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1.
J Allergy Clin Immunol ; 139(4): 1282-1292, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27697500

RESUMO

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tempo , Adulto Jovem
2.
Curr Gene Ther ; 15(4): 416-27, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25981636

RESUMO

We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.


Assuntos
Terapia Genética/métodos , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Aspergilose/terapia , Aspergillus nidulans/patogenicidade , Criança , Deleção Cromossômica , Cromossomos Humanos Par 7 , Proteínas de Ligação a DNA/genética , Gammaretrovirus/genética , Terapia Genética/efeitos adversos , Humanos , Proteína do Locus do Complexo MDS1 e EVI1 , Masculino , Glicoproteínas de Membrana/genética , Síndromes Mielodisplásicas/etiologia , NADPH Oxidase 2 , NADPH Oxidases/genética , Proto-Oncogenes/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética
3.
Pediatr Allergy Immunol ; 25(4): 300-13, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24383740

RESUMO

The study of human T-cell PIDs with Mendelian inheritance has enabled the molecular characterization of important key functions and pathways in T-cell biology. In most cases, T-cell PIDs become apparent as combined T- and B-cell deficiencies. Severe combined immunodeficiencies (SCIDs) are characterized by a complete lack of T-cell development and, in some cases, a developmental block in other lymphoid lineages and manifest within the first year of life. Combined immunodeficiency syndromes (CIDs) result from hypomorphic mutations in typical SCID associated genes or from partial defects of T-cell development and manifest later in childhood by increased susceptibility to infection often combined with disturbances in immune homeostasis, e.g., autoimmunity and increased incidence in lymphoproliferation. The discovery of mutations and characterization of the cellular changes that underlie lymphocyte defects and immune dysregulation have led to novel, specific, successful therapies for severe diseases which are often fatal if left untreated. Over the last few years, impressive progress has been made in understanding the disease mechanisms of T-cell immunodeficiencies and in improving the long-term outcomes of potentially curative treatments, including gene therapy.


Assuntos
Terapia Genética , Síndromes de Imunodeficiência/terapia , Subunidade gama Comum de Receptores de Interleucina/genética , Linfócitos T/imunologia , Adenosina Desaminase/genética , Criança , Rearranjo Gênico do Linfócito T/genética , Terapia Genética/tendências , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Imunossupressão/tendências , Mutação/genética , Linfócitos T/transplante
4.
Lancet ; 383(9915): 436-48, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24161820

RESUMO

BACKGROUND: In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. METHODS: This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants <9 kg 1·2 mg/kg]; one dose per day on days -8 to -3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days -4 to -1; or thymoglobuline 2·5 mg/kg, one dose per day on days -5 to -3]; or low-dose alemtuzumab [<1 mg/kg on days -8 to -6]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/L × h). Busulfan was administered mainly intravenously and exceptionally orally from days -5 to -3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. FINDINGS: 56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients. INTERPRETATION: This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease. FUNDING: None.


Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Alemtuzumab , Anticorpos Monoclonais Humanizados/administração & dosagem , Soro Antilinfocitário/administração & dosagem , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Quimioterapia Combinada , Sobrevivência de Enxerto/efeitos dos fármacos , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA , Humanos , Imunossupressores/administração & dosagem , Lactente , Estudos Prospectivos , Quimeras de Transplante/fisiologia , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto Jovem
5.
J Clin Immunol ; 33(6): 1078-87, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23657403

RESUMO

The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician's observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.


Assuntos
Síndromes de Imunodeficiência/classificação , Síndromes de Imunodeficiência/diagnóstico , Guias de Prática Clínica como Assunto , Algoritmos , Diagnóstico Diferencial , Testes Diagnósticos de Rotina/normas , Genótipo , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Testes Imunológicos/métodos , Fenótipo
6.
Hum Gene Ther Methods ; 24(3): 151-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23489116

RESUMO

Targeting transgene expression to specific hematopoietic cell lineages could contribute to the safety of retroviral vectors in gene therapeutic applications. Chronic granulomatous disease (CGD), a defect of phagocytic cells, can be managed by gene therapy, using retroviral vectors with targeted expression to myeloid cells. In this context, we analyzed the myelospecificity of the human miR223 promoter, which is known to be strongly upregulated during myeloid differentiation, to drive myeloid-restricted expression of p47(phox) and gp91(phox) in mouse models of CGD and in primary patient-derived cells. The miR223 promoter restricted the expression of p47(phox), gp91(phox), and green fluorescent protein (GFP) within self-inactivating (SIN) gamma- and lentiviral vectors to granulocytes and macrophages, with only marginal expression in lymphocytes or hematopoietic stem and progenitor cells. Furthermore, gene transfer into primary CD34+ cells derived from a p47(phox) patient followed by ex vivo differentiation to neutrophils resulted in restoration of Escherichia coli killing activity by miR223 promoter-mediated p47(phox) expression. These results indicate that the miR223 promoter as an internal promoter within SIN gene therapy vectors is able to efficiently correct the CGD phenotype with negligible activity in hematopoietic progenitors, thereby limiting the risk of insertional oncogenesis and development of clonal dominance.


Assuntos
Terapia Genética/métodos , Doença Granulomatosa Crônica/terapia , MicroRNAs/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Escherichia coli/isolamento & purificação , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Granulócitos/imunologia , Granulócitos/metabolismo , Granulócitos/microbiologia , Doença Granulomatosa Crônica/metabolismo , Doença Granulomatosa Crônica/patologia , Humanos , Lentivirus/genética , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , NADPH Oxidase 2 , NADPH Oxidases/deficiência , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Fagocitose , Regiões Promotoras Genéticas
8.
Curr Opin Immunol ; 24(5): 585-91, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22909900

RESUMO

Gene therapy has become an attractive alternative therapeutic strategy to allogeneic transplant for primary immunodeficiencies (PIDs) owing to known genetic defects. Clinical trials using gammaretroviral vectors have demonstrated the proof of principle of gene therapy for Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD), but have also highlighted limitations of the technology. New strategies based on vectors that can achieve more robust correction with less risk of insertional mutagenesis are being developed. In this review we present the status of gene therapy for WAS and CGD, and discuss the emerging application of similar strategies to a broader range of PIDs, such as IPEX syndrome.


Assuntos
Terapia Genética/métodos , Terapia Genética/tendências , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Animais , Ensaios Clínicos como Assunto/tendências , Síndrome de Exfoliação/genética , Síndrome de Exfoliação/imunologia , Síndrome de Exfoliação/terapia , Previsões/métodos , Técnicas de Transferência de Genes/tendências , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Vetores Genéticos/uso terapêutico , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/terapia , Humanos , Síndromes de Imunodeficiência/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/imunologia , Síndrome de Wiskott-Aldrich/terapia
9.
Stem Cells ; 30(4): 599-611, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22311747

RESUMO

Chronic granulomatous disease (CGD) is an inherited disorder of phagocytes in which NADPH oxidase is defective in generating reactive oxygen species. In this study, we reprogrammed three normal unrelated patient's fibroblasts (p47(phox) and gp91(phox) ) to pluripotency by lentiviral transduction with defined pluripotency factors. These induced pluripotent stem cells (iPSC) share the morphological features of human embryonic stem cells, express the key pluripotency factors, and possess high telomerase activity. Furthermore, all the iPSC lines formed embryoid bodies in vitro containing cells originating from all three germ layers and were capable of teratoma formation in vivo. They were isogenic with the original patient fibroblasts, exhibited normal karyotype, and retained the p47(phox) or gp91(pho) (x) mutations found in the patient fibroblasts. We further demonstrated that these iPSC could be differentiated into monocytes and macrophages with a similar cytokine profile to blood-derived macrophages under resting conditions. Most importantly, CGD-patient-specific iPSC-derived macrophages showed normal phagocytic properties but lacked reactive oxygen species production, which correlates with clinical diagnosis of CGD in the patients. Together these results suggest that CGD-patient-specific iPSC lines represent an important tool for modeling CGD disease phenotypes, screening candidate drugs, and the development of gene therapy.


Assuntos
Técnicas de Cultura de Células/métodos , Doença Granulomatosa Crônica/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Modelos Biológicos , Diferenciação Celular , Linhagem Celular , Citocinas/metabolismo , Humanos , Cariotipagem , Cinética , Macrófagos/citologia , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/metabolismo , NADPH Oxidases/metabolismo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo
10.
Pediatr Allergy Immunol ; 22(8): 758-69, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22122788

RESUMO

B-cell defects constitute the majority of primary immunodeficiencies. Although a heterogeneous group of diseases, all are characterized by the reduction in or absence of immunoglobulins and/or specific antimicrobial antibodies. Substitution of immunoglobulin G (IgG) is therefore the mainstay of treatment. While from the late 1970s, the intravenous route of administration was the most common, in the past decades, subcutaneous immunoglobulin replacement therapy has become more popular among patients and physicians. Independently of the optimal route of administration, dosage and IgG trough level remain subjects of debate. Higher IgG trough levels seem to improve the protection against recurrent infections and thus better prevent complications such as bronchiectasis. Some patients, however, achieve protection with IgG trough levels on the lower IgG limit of healthy persons. Therefore, an individual protective IgG trough level needs to be defined for each patient. Use of additional prophylactic antibiotics and immunosuppressive drugs differs amongst specialized immunodeficiency centres and clearly requires future investigation in multi-centre trials. Haematopoietic stem cell transplantation (HSCT) is to date indicated as curative treatment in certain patients with B-cell defects associated with cell deficiencies, for example in two class-switch recombination defects and in selected severe forms of common variable immunodeficiency.


Assuntos
Linfócitos B/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoglobulinas/biossíntese , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Animais , Antígenos CD19/genética , Linfócitos B/metabolismo , Humanos , Switching de Imunoglobulina/genética , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/fisiopatologia
11.
Mol Ther ; 19(11): 2031-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21862999

RESUMO

Vector-associated side effects in clinical gene therapy have provided insights into the molecular mechanisms of hematopoietic regulation in vivo. Surprisingly, many retrovirus insertion sites (RIS) present in engrafted cells have been found to cluster nonrandomly in close association with specific genes. Our data demonstrate that these genes directly influence the in vivo fate of hematopoietic cell clones. Analysis of insertions thus far has been limited to individual clinical studies. Here, we studied >7,000 insertions retrieved from various studies. More than 40% of all insertions found in engrafted gene-modified cells were clustered in the same genomic areas covering only 0.36% of the genome. Gene classification analyses displayed significant overrepresentation of genes associated with hematopoietic functions and relevance for cell growth and survival in vivo. The similarity of insertion distributions indicates that vector insertions in repopulating cells cluster in predictable patterns. Thus, insertion analyses of preclinical in vitro and murine in vivo studies as well as vector insertion repertoires in clinical trials yielded concerted results and mark a small number of interesting genomic loci and genes that warrants further investigation of the biological consequences of vector insertions.


Assuntos
Gammaretrovirus/genética , Terapia Genética/efeitos adversos , Vetores Genéticos/efeitos adversos , Genoma , Integração Viral , Animais , Mapeamento Cromossômico , Redes Reguladoras de Genes , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Primatas , Transplantes , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
12.
J Exp Med ; 208(8): 1635-48, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21727188

RESUMO

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/ß, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/ß, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.


Assuntos
Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Interleucina-17/imunologia , Modelos Moleculares , Fator de Transcrição STAT1/genética , Linfócitos T/imunologia , Sequência de Bases , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Mutação em Linhagem Germinativa/genética , Humanos , Immunoblotting , Interferon gama/sangue , Interferon gama/metabolismo , Interleucinas/metabolismo , Masculino , Dados de Sequência Molecular , Linhagem , Fosforilação , Receptor de Interferon alfa e beta/imunologia , Fator de Transcrição STAT1/química , Fator de Transcrição STAT1/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA
14.
Front Immunol ; 2: 54, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22566844

RESUMO

We report the updated classification of primary immunodeficiency diseases, compiled by the ad hoc Expert Committee of the International Union of Immunological Societies. As compared to the previous edition, more than 15 novel disease entities have been added in the updated version. For each disorders, the key clinical and laboratory features are provided. This updated classification is meant to help in the diagnostic approach to patients with these diseases.

15.
Mol Ther ; 19(1): 28-35, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21045810

RESUMO

The potential of gene therapy as a curative treatment for monogenetic disorders has been clearly demonstrated in a series of recent Phase I/II clinical trials. Among primary immunodeficiencies, gene transfer into hematopoietic stem (HSC)/progenitor cells has resulted in the long-term correction of immune and metabolic defects in treated patients. In most cases, successes were augmented by a recognized biological selection for successfully treated cells in vivo, perhaps even to some extent at the HSC level. In contrast, similar achievements have not turned into reality for immunodeficiencies in which gene-transduced cells lack selective advantages in vivo. This is the case for chronic granulomatous disease (CGD), a primary immunodeficiency, characterized by deficient antimicrobial activity in phagocytic cells. Several attempts to correct CGD by gene transfer in combination with bone marrow conditioning have resulted in low-level long-term engraftment and transient clinical benefits despite high levels of gene marking and high numbers of reinfused cells. This review summarizes the data from clinical trials for CGD and provides some insights into treatment options that may lead to a successful application of gene therapy for CGD.


Assuntos
Terapia Genética/métodos , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/terapia , Animais , Transplante de Medula Óssea , Humanos , Condicionamento Pré-Transplante
16.
Curr Opin Hematol ; 18(1): 36-41, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21076296

RESUMO

PURPOSE OF REVIEW: Chronic granulomatous disease (CGD), characterized 50 years ago as a primary immunodeficiency disorder of phagocytic cells (resulting in failure to kill a defined spectrum of bacteria and fungi and in concomitant chronic granulomatous inflammation) now comprises five genetic defects impairing one of the five subunits of phagocyte NADPH oxidase (Phox). Phox normally generates reactive oxygen species (ROS) engaged in intracellular and extracellular host defence and resolving accompanying inflammatory processes. 'Fatal' granulomatous disease has now changed into a chronic inflammatory condition with a median survival of 35 years and is now of interest to both paediatricians and internists. Clinical vigilance and expert knowledge are needed for early recognition and tailored treatment of this relatively rare genetic disorder. RECENT FINDINGS: Infections by unanticipated pathogens and noncirrhotic portal hypertension need to be recognized as new CGD manifestations. Adult-onset CGD too is increasingly observed even in the elderly. Conservative treatment of fungal infections needs close monitoring due to the spread of azole resistance following extensive use of azoles in agriculture. Curative haematopoietic stem cell transplantation (HSCT) in early childhood has expanded with impressive results following use of matched, unrelated or cord blood donors and of a reduced intensity conditioning (RIC) regimen. Gene therapy, however, still has major limitations, remaining experimental. SUMMARY: CGD is more prevalent than initially believed with a birth prevalence of 1: 120 000. As patients are increasingly diagnosed around the world and grow older, further manifestations of CGD are expected. While fungal infections have lost some threat, therapeutic research focuses on two other important aims: pharmacologic cure of chronic inflammation and long-term cure of CGD by gene therapy.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/terapia , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/etiologia , Humanos
17.
J Allergy Clin Immunol ; 126(3): 611-7.e1, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20816194

RESUMO

BACKGROUND: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis. OBJECTIVE: To facilitate early diagnosis of AD-HIES to initiate appropriate therapy. METHODS: The clinical phenotype (suggested by a National Institutes of Health [NIH] score of >or=40 points), STAT3 genotype, and T(H)17 cell counts were compared in a cohort of 78 patients suspected of having HIES. RESULTS: Heterozygous STAT3 missense mutations and in-frame deletions were identified in 48 patients, all but 2 with an NIH score >or=40 points. Patients with STAT3 mutations with HIES showed significantly lower T(H)17 cell counts compared with patients with wild-type STAT3 and control subjects. Only 1 patient with wild-type STAT3 had both an NIH score >or=40 points and abnormal T(H)17 cell counts (

Assuntos
Dermatite Atópica/diagnóstico , Síndrome de Job/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Feminino , Deleção de Genes , Humanos , Lactente , Interleucina-17/metabolismo , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Transcrição STAT3/genética , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia
18.
J Allergy Clin Immunol ; 126(3): 602-10.e1-11, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20673987

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation remains the only treatment for most patients with severe combined immunodeficiencies (SCIDs) or other primary immunodeficiencies (non-SCID PIDs). OBJECTIVE: To analyze the long-term outcome of patients with SCID and non-SCID PID from European centers treated between 1968 and 2005. METHODS: The product-limit method estimated cumulative survival; the log-rank test compared survival between groups. A Cox proportional-hazard model evaluated the impact of independent predictors on patient survival. RESULTS: In patients with SCID, survival with genoidentical donors (n = 25) from 2000 to 2005 was 90%. Survival using a mismatched relative (n = 96) has improved (66%), similar to that using an unrelated donor (n = 46; 69%; P = .005). Transplantation after year 1995, a younger age, B(+) phenotype, genoidentical and phenoidentical donors, absence of respiratory impairment, or viral infection before transplantation were associated with better prognosis on multivariate analysis. For non-SCID PID, in contrast with patients with SCID, we confirm that, in the 2000 to 2005 period, using an unrelated donor (n = 124) gave a 3-year survival rate similar to a genoidentical donor (n = 73), 79% for both. Survival was 76% in phenoidentical transplants (n = 23) and worse in mismatched related donor transplants (n = 47; 46%; P = .016). CONCLUSION: This is the largest cohort study of such patients with the longest follow-up. Specific issues arise for different patient groups. Patients with B-SCID have worse survival than other patients with SCID, despite improvements in each group. For non-SCID PID, survival is worse than SCID, although more conditions are now treated. Individual disease categories now need to be analyzed so that disease-specific prognosis may be better understood and the best treatments planned.


Assuntos
Transplante de Células-Tronco Hematopoéticas/normas , Imunodeficiência Combinada Severa/terapia , Criança , Pré-Escolar , Europa (Continente) , Seguimentos , Transplante de Células-Tronco Hematopoéticas/tendências , História do Século XX , História do Século XXI , Humanos , Análise Multivariada , Prognóstico , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
19.
Immunol Allergy Clin North Am ; 30(2): 195-208, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20493396

RESUMO

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is caused by the lack of 1 of 5 subunits of the superoxide-producing nicotinamide adenine dinucleotide phosphate oxidase of neutrophils, macrophages, and eosinophils. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for CGD and can be offered to selected patients. Improved outcome with supportive care and high clinical variability in the disease course, however, make selection of eligible patients for HSCT difficult. This article addresses recent progress in HSCT for CGD, delineates present limitations, and points to future developments.


Assuntos
Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/tendências , Animais , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Granulomatosa Crônica/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade , Humanos , NADPH Oxidases/deficiência , Fagocitose/genética , Fagocitose/imunologia , Condicionamento Pré-Transplante
20.
Immunol Allergy Clin North Am ; 30(2): 261-2, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20493401

RESUMO

A complete list of definite, as well as possible, indications for hemopoietic stem cell transplantation in primary immunodeficiency is provided. Included are: severe combined immunodeficiency, profound T cell defects, autoimmune and autoinflammatory syndromes, innate immune defects, hemophagocytic disorders, and other conditions. Some causes and limitations are included.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/terapia , Seleção de Pacientes , Diretrizes para o Planejamento em Saúde , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Guias de Prática Clínica como Assunto
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