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1.
J Allergy Clin Immunol Pract ; 7(3): 848-855, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (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 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent 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 with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: 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.

3.
Biol Blood Marrow Transplant ; 24(3): 529-536, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29155317

RESUMO

We previously published results for 70 children who received conditioning with treosulfan and cyclophosphamide (n = 30) or fludarabine (n = 40) before undergoing hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency (PID). Toxicity was lower and T cell chimerism was better in the patients receiving fludarabine, but cohort numbers were relatively small and follow-up was short. Here we report outcomes of 160 children who received homogeneous conditioning with treosulfan, fludarabine, and, in most cases, alemtuzumab (n = 124). The median age at transplantation was 1.36 years (range, .09 to 18.25 years). Donors included 73 matched unrelated, 54 1 to 3 antigen-mismatched unrelated, 12 matched sibling, 17 other matched family, and 4 haploidentical donors. Stem cell source was peripheral blood stem cells (PBSCs) in 70, bone marrow in 49, and cord blood in 41. Median duration of follow-up was 4.3 years (range, .8 to 9.4 years). Overall survival was 83%. No patients had veno-occlusive disease. Seventy-four patients (46%) had acute GVHD, but only 14 (9%) greater than grade II. Four patients underwent successful retransplantation for graft loss or poor immune reconstitution. Another patient experienced graft rejection and died. There was no association between T cell chimerism >95% and stem cell source, but a significant association was seen between myeloid chimerism >95% and use of PBSCs without an increased risk of significant GVHD compared with other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth were alive at up to 8.7 years of follow-up. Long-term studies are needed to determine late gonadotoxic effects, and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine, and alemtuzumab is associated with excellent results in HSCT for PID.


Assuntos
Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adolescente , Adulto , Alemtuzumab/administração & dosagem , Aloenxertos , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , Fatores de Risco , Taxa de Sobrevida , Reino Unido , Vidarabina/administração & dosagem
4.
Br J Haematol ; 180(5): 644-653, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29270983

RESUMO

Reticular Dysgenesis is a rare immunodeficiency which is clinically characterized by the combination of Severe Combined Immunodeficiency (SCID) with agranulocytosis and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 (AK2) were identified to cause this phenotype. In this review, we will demonstrate important clinical differences between reticular dysgenesis and other SCID entities and summarize recent concepts in the understanding of the pathophysiology of the disease and the management strategies for this difficult condition.


Assuntos
Leucopenia/genética , Leucopenia/terapia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Adenilato Quinase/química , Adenilato Quinase/deficiência , Adenilato Quinase/genética , Animais , Modelos Animais de Doenças , Perda Auditiva Neurossensorial/genética , Humanos , Síndromes de Imunodeficiência/genética , Leucopenia/diagnóstico , Mutação/genética , Imunodeficiência Combinada Severa/diagnóstico
5.
J Clin Immunol ; 37(7): 626-637, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28842866

RESUMO

Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme of purine metabolism encoded by the Ada gene, is a cause of human severe combined immune deficiency (SCID). Numerous deleterious mutations occurring in the ADA gene have been found in patients with profound lymphopenia (T- B- NK-), thus underscoring the importance of functional purine metabolism for the development of the immune defense. While untreated ADA SCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADA activity and reconstitute protective immunity, including enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells (HSC). We review the pathogenic mechanisms and clinical manifestations of ADA SCID.


Assuntos
Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Imunodeficiência Combinada Severa/genética , Animais , Modelos Animais de Doenças , Humanos
6.
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
7.
Front Immunol ; 7: 314, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27579027

RESUMO

Adenosine deaminase (ADA) deficiency is best known as a form of severe combined immunodeficiency (SCID) that results from mutations in the gene encoding ADA. Affected patients present with clinical and immunological manifestations typical of a SCID. Therapies are currently available that can target these immunological disturbances and treated patients show varying degrees of clinical improvement. However, there is now a growing body of evidence that deficiency of ADA has significant impact on non-immunological organ systems. This review will outline the impact of ADA deficiency on various organ systems, starting with the well-understood immunological abnormalities. We will discuss possible pathogenic mechanisms and also highlight ways in which current treatments could be improved. In doing so, we aim to present ADA deficiency as more than an immunodeficiency and suggest that it should be recognized as a systemic metabolic disorder that affects multiple organ systems. Only by fully understanding ADA deficiency and its manifestations in all organ systems can we aim to deliver therapies that will correct all the clinical consequences.

9.
Br J Haematol ; 161(3): 449-52, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23432400
10.
Blood ; 117(16): 4367-75, 2011 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-21325599

RESUMO

Children with primary immunodeficiency diseases, particularly those less than 1 year of age, experience significant toxicity after hematopoietic stem cell transplantation, with busulfan- or melphalan-based conditioning. Treosulfan causes less veno-occlusive disease than busulfan and does not require pharmacokinetic monitoring. We report its use in 70 children. Children received 42 g/m(2) or 36 g/m(2) with cyclophosphamide 200 mg/kg (n = 30) or fludarabine 150 mg/m(2) (n = 40), with alemtuzumab in most. Median age at transplantation was 8.5 months (range, 1.2-175 months); 46 (66%) patients were 12 months of age or younger. Donors were as follows: matched sibling donor, 8; matched family donor, 13; haploidentical, 4; and unrelated, 45. Median follow-up was 19 months (range, 1-47 months). Overall survival was 81%, equivalent in those age less or greater than 1 year. Skin toxicity was common. Veno-occlusive disease occurred twice with cyclophosphamide. Eighteen patients (26%) had graft-versus-host disease, and only 7 (10%) greater than grade 2. Two patients rejected; 24 of 42 more than 1 year after transplantation had 100% donor chimerism. The remainder had stable mixed chimerism. T-cell chimerism was significantly better with fludarabine. Long-term follow-up is required, but in combination with fludarabine, treosulfan is a good choice of conditioning for hematopoietic stem cell transplantation in primary immunodeficiency disease.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/cirurgia , Imunossupressores/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Antineoplásicos Alquilantes/efeitos adversos , Bussulfano/efeitos adversos , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Quimerismo , Estudos de Coortes , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Análise de Sobrevida , Reino Unido
11.
Blood ; 117(1): 53-62, 2011 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-20926771

RESUMO

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.


Assuntos
Antígenos CD/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfo-Histiocitose Hemofagocítica/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4/genética , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/terapia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Taxa de Sobrevida , Adulto Jovem
12.
Clin Gastroenterol Hepatol ; 6(2): 248-50, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18187369

RESUMO

BACKGROUND & AIMS: Intractable ulcerating enterocolitis of infancy (IE) is an uncommon, autosomal-recessive, and devastating inflammatory bowel disorder that arises as a consequence of a poorly defined underlying immunologic disorder. Infants with IE suffer from recurrent severe oro-anal disease and an enterocolitis that is unresponsive to conventional immunosuppressive therapy and requires early pancolectomy to control the severity of the disease. Despite such aggressive treatment these individuals remain at high risk of Epstein-Barr virus-driven lymphomatous proliferations, including non-Hodgkin's lymphoma. The underlying genetic basis for this disease remains undefined. This report aims to describe the use of bone marrow transplantation as a treatment for this condition. METHODS: This was a case series report. RESULTS: We describe the successful treatment of IE by allogeneic bone marrow transplantation in 2 brothers, now aged 7 and 11 years, one of whom had developed an Epstein-Barr virus-related monomorphous B-lymphocyte lymphoproliferative disorder. This treatment has resulted in prolonged clinical remission in both boys and abrogated the need for aggressive immunosuppression. CONCLUSIONS: Bone marrow transplantation can be used for the treatment of intractable ulcerating enterocolitis of infancy, which may support a role in other intractable inflammatory bowel conditions in the pediatric population.


Assuntos
Transplante de Medula Óssea , Anormalidades Congênitas/terapia , Enterocolite Necrosante/terapia , Colectomia , Colo/patologia , Anormalidades Congênitas/cirurgia , Enterocolite Necrosante/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino
13.
J Pediatr ; 144(2): 278-80, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14760277

RESUMO

Adenosine deaminase deficiency presents with severe combined immunodeficiency and is treatable by bone marrow transplantation. With improved survival, the nonimmunologic manifestations of this condition are becoming apparent. We report a high incidence of bilateral sensorineural deafness in transplanted patients, which highlights the systemic nature of the disease.


Assuntos
Adenosina Desaminase/deficiência , Perda Auditiva Neurossensorial/complicações , Imunodeficiência Combinada Severa/complicações , Adolescente , Adulto , Fatores Etários , Audiometria de Tons Puros , Transplante de Medula Óssea , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Imunodeficiência Combinada Severa/cirurgia
15.
Br J Haematol ; 123(4): 712-9, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14616977

RESUMO

Retroviral vectors encoding the herpes simplex thymidine kinase gene have been used to render T cells sensitive to the prodrug ganciclovir. Such genetically modified T cells have been used in clinical trials for their graft-versus-leukaemia effects following allogeneic haematopoietic stem cell transplantation. In the event of graft-versus-host disease (GVHD) the cells were susceptible to elimination through exposure to ganciclovir. We have investigated the impact of T-cell activation, required for successful retrovirus-mediated gene transfer, on T-cell receptor repertoire profile, subset distribution and antiviral potential. Using a combination of antibodies against CD3 and CD28, T cells were transduced at high efficiency when exposed to retrovirus between 48 and 72 h later. Lymphocytes had undergone up to seven cycles of cell division by the end of the procedure. Although the T-cell receptor Vbeta repertoire was not altered after retroviral transduction, there were notable shifts in subset profiles with an increased proportion of CD45RO cells in transduced populations. T cells continued to proliferate for several days after transduction and were difficult to sustain under the extended culture conditions required to generate virus-specific T cells. These observations may explain the lower than expected levels of GVHD and poor antiviral immunity reported in recent trials.


Assuntos
Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Retroviridae/genética , Simplexvirus/enzimologia , Linfócitos T/virologia , Timidina Quinase/genética , Animais , Antivirais/uso terapêutico , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Região Variável de Imunoglobulina/análise , Camundongos , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Linfócitos T/imunologia , Linfócitos T/transplante , Transdução Genética/métodos
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