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1.
Artigo em Inglês | MEDLINE | ID: mdl-31775018

RESUMO

We describe the first case of MAN2B2 deficiency in a patient with immune dysregulation, developmental delay, and stroke. Altered mannosylation profile was restored in patient cells upon transduction of wild-type MAN2B2.

2.
J Clin Immunol ; 39(7): 653-667, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376032

RESUMO

INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking. METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016. RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT. CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

4.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

5.
Cell Stem Cell ; 23(6): 775-776, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30526877

RESUMO

In this issue of Cell Stem Cell, Petrillo et al. (2018) improve lentiviral transduction of hematopoietic stem cells (HSCs) by using cyclosporine H to relieve viral entry restriction by interferon-induced transmembrane protein 3 (IFITM3). This finding promises to enhance the efficiency of ex vivo therapeutic gene transfer and gene editing of HSCs.


Assuntos
Edição de Genes , Lentivirus/genética , Ciclosporina , Células-Tronco Hematopoéticas , Humanos , Imunidade Inata , Proteínas de Membrana , Proteínas de Ligação a RNA
6.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the DOCK8 gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8 deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range: 0.7-27.2) between 1995 and 2015. After median follow-up of 26 months (3-135), 68 of 81 patients are alive (84%). Severe acute (III-IV) or chronic graft versus host disease (GVHD) occurred in 11% and 10% respectively. Causes of death wereinfections (n=5), GVHD (5), multi-organ failure (2) and pre-existent lymphoma (1). Survival after matched related (n=40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared to fully myeloablative busulfan-based regimens (97% vs. 78%; p=0.049). 96% of patients aged <8 years at HSCT survived, compared to 78% of those ≥8 years (p=0.06). Of 73 patients with chimerism data available, 65 (89%) had >90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections and Mollusca resolved better than food allergies or failure to thrive. CONCLUSION: HSCT is curative in most DOCK8 deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced toxicity regimen may offer the best chance for survival.

7.
Genome Med ; 10(1): 70, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30261899

RESUMO

BACKGROUND: Mutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction. METHODS: Here we interrogate T cell reconstitution using four forms of high throughput analysis. (1) Estimation of the numbers of transduced progenitor cells by monitoring unique positions of integration of the therapeutic gene transfer vector. (2) Estimation of T cell population structure by sequencing of the recombined T cell receptor (TCR) beta locus. (3) Metagenomic analysis of microbial populations in oropharyngeal, nasopharyngeal, and gut samples. (4) Metagenomic analysis of viral populations in gut samples. RESULTS: Comparison of progenitor and mature T cell populations allowed estimation of a minimum number of cell divisions needed to generate the observed populations. Analysis of microbial populations showed the effects of immune reconstitution, including normalization of gut microbiota and clearance of viral infections. Metagenomic analysis revealed enrichment of genes for antibiotic resistance in gene-corrected subjects relative to healthy controls, likely a result of higher healthcare exposure. CONCLUSIONS: This multi-omic approach enables the characterization of multiple effects of SCID-X1 gene therapy, including T cell repertoire reconstitution, estimation of numbers of cell divisions between progenitors and daughter T cells, normalization of the microbiome, clearance of microbial pathogens, and modulations in antibiotic resistance gene levels. Together, these results quantify several aspects of the long-term efficacy of gene therapy for SCID-X1. This study includes data from ClinicalTrials.gov numbers NCT01410019, NCT01175239, and NCT01129544.

9.
Blood ; 132(13): 1438-1451, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-29997222

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced-intensity conditioning with melphalan, fludarabine, and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary end point was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow-up of 20 months, the 1-year OS for transplanted patients was 80.4% (90% confidence interval [CI], 68.6%-88.2%). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI, 52.9%-77.3%). Two patients experienced primary graft failure, and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion [DLI]). At 1 year, the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI, 25.2%-54.6%), and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI, 45.4 %-74.9%). The day 100 incidence of grade II to IV acute GVHD was 17.4% (95% CI, 8.1%-29.7%), and 1-year incidence of chronic GVHD was 26.7% (95% CI, 14.6%-40.4%). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).

11.
Nat Commun ; 9(1): 1779, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29725003

RESUMO

Mutations in Wiskott-Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. The generation and function of anti-inflammatory macrophages are defective in both human and mice in the absence of WASP. Expression of WASP specifically in macrophages, but not in dendritic cells, is critical for regulation of colitis development. Importantly, transfer of WT anti-inflammatory macrophages prevents the development of colitis. DOCK8-deficient macrophages phenocopy the altered macrophage properties associated with WASP deficiency. Mechanistically, we show that both WASP and DOCK8 regulates macrophage function by modulating IL-10-dependent STAT3 phosphorylation. Overall, our study indicates that anti-inflammatory macrophage function and mucosal immune tolerance require both WASP and DOCK8, and that IL-10 signalling modulates a WASP-DOCK8 complex.

12.
Blood ; 131(26): 2967-2977, 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29728406

RESUMO

Allogeneic hematopoietic stem cell transplant (HSCT) typically results in donor T-cell engraftment and function in patients with severe combined immunodeficiency (SCID), but humoral immunity, particularly when using donors other than matched siblings, is variable. B-cell function after HSCT for SCID depends on the genetic cause, the use of pre-HSCT conditioning, and whether donor B-cell chimerism is achieved. Patients with defects in IL2RG or JAK3 undergoing HSCT without conditioning often have poor B-cell function post-HSCT, perhaps as a result of impairment of IL-21 signaling in host-derived B cells. To investigate the effect of pre-HSCT conditioning on B-cell function, and the relationship of in vitro B-cell function to clinical humoral immune status, we analyzed 48 patients with IL2RG/JAK3 SCID who were older than 2 years after HSCT with donors other than matched siblings. T follicular helper cells (TFH) developed in these patients with kinetics similar to healthy young children; thus, poor B-cell function could not be attributed to a failure of TFH development. In vitro differentiation of B cells into plasmablasts and immunoglobulin secretion in response to IL-21 strongly correlated with the use of conditioning, donor B-cell engraftment, freedom from immunoglobulin replacement, and response to tetanus vaccine. Patients receiving immunoglobulin replacement who had normal serum immunoglobulin M showed poor response to IL-21 in vitro, similar to those with low serum IgM. In vitro response of B cells to IL-21 may predict clinically relevant humoral immune function in patients with IL2RG/JAK3 SCID after HSCT.

13.
Blood ; 131(21): 2335-2344, 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29653965

RESUMO

Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, CD3D, CD3E, and CD3Z gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in CD3G associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor ß (TRB) repertoire in regulatory T cells (Tregs), conventional CD4+ (Tconv), and CD8+ T cells from 6 patients with CD3G mutations and healthy controls. Treg function was assessed by studying its ability to suppress proliferation of Tconv cells. Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.

15.
Blood ; 130(25): 2718-2727, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29021228

RESUMO

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/µL, CD8 < 50 cells/µL, CD45RA < 10%, or a restricted Vß T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Reconstituição Imune , Imunodeficiência Combinada Severa/terapia , Pré-Escolar , Feminino , Genótipo , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Reconstituição Imune/genética , Lactente , Recém-Nascido , Infecção/etiologia , Masculino , Triagem Neonatal , Estudos Prospectivos , Fatores de Risco , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/mortalidade , Análise de Sobrevida , Doadores de Tecidos
16.
Front Immunol ; 8: 798, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769923

RESUMO

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

17.
Biol Blood Marrow Transplant ; 23(10): 1701-1713, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28684371

RESUMO

A prospective multicenter study was conducted to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of fludarabine plasma (f-ara-a) and intracellular triphosphate (f-ara-ATP) in children undergoing hematopoietic cell transplantation (HCT) and receiving fludarabine with conditioning. Plasma and peripheral blood mononuclear cells (PBMCs) were collected over the course of therapy for quantitation of f-ara-a and f-ara-ATP. Nonlinear mixed-effects modeling was used to develop the PK model, including identification of covariates impacting drug disposition. Data from a total of 133 children (median age, 5 years; range, .2 to 17.9) undergoing HCT for a variety of malignant and nonmalignant disorders were available for PK-PD modeling. The implementation of allometric scaling of PK parameters alone was insufficient to describe drug clearance, particularly in very young children. Renal impairment was predicted to increase drug exposure across all ages. The rate of f-ara-a entry into PBMCs (expressed in pmoles per million cells) decreased over the course of therapy, resulting in 78% lower f-ara-ATP after the fourth dose (1.7 pmoles/million cells [range, .2 to 7.2]) compared with first dose (7.9 pmoles/million cells [range, .7 to 18.2]). The overall incidence of treatment-related mortality (TRM) was low at 3% and 8% at days 60 and 360, respectively, and no association with f-ara-a exposure and TRM was found. In the setting of malignancy, disease-free survival was highest at 1 year after HCT in subjects achieving a systemic f-ara-a cumulative area under the curve (cAUC) greater than 15 mg*hour/L compared to patients with a cAUC less than 15 mg*hour/L (82.6% versus 52.8% P = .04). These results suggest that individualized model-based dosing of fludarabine in infants and young children may reduce morbidity and mortality through improved rates of disease-free survival and limiting drug-related toxicity. ClinicalTrials.gov Identifier: NCT01316549.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Modelagem Computacional Específica para o Paciente , Vidarabina/análogos & derivados , Adolescente , Arabinonucleotídeos , Biomarcadores Farmacológicos , Criança , Pré-Escolar , Intervalo Livre de Doença , Humanos , Lactente , Taxa de Depuração Metabólica , Medicina de Precisão , Estudos Prospectivos , Transplantados , Condicionamento Pré-Transplante/métodos , Vidarabina/administração & dosagem , Vidarabina/farmacocinética , Vidarabina/uso terapêutico , Vidarabina/toxicidade
18.
Rev. méd. hondur ; 85(1-2): 27-29, ene.-jun. 2017.
Artigo em Espanhol | LILACS | ID: biblio-884083

RESUMO

Introducción. Las inmunodeficiencias primarias son un grupo de enfermedades de origen genético que implican altera - ciones asociadas a la respuesta inmunológica. El infra diagnóstico de estas conlleva al retraso de tratamiento, evitables en gran parte; Entre estas existe el síndrome de Wiskott-Aldrich; es un trastorno raro, ligado al cromosoma X, recesivo, que se caracteriza por trom - bocitopenia, eczema e inmunodeficiencia donde su tratamiento curativo es el trasplante de medula ósea. CASO CLÍNICO : Paciente de 10 años, con antecedentes de múltiples hospitalizaciones por procesos infecciosos importantes: neumonías recurrentes, menin - gitis, diarreas, erupción cutánea generalizada y trombocitopenia de hasta 9,000 mm³. Después de múltiples estudios realizados, se confirma el diagnóstico de síndrome de Wiskott -Aldrich por inmunogenetica (mutación del gen WAS) y mediante colaboración médica internacional, se realiza trasplante de médula ósea con posterior resolución de su enfermedad. DISCUSION: Las inmunodeficiencias primarias son patologías más comunes de lo que se creía (prevalencia de hasta 1/1200), la evidencia de aparición y su importancia clínica deben ser tomadas en consideración. En este caso de Síndrome de Wiskot-Aldrich en donde el diagnóstico definitivo es in - munogenetico, (actualmente el país no cuenta), además de tratamiento inmuno-oncológico adecuado, el paciente pudo sobrevivir y mejorar su calidad de vida gracias a soporte investigativo y terapéutico multinacional. Existen colaboraciones multicentricas como el consorcio de tratamiento inmunodeficiencias primarias, que tienen como objetivo colaborar activamente en el diagnóstico y tratamien - to estos casos, salvaguardando la vida de estos pacientes y ayudando a comprender estas enfermedades raras...(AU)


Assuntos
Humanos , Doenças Autoimunes , Transplante de Medula Óssea/métodos , Trombocitopenia/complicações , Síndrome de Wiskott-Aldrich/diagnóstico , Cromossomo X
19.
Blood ; 129(21): 2928-2938, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28331055

RESUMO

Reticular dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis, and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease. Retrospective data on clinical presentation, genetics, and outcome of HSCT were collected from centers in Europe, Asia, and North America for a total of 32 patients born between 1982 and 2011. Age at presentation was <4 weeks in 30 of 32 patients (94%). Grafts originated from mismatched family donors in 17 patients (55%), from matched family donors in 6 patients (19%), and from unrelated marrow or umbilical cord blood donors in 8 patients (26%). Thirteen patients received secondary or tertiary transplants. After transplantation, 21 of 31 patients were reported alive at a mean follow-up of 7.9 years (range: 0.6-23.6 years). All patients who died beyond 6 months after HSCT had persistent or recurrent agranulocytosis due to failure of donor myeloid engraftment. In the absence of conditioning, HSCT was ineffective to overcome agranulocytosis, and inclusion of myeloablative components in the conditioning regimens was required to achieve stable lymphomyeloid engraftment. In comparison with other SCID entities, considerable differences were noted regarding age at presentation, onset, and type of infectious complications, as well as the requirement of conditioning prior to HSCT. Although long-term survival is possible in the presence of mixed chimerism, high-level donor myeloid engraftment should be targeted to avoid posttransplant neutropenia.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Leucopenia/mortalidade , Leucopenia/terapia , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Condicionamento Pré-Transplante , Doadores não Relacionados , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Adolescente , Adulto , Idade de Início , Aloenxertos , Criança , Intervalo Livre de Doença , Feminino , Humanos , Leucopenia/enzimologia , Leucopenia/genética , Masculino , Imunodeficiência Combinada Severa/enzimologia , Imunodeficiência Combinada Severa/genética , Taxa de Sobrevida
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