Espiratorio Forzado/fisiología , Enfermedades Pulmonares/terapia , Pruebas de Función Respiratoria/métodos , Insuficiencia Respiratoria/fisiopatología , Niño , Preescolar , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Pronóstico , Insuficiencia Respiratoria/etiología , Tasa de Supervivencia
9.
Biol Blood Marrow Transplant ; 22(9): 1636-1645, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27343716

RESUMEN

Alternative graft sources (umbilical cord blood [UCB], matched unrelated donors [MUD], or mismatched unrelated donors [MMUD]) enable patients without a matched sibling donor to receive potentially curative hematopoietic cell transplantation (HCT). Retrospective studies demonstrate comparable outcomes among different graft sources. However, the risk and types of infections have not been compared among graft sources. Such information may influence the choice of a particular graft source. We compared the incidence of bacterial, viral, and fungal infections in 1781 adults with acute leukemia who received alternative donor HCT (UCB, n= 568; MUD, n = 930; MMUD, n = 283) between 2008 and 2011. The incidences of bacterial infection at 1 year were 72%, 59%, and 65% (P < .0001) for UCB, MUD, and MMUD, respectively. Incidences of viral infection at 1 year were 68%, 45%, and 53% (P < .0001) for UCB, MUD, and MMUD, respectively. In multivariable analysis, bacterial, fungal, and viral infections were more common after either UCB or MMUD than after MUD (P < .0001). Bacterial and viral but not fungal infections were more common after UCB than MMUD (P = .0009 and <.0001, respectively). The presence of viral infection was not associated with an increased mortality. Overall survival (OS) was comparable among UCB and MMUD patients with Karnofsky performance status (KPS) ≥ 90% but was inferior for UCB for patients with KPS < 90%. Bacterial and fungal infections were associated with poorer OS. Future strategies focusing on infection prevention and treatment are indicated to improve HCT outcomes.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones/etiología , Leucemia/complicaciones , Leucemia/terapia , Enfermedad Aguda , Adolescente , Adulto , Anciano , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Trasplante de Células Madre de Sangre del Cordón Umbilical/mortalidad , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Histocompatibilidad , Humanos , Incidencia , Infecciones/mortalidad , Leucemia/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Donante no Emparentado , Adulto Joven
11.
Blood ; 121(26): 5113-23, 2013 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-23610374

RESUMEN

Virus-specific T cell (VST) lines could provide useful antiviral prophylaxis and treatment of immune-deficient patients if it were possible to avoid the necessity of generating a separate line for each patient, often on an emergency basis. We prepared a bank of 32 virus-specific lines from individuals with common HLA polymorphisms who were immune to Epstein-Barr virus (EBV), cytomegalovirus, or adenovirus. A total of 18 lines were administered to 50 patients with severe, refractory illness because of infection with one of these viruses after hematopoietic stem cell transplant. The cumulative rates of complete or partial responses at 6 weeks postinfusion were 74.0% (95% CI, 58.5%-89.5%) for the entire group (n = 50), 73.9% (95% CI, 51.2% -96.6%) for cytomegalovirus (n = 23), 77.8% for adenovirus (n = 18), and 66.7% (95% CI, 36.9%-96.5%) for EBV (n = 9). Only 4 responders had a recurrence or progression. There were no immediate infusion-related adverse events, and de novo graft-versus-host disease developed in only 2 patients. Despite the disparity between the lines and their recipients, the mean frequency of VSTs increased significantly postinfusion, coincident with striking decreases in viral DNA and resolution of clinical symptoms. The use of banked third-party VSTs is a feasible and safe approach to rapidly treat severe or intractable viral infections after stem cell transplantation. This study is registered at www.clinicaltrials.gov as NCT00711035.


Asunto(s)
Infecciones por Adenoviridae/prevención & control , Infecciones por Citomegalovirus/prevención & control , Infecciones por Virus de Epstein-Barr/prevención & control , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfocitos T Citotóxicos/inmunología , Adenoviridae/patogenicidad , Infecciones por Adenoviridae/etiología , Adolescente , Adulto , Citomegalovirus/patogenicidad , Infecciones por Citomegalovirus/etiología , Infecciones por Virus de Epstein-Barr/etiología , Femenino , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virología , Herpesvirus Humano 4/patogenicidad , Humanos , Masculino , Pronóstico , Trasplante Homólogo
12.
Pediatr Blood Cancer ; 62(12): 2216-22, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26291959

RESUMEN

BACKGROUND: X-linked hyper-IgM syndrome (X-HIGM) due to mutations in the gene encoding CD40 ligand results in failure of Ig class switching and an increased propensity for recurrent sinopulmonary and other infections, and thus decreased life expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) is curative, but long-term follow-up data are limited. PROCEDURES: We conducted a retrospective analysis of seven patients who have undergone allogeneic HSCT for HIGM syndrome at Duke University Medical Center. RESULTS: Median age at transplant was 5.2 years (range 0.7-19.3). None of the patients had active hepatic or pulmonary disease immediately prior to transplant, but all had a history of serious infections. Five patients received myeloablative conditioning, and two patients received reduced intensity conditioning. Graft sources included bone marrow, peripheral blood, and unrelated umbilical cord blood. Post-transplantation complications included veno-occlusive disease, hemorrhagic cystitis, adenoviremia, and cryptosporidium recurrence in one patient each. Two patients developed acute GVHD grades II-IV that resolved promptly with treatment and none developed extensive chronic GVHD. All patients are intravenous IgG-independent and 6/7 have normal antibody titers. Immunoglobulin (Ig) A levels normalized in all but one patient and T and B cell numbers and function are otherwise normal in all. All patients are alive at a median follow-up of 9.7 (range 9.7-16.1) years post-transplantation with predominantly donor chimerism and no recurrent infections. CONCLUSIONS: Allogeneic HSCT results in excellent survival and sustained immune reconstitution in patients with CD40 ligand deficiency using both myeloablative and reduced intensity conditioning approaches and various graft sources, including bone marrow, peripheral blood, and umbilical cord blood.


Asunto(s)
Ligando de CD40/deficiencia , Trasplante de Células Madre Hematopoyéticas , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/terapia , Recuperación de la Función/inmunología , Acondicionamiento Pretrasplante , Infecciones por Adenoviridae/tratamiento farmacológico , Infecciones por Adenoviridae/etiología , Infecciones por Adenoviridae/inmunología , Infecciones por Adenoviridae/mortalidad , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Criptosporidiosis/tratamiento farmacológico , Criptosporidiosis/etiología , Criptosporidiosis/inmunología , Criptosporidiosis/mortalidad , Cistitis/tratamiento farmacológico , Cistitis/etiología , Cistitis/inmunología , Cistitis/mortalidad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/inmunología , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/mortalidad , Inmunoglobulinas Intravenosas/administración & dosificación , Lactante , Masculino , Enfermedad Veno-Oclusiva Pulmonar/tratamiento farmacológico , Enfermedad Veno-Oclusiva Pulmonar/etiología , Enfermedad Veno-Oclusiva Pulmonar/inmunología , Enfermedad Veno-Oclusiva Pulmonar/mortalidad , Estudios Retrospectivos
13.
J Allergy Clin Immunol ; 133(2): 335-47, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24139498

RESUMEN

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.


Asunto(s)
Síndromes de Inmunodeficiencia , Trasplante de Células Madre Hematopoyéticas , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/terapia , Recién Nacido , Tamizaje Neonatal , Proyectos Piloto , Sociedades Científicas
14.
Biol Blood Marrow Transplant ; 20(3): 326-36, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24296492

RESUMEN

Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).


Asunto(s)
Anemia de Diamond-Blackfan/terapia , Inmunodeficiencia Variable Común/terapia , Trasplante de Células Madre de Sangre del Cordón Umbilical , Hemoglobinopatías/terapia , Enfermedades Metabólicas/terapia , Acondicionamiento Pretrasplante/métodos , Anemia de Diamond-Blackfan/inmunología , Anemia de Diamond-Blackfan/mortalidad , Antineoplásicos/uso terapéutico , Niño , Preescolar , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/mortalidad , Femenino , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/inmunología , Hemoglobinopatías/inmunología , Hemoglobinopatías/mortalidad , Humanos , Lactante , Masculino , Enfermedades Metabólicas/inmunología , Enfermedades Metabólicas/mortalidad , Análisis de Supervivencia , Quimera por Trasplante , Trasplante Homólogo , Donante no Emparentado
16.
Blood ; 117(2): 530-41, 2011 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-20962324

RESUMEN

Regulatory B cells control inflammation and autoimmunity in mice, including the recently identified IL-10-competent B10 cell subset that represents 1% to 3% of spleen B cells. In this study, a comparable IL-10-competent B10 cell subset was characterized in human blood. B10 cells were functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of ex vivo stimulation, whereas progenitor B10 (B10pro) cells required 48 hours of in vitro stimulation before they acquired the ability to express IL-10. B10 and B10pro cells represented 0.6% and approximately 5% of blood B cells, respectively. Ex vivo B10 and B10pro cells were predominantly found within the CD24(hi)CD27(+) B-cell subpopulation that was able to negatively regulate monocyte cytokine production through IL-10-dependent pathways during in vitro functional assays. Blood B10 cells were present in 91 patients with rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis, and were expanded in some cases as occurs in mice with autoimmune disease. Mean B10 + B10pro-cell frequencies were also significantly higher in patients with autoimmune disease compared with healthy controls. The characterization of human B10 cells will facilitate their identification and the study of their regulatory activities during human disease.


Asunto(s)
Enfermedades Autoinmunes/sangre , Subgrupos de Linfocitos B/inmunología , Interleucina-10/inmunología , Células Precursoras de Linfocitos B/inmunología , Adolescente , Adulto , Anciano , Animales , Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos B/citología , Separación Celular , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Interleucina-10/metabolismo , Ratones , Persona de Mediana Edad , Células Precursoras de Linfocitos B/citología , Adulto Joven
17.
Transplant Cell Ther ; 29(8): 517.e1-517.e12, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37120136

RESUMEN

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for hematologic malignancies and nonmalignant disorders. Rapid immune reconstitution (IR) following allogeneic HCT has been shown to be associated with improved clinical outcomes and lower infection rates. A global phase 3 trial (ClinicalTrials.gov NCT02730299) of omidubicel, an advanced cell therapy manufactured from an appropriately HLA-matched single umbilical cord blood (UCB) unit, showed faster hematopoietic recovery, reduced rates of infection, and shorter hospitalizations in patients randomized to omidubicel compared with those randomized to standard UCB. This optional, prospective substudy of the global phase 3 trial characterized the IR kinetics following HCT with omidubicel compared with UCB in a systematic and detailed manner. This substudy included 37 patients from 14 global sites (omidubicel, n = 17; UCB, n = 20). Peripheral blood samples were collected at 10 predefined time points from 7 to 365 days post-HCT. Flow cytometry immunophenotyping, T cell receptor excision circle quantification, and T cell receptor sequencing were used to evaluate the longitudinal IR kinetics post-transplantation and their association with clinical outcomes. Patient characteristics in the 2 comparator cohorts were overall statistically similar except for age and total body irradiation (TBI)-based conditioning regimens. The median patient age was 30 years (range, 13 to 62 years) for recipients of omidubicel and 43 years (range, 19 to 55 years) for UCB recipients. A TBI-based conditioning regimen was used in 47% of omidubicel recipients and in 70% of UCB recipients. Graft characteristics differed in their cellular composition. Omidubicel recipients received a 33-fold higher median dose of CD34+ stem cells and one-third of the median CD3+ lymphocyte dose infused to UCB recipients. Compared with UCB recipients, omidubicel recipients exhibited faster IR of all measured lymphoid and myelomonocytic subpopulations, predominantly in the first 14 days post-transplantation. This effect involved circulating natural killer (NK) cells, helper T (Th) cells, monocytes, and dendritic cells, with superior long-term B cell recovery from day +28. At 1 week post-HCT, omidubicel recipients exhibited 4.1- and 7.7 -fold increases in the median Th cell and NK cell counts, respectively, compared to UCB recipients. By 3 weeks post-HCT, omidubicel recipients were 3-fold more likely to achieve clinically relevant Th cell and NK cell counts ≥100 cells/µL. Similar to UCB, omidubicel yielded a balanced cellular subpopulation composition and diverse T cell receptor repertoire in both the short term and the long term. Omidubicel's CD34+ cell content correlated with faster IR by day +7 post-HCT, which in turn coincided with earlier hematopoietic recovery. Finally, early NK and Th cell reconstitution correlated with a decreased rate of post-HCT viral infections, suggesting a plausible explanation for this phenomenon among omidubicel recipients in the phase 3 study. Our findings suggest that omidubicel efficiently promotes IR across multiple immune cells, including CD4+ T cells, B cells, NK cells, and dendritic cell subtypes as early as 7 days post-transplantation, potentially endowing recipients of omidubicel with early protective immunity.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune , Adolescente , Adulto , Humanos , Persona de Mediana Edad , Adulto Joven , Antivirales , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Estudios Prospectivos , Trasplante Homólogo/efectos adversos
18.
Biol Blood Marrow Transplant ; 18(1): 6-15, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22100979

RESUMEN

Defective immune reconstitution is a major barrier to successful hematopoietic cell transplantation (HCT), and has important implications in the pediatric population. There are many factors that affect immune recovery, including stem cell source and graft-versus-host disease (GVHD). Complete assessment of immune recovery, including T and B lymphocyte evaluation, innate immunity, and response to neoantigens, may provide insight as to infection risk and optimal time for immunizations. The increasing use of cord blood grafts requires additional study regarding early reconstitution and impact upon survival. Immunization schedules may require modification based upon stem cell source and immune reconstitution, and this is of particular importance as many children have been incompletely immunized, or not at all, before school entry. Additional studies are needed in children post-HCT to evaluate the impact of differing stem cell sources upon immune reconstitution, infectious risks, and immunization responses.


Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Síndromes de Inmunodeficiencia/etiología , Sangre Fetal , Humanos , Síndromes de Inmunodeficiencia/inmunología
19.
Biol Blood Marrow Transplant ; 18(9): 1438-45, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22430083

RESUMEN

It is uncertain whether late mortality rates after hematopoietic cell transplantation for severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency diseases (non-SCID PIDD), and inborn errors of metabolism (IEM) return to rates observed in the general population, matched for age, sex, and nationality. We studied patients with SCID (n = 201), non-SCID PIDD (n = 405), and IEM (n = 348) who survived for at least 2 years after transplantation with normal T cell function (SCID) or >95% donor chimerism (non-SCID PIDD and IEM). Importantly, mortality rate was significantly higher in these patients compared with the general population for several years after transplantation. The rate decreased toward the normal rate in patients with SCID and non-SCID PIDD beyond 6 years after transplantation, but not in patients with IEM. Active chronic graft-versus-host disease at 2 years was associated with increased risk of late mortality for all diseases (hazard ratio [HR], 1.87; P = .05). In addition, late mortality was higher in patients with non-SCID PIDD who received T cell-depleted grafts (HR 4.16; P = .007) and in patients with IEM who received unrelated donor grafts (HR, 2.72; P = .03) or mismatched related donor grafts (HR, 3.76; P = .01). The finding of higher mortality rates in these long-term survivors for many years after transplantation confirms the need for long-term surveillance.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia/mortalidad , Errores Innatos del Metabolismo/mortalidad , Inmunodeficiencia Combinada Grave/mortalidad , Acondicionamiento Pretrasplante , Adolescente , Niño , Preescolar , Enfermedad Crónica , Europa (Continente) , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/terapia , Lactante , Cooperación Internacional , Masculino , Errores Innatos del Metabolismo/inmunología , Errores Innatos del Metabolismo/terapia , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/terapia , Análisis de Supervivencia , Factores de Tiempo , Quimera por Trasplante , Trasplante Homólogo , Estados Unidos , Donante no Emparentado
20.
Biol Blood Marrow Transplant ; 18(11): 1664-1676.e1, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22698485

RESUMEN

Immunologic reconstitution after allogeneic hematopoietic cell transplantation is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients after a dual UCB (n = 29) and matched sibling donor (n = 33) or matched unrelated donor (n = 33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of matched sibling donor and matched unrelated donor recipients. Significantly lower levels of CD3+, CD4+, and CD8+ T cells were observed in UCB recipients until 6 months after transplantation. Lower levels of regulatory T cells persisted until 1 year after transplantation. Thymopoiesis as measured by TCR rearrangement excision circle was comparable among all recipients by 6 months after transplantation. In a subset of patients 1 year after transplantation with similar levels of circulating T cells and TCR rearrangement excision circle, there was no difference in TCR diversity. Compared to HLA-identical matched sibling donor and matched unrelated donor adult hematopoietic cell transplantation recipients, quantitative lymphoid recovery in UCB transplantation recipients is slower in the first 3 months, but these differences disappeared by 6 to 12 months after transplantation.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Agonistas Mieloablativos/uso terapéutico , Recuperación de la Función/inmunología , Acondicionamiento Pretrasplante , Adulto , Antígenos CD/inmunología , Femenino , Supervivencia de Injerto , Prueba de Histocompatibilidad , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Hermanos , Linfocitos T/inmunología , Trasplante Homólogo , Donante no Emparentado
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