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J Allergy Clin Immunol ; 141(4): 1417-1426.e1, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28780238


BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft-versus-host disease (GvHD) and rejection associated with such transplants. OBJECTIVE: We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD-causing T-cell receptor (TCR) αß CD3+ cells from the graft. METHODS: CD3+TCRαß+/CD19+ depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti-thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis. RESULTS: Twenty-five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow-up of 20.8 months (range, 5 month-3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event-free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant-related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%). CONCLUSION: CD3+TCRαß+ and CD19+ cell-depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.

Antígenos CD19/imunologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Alemtuzumab/imunologia , Soro Antilinfocitário/imunologia , Bussulfano/análogos & derivados , Bussulfano/imunologia , Complexo CD3/imunologia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Estudos Retrospectivos , Tiotepa/imunologia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Vidarabina/imunologia
Mol Immunol ; 56(1-2): 12-22, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23644631


The spleen is a crucial lymphoid organ. It is involved in the recruitment of various immunocytes to their correct locations using specific chemokines, but little is known concerning the role of type-I interferon (IFN) in the regulation of chemokines. In this study, we first used protein microarrays to assess the expression of keratinocyte-derived chemokine (KC) and lipopolysaccharide-induced CXC chemokine (LIX) in murine spleens. Both expressions were smoothly enhanced by IFN-α pretreatment after LPS injection. Then, we focused on the IFN-α regulation of KC, LIX, and their target cells, neutrophils, using an IFN-α neutralizing antibody and fludarabine (specific signal transducers and activators of transcription 1 - STAT1 inhibitor). Next, LPS was found to attenuate the production of KC and LIX in spleen. Even the elevated production of chemokines caused by exogenous IFN-α was found to be attenuated by fludarabine pretreatment. We later determined that the marginal zone and red pulp are the main sites of KC and LIX production. Last, we determined that the number of neutrophils was slightly increased by IFN-α treatment and diminished by IFN-α neutralization or fludarabine treatment. Further, the elevated neutrophils due to exogenous IFN-α were partially reversed by fludarabine pretreatment. In this way, these results indicate that IFN-α facilitates KC and LIX expression in mouse spleens after an LPS challenge. This effect was found to be mainly dependent upon the activation of STAT1, it may be involved in the recruitment of neutrophils to the spleen for the clearance of pathogens.

Quimiocinas CXC/imunologia , Quimiocinas/imunologia , Interferon-alfa/imunologia , Fator de Transcrição STAT1/imunologia , Baço/imunologia , Animais , Western Blotting , Quimiocinas/genética , Quimiocinas/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Imidazóis/imunologia , Imidazóis/farmacologia , Imuno-Histoquímica , Interferon-alfa/farmacologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Piridinas/imunologia , Piridinas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismo , Vidarabina/análogos & derivados , Vidarabina/imunologia , Vidarabina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
Blood ; 100(6): 2260-2, 2002 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12200396


Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/microL, 118 000/microL, and 70 000/microL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/microL, 1000/microL, and 2000/microL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m(2) per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/microL at day 21 and more than 133 000/microL at day 28, patient 2 achieved a platelet count of more than 50 000/microL at day 4 and more than 150 000/microL at day 10, and patient 3 achieved a platelet count of more than 50 000/microL at day 5 and 72 000/microL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP.

Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/complicações , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Vidarabina/efeitos adversos , Anticorpos Monoclonais Murinos , Antineoplásicos/administração & dosagem , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/imunologia , Rituximab , Terapia de Salvação , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/imunologia
Leuk Lymphoma ; 40(5-6): 541-50, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11426527


The purine nucleoside analogs fludarabine and 2-chloro-2'-deoxyadenosine display substantial activity in the treatment of various chronic lymphoproliferative disorders. Their major toxicities are primarily immunosuppression and myelosuppression. The profound influence of these drugs on the immune system has raised questions as to the emergence of secondary neoplasms or auto-immune disorders after their use. Based on a literature review and on personal observations, this article reviews the potential clinical importance of these concerns.

Antineoplásicos/efeitos adversos , Cladribina/efeitos adversos , Imunossupressores/efeitos adversos , Segunda Neoplasia Primária/etiologia , Neoplasias/tratamento farmacológico , Vidarabina/efeitos adversos , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Autoimunidade , Cladribina/imunologia , Cladribina/uso terapêutico , Humanos , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Neoplasias/imunologia , Neoplasias/patologia , Segunda Neoplasia Primária/imunologia , Vidarabina/análogos & derivados , Vidarabina/imunologia , Vidarabina/uso terapêutico
Clin Lab Haematol ; 22(3): 163-5, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10931166


We report the development of a high titre antibody to factor VIII in a patient with previous high grade B cell non-Hodgkin's lymphoma treated with fludarabine. Unlike previous reports of factor VIII inhibitors and lymphoproliferative disease this patient's lymphoma was in remission. We speculate that the occurrence of the inhibitor is another manifestation of the increasingly recognized autoimmune side-effects of fludarabine.

Hemofilia A/induzido quimicamente , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Vidarabina/análogos & derivados , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Autoanticorpos/sangue , Autoimunidade , Contusões/induzido quimicamente , Contusões/imunologia , Hemofilia A/imunologia , Hemorragia/induzido quimicamente , Hemorragia/imunologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/imunologia , Masculino , Pessoa de Meia-Idade , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/imunologia