Base de dados : MEDLINE
Pesquisa : D12.776.543.750.705.852.420.340.500 [Categoria DeCS]
Referências encontradas : 276 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 28 ir para página                         

  1 / 276 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29374162
[Au] Autor:Broughton SE; Hercus TR; Nero TL; Kan WL; Barry EF; Dottore M; Cheung Tung Shing KS; Morton CJ; Dhagat U; Hardy MP; Wilson NJ; Downton MT; Schieber C; Hughes TP; Lopez AF; Parker MW
[Ad] Endereço:Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
[Ti] Título:A dual role for the N-terminal domain of the IL-3 receptor in cell signalling.
[So] Source:Nat Commun;9(1):386, 2018 01 26.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3Rα regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function.
[Mh] Termos MeSH primário: Subunidade alfa de Receptor de Interleucina-3/química
Subunidade alfa de Receptor de Interleucina-3/metabolismo
Domínios Proteicos
Transdução de Sinais
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sítios de Ligação/genética
Células COS
Linhagem Celular Tumoral
Cercopithecus aethiops
Cristalografia por Raios X
Células HEK293
Seres Humanos
Interleucina-3/química
Interleucina-3/genética
Interleucina-3/metabolismo
Subunidade alfa de Receptor de Interleucina-3/genética
Simulação de Dinâmica Molecular
Mutação
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (IL3RA protein, human); 0 (Interleukin-3); 0 (Interleukin-3 Receptor alpha Subunit)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180128
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02633-7


  2 / 276 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28935249
[Au] Autor:Mohammadi S; Zahedpanah M; Ghaffari SH; Shaiegan M; Nikbakht M; Nikugoftar M
[Ad] Endereço:Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: smohammadi@sina.tums.ac.ir.
[Ti] Título:Osteopontin plays a unique role in resistance of CD34+/CD123+ human leukemia cell lines KG1a to parthenolide.
[So] Source:Life Sci;189:89-95, 2017 Nov 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To determine if parthenolide (PTL) is cytotoxic for leukemia-like KG1a cells and if it involves in certain molecular-mediated resistance, especially osteopontin (OPN). METHODS: PTL/daunorubicin (DNR)-treated KG1a cells were examined for viability using MTT and colony-formation assay, and stained for apoptosis using AV/PI. The gene and protein expression were evaluated by qReal-time PCR and Western blotting analysis, respectively. OPN gene was inhibited by OPN siRNA. The cells were stained for various fractions using PE anti-CD34, FITC anti-CD38 and PerCP anti-CD123. RESULTS: Cell viability and proliferation assay exhibited KG1a cells are relatively refractory to used concentrations of PTL. OPN mRNA and protein levels increased in response to PTL. Suppression of OPN with siRNA increased the cytotoxic effects of PTL on KG1a cells. PTL treatment and OPN siRNA suppression in KG1a cells resulted in a decrease of mRNA expression of AKT, mTOR, ß-catenin, and Phosphatase and tensin homolog (PTEN). The sub-population cells of CD34 and CD123 from KG1a cells are enriched by PTL treatment. CONCLUSION: Parthenolide in spite of the reduction in gene expression of AKT, mTOR or beta-catenin, stimulates the OPN expression in KG1a cells. The OPN expression pattern in KG1a cells could be compatible with CD34 /CD123 subtype enrichment by PTL which in turn implies OPN's unique role in resistance of cell populations characterized by CD34 /CD123 phenotype.
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/farmacologia
Leucemia Mieloide Aguda/tratamento farmacológico
Células-Tronco Neoplásicas/metabolismo
Osteopontina/metabolismo
Sesquiterpenos/farmacologia
[Mh] Termos MeSH secundário: Antígenos CD34/metabolismo
Apoptose/efeitos dos fármacos
Western Blotting
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/genética
Seres Humanos
Subunidade alfa de Receptor de Interleucina-3/metabolismo
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/patologia
Osteopontina/genética
RNA Interferente Pequeno/administração & dosagem
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD34); 0 (Antineoplastic Agents, Phytogenic); 0 (Interleukin-3 Receptor alpha Subunit); 0 (RNA, Small Interfering); 0 (Sesquiterpenes); 106441-73-0 (Osteopontin); 2RDB26I5ZB (parthenolide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE


  3 / 276 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28301819
[Au] Autor:Sadras T; Kok CH; Perugini M; Ramshaw HS; D'Andrea RJ
[Ad] Endereço:Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia; School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia. Electronic address: teresa.sadras@sahmri.com.
[Ti] Título:miR-155 as a potential target of IL-3 signaling in primary AML cells.
[So] Source:Leuk Res;57:57-59, 2017 Jun.
[Is] ISSN:1873-5835
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:miR-155 has emerged as one of the key microRNAs (miRNAs) involved in normal and malignant myelopoiesis, and high expression of this miRNA has been flagged as a strong independent prognostic marker in Acute Myeloid Leukemia (AML). While elevated expression of miR-155 has been associated with FLT3-ITD mutations, other mechanisms which may regulate expression of this miRNA in AML remain largely unknown. Here, we present new evidence that miR-155 may be a prime target of IL-3 signaling in primary AML cells. This finding, together with the increasingly apparent role for miR-155 in oncogenesis, and the upregulation of the IL-3 receptor alpha subunit in AML, lead us to propose this pathway may significantly contribute to the leukemic transformation.
[Mh] Termos MeSH primário: Interleucina-3/metabolismo
Leucemia Mieloide Aguda/metabolismo
MicroRNAs/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Transformação Celular Neoplásica
Regulação Leucêmica da Expressão Gênica
Seres Humanos
Subunidade alfa de Receptor de Interleucina-3/genética
Leucemia Mieloide Aguda/genética
Células Tumorais Cultivadas
Regulação para Cima
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (IL3 protein, human); 0 (IL3RA protein, human); 0 (Interleukin-3); 0 (Interleukin-3 Receptor alpha Subunit); 0 (MIRN155 microRNA, human); 0 (MicroRNAs)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE


  4 / 276 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28246194
[Au] Autor:Tasian SK; Kenderian SS; Shen F; Ruella M; Shestova O; Kozlowski M; Li Y; Schrank-Hacker A; Morrissette JJD; Carroll M; June CH; Grupp SA; Gill S
[Ad] Endereço:Division of Oncology and.
[Ti] Título:Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia.
[So] Source:Blood;129(17):2395-2407, 2017 Apr 27.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We and others previously reported potent antileukemia efficacy of CD123-redirected chimeric antigen receptor (CAR) T cells in preclinical human acute myeloid leukemia (AML) models at the cost of severe hematologic toxicity. This observation raises concern for potential myeloablation in patients with AML treated with CD123-redirected CAR T cells and mandates novel approaches for toxicity mitigation. We hypothesized that CAR T-cell depletion with optimal timing after AML eradication would preserve leukemia remission and allow subsequent hematopoietic stem cell transplantation. To test this hypothesis, we compared 3 CAR T-cell termination strategies: (1) transiently active anti-CD123 messenger RNA-electroporated CART (RNA-CART123); (2) T-cell ablation with alemtuzumab after treatment with lentivirally transduced anti-CD123-4-1BB-CD3ζ T cells (CART123); and (3) T-cell ablation with rituximab after treatment with CD20-coexpressing CART123 (CART123-CD20). All approaches led to rapid leukemia elimination in murine xenograft models of human AML. Subsequent antibody-mediated depletion of CART123 or CART123-CD20 did not impair leukemia remission. Time-course studies demonstrated that durable leukemia remission required CAR T-cell persistence for 4 weeks prior to ablation. Upon CAR T-cell termination, we further demonstrated successful hematopoietic engraftment with a normal human donor to model allogeneic stem cell rescue. Results from these studies will facilitate development of T-cell depletion strategies to augment the feasibility of CAR T-cell therapy for patients with AML.
[Mh] Termos MeSH primário: Transplante de Células-Tronco Hematopoéticas
Imunoterapia Adotiva/métodos
Subunidade alfa de Receptor de Interleucina-3/imunologia
Leucemia Mieloide Aguda/terapia
Receptores de Antígenos de Linfócitos T/imunologia
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Alemtuzumab
Animais
Anticorpos Monoclonais Humanizados/farmacologia
Antígenos CD20/genética
Antígenos CD20/imunologia
Complexo CD3/genética
Complexo CD3/imunologia
Feminino
Expressão Gênica
Vetores Genéticos/química
Vetores Genéticos/metabolismo
Seres Humanos
Subunidade alfa de Receptor de Interleucina-3/antagonistas & inibidores
Subunidade alfa de Receptor de Interleucina-3/genética
Lentivirus/genética
Lentivirus/metabolismo
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/imunologia
Leucemia Mieloide Aguda/patologia
Depleção Linfocítica
Masculino
Camundongos
Camundongos Endogâmicos NOD
RNA Antissenso/genética
RNA Antissenso/imunologia
RNA Mensageiro/genética
RNA Mensageiro/imunologia
Receptores de Antígenos de Linfócitos T/genética
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/imunologia
Indução de Remissão
Rituximab/farmacologia
Linfócitos T/citologia
Linfócitos T/efeitos dos fármacos
Linfócitos T/transplante
Transplante Heterólogo
Resultado do Tratamento
Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Antigens, CD20); 0 (CD3 Complex); 0 (CD3 antigen, zeta chain); 0 (IL3RA protein, human); 0 (Interleukin-3 Receptor alpha Subunit); 0 (RNA, Antisense); 0 (RNA, Messenger); 0 (Receptors, Antigen, T-Cell); 0 (Recombinant Fusion Proteins); 0 (TNFRSF9 protein, human); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9); 3A189DH42V (Alemtuzumab); 4F4X42SYQ6 (Rituximab)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170302
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-08-736041


  5 / 276 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27734262
[Au] Autor:Garfin PM; Feldman EJ
[Ad] Endereço:Seattle Genetics, Inc., 21823-30th Drive Southeast, Bothell, WA, 98021, USA.
[Ti] Título:Antibody-Based Treatment of Acute Myeloid Leukemia.
[So] Source:Curr Hematol Malig Rep;11(6):545-552, 2016 Dec.
[Is] ISSN:1558-822X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:While antibody-based therapies have emerged as clinically effective approaches for several hematologic and solid malignancies, they have not played a significant role to date in the treatment of acute myeloid leukemia (AML). More recently, improvements in antibody-drug conjugate technology, bispecific antibodies, as well as identification of novel AML antigens have re-invigorated enthusiasm for antibody-based therapies for AML. This review describes experiences with former and existing antibody-based therapies for AML, including unconjugated antibodies, antibody-drug conjugates (ADCs), radio-labelled antibodies, and immune-engaging antibodies, and discusses the promise and challenges associated with each.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/uso terapêutico
Leucemia Mieloide Aguda/tratamento farmacológico
[Mh] Termos MeSH secundário: Aminoglicosídeos/uso terapêutico
Anticorpos Monoclonais/imunologia
Anticorpos Monoclonais Humanizados/uso terapêutico
Seres Humanos
Imunoconjugados/uso terapêutico
Subunidade alfa de Receptor de Interleucina-3/imunologia
Radioimunoterapia
Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Aminoglycosides); 0 (Antibodies, Monoclonal); 0 (Antibodies, Monoclonal, Humanized); 0 (Immunoconjugates); 0 (Interleukin-3 Receptor alpha Subunit); 0 (SGN-30 monoclonal antibody); 0 (Sialic Acid Binding Ig-like Lectin 3); 93NS566KF7 (gemtuzumab)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161014
[St] Status:MEDLINE
[do] DOI:10.1007/s11899-016-0349-7


  6 / 276 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27687970
[Au] Autor:Li B; Zhao W; Zhang X; Wang J; Luo X; Baker SD; Jordan CT; Dong Y
[Ad] Endereço:Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
[Ti] Título:Design, synthesis and evaluation of anti-CD123 antibody drug conjugates.
[So] Source:Bioorg Med Chem;24(22):5855-5860, 2016 Nov 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate (CD123-CPT) by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker. The linker is biodegradable in the presence of Glutathione (GSH, an endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/química
Antineoplásicos/síntese química
Antineoplásicos/farmacologia
Camptotecina/química
Camptotecina/farmacologia
Desenho de Drogas
Indóis/química
Subunidade alfa de Receptor de Interleucina-3/imunologia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/imunologia
Antineoplásicos/química
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(2-(2-chloro-3-((1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene)-1-cyclohexen-1-yl)ethenyl)-3,3-dimethyl-1-propylindolium); 0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (IL3RA protein, human); 0 (Indoles); 0 (Interleukin-3 Receptor alpha Subunit); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161001
[St] Status:MEDLINE


  7 / 276 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27571406
[Au] Autor:Ruella M; Barrett DM; Kenderian SS; Shestova O; Hofmann TJ; Perazzelli J; Klichinsky M; Aikawa V; Nazimuddin F; Kozlowski M; Scholler J; Lacey SF; Melenhorst JJ; Morrissette JJ; Christian DA; Hunter CA; Kalos M; Porter DL; June CH; Grupp SA; Gill S
[Ti] Título:Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies.
[So] Source:J Clin Invest;126(10):3814-3826, 2016 Oct 03.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.
[Mh] Termos MeSH primário: Antígenos CD19/metabolismo
Antineoplásicos/administração & dosagem
Subunidade alfa de Receptor de Interleucina-3/administração & dosagem
Subunidade alfa de Receptor de Interleucina-3/metabolismo
Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico
Receptores de Antígenos de Linfócitos T/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Seres Humanos
Imunoterapia/métodos
Camundongos Endogâmicos NOD
Camundongos SCID
Recidiva Local de Neoplasia/prevenção & controle
Células-Tronco Neoplásicas/metabolismo
Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo
Linfócitos T/imunologia
Linfócitos T/transplante
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD19); 0 (Antineoplastic Agents); 0 (CD19 molecule, human); 0 (CTL019 chimeric antigen receptor); 0 (IL3RA protein, human); 0 (Interleukin-3 Receptor alpha Subunit); 0 (Receptors, Antigen, T-Cell)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160830
[St] Status:MEDLINE


  8 / 276 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
PubMed Central Texto completo
Texto completo
[PMID]:27548616
[Au] Autor:Thokala R; Olivares S; Mi T; Maiti S; Deniger D; Huls H; Torikai H; Singh H; Champlin RE; Laskowski T; McNamara G; Cooper LJ
[Ad] Endereço:Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
[Ti] Título:Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of VL and VH Domains Targeting CD123+ Tumors.
[So] Source:PLoS One;11(8):e0159477, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B- cell malignancies is generating enthusiasm to extend this approach to other hematological malignancies, such as acute myelogenous leukemia (AML). CD123, or interleukin 3 receptor alpha, is overexpressed on most AML and some lymphoid malignancies, such as acute lymphocytic leukemia (ALL), and has been an effective target for T cells expressing chimeric antigen receptors (CARs). The prototypical CAR encodes a VH and VL from one monoclonal antibody (mAb), coupled to a transmembrane domain and one or more cytoplasmic signaling domains. Previous studies showed that treatment of an experimental AML model with CD123-specific CAR T cells was therapeutic, but at the cost of impaired myelopoiesis, highlighting the need for systems to define the antigen threshold for CAR recognition. Here, we show that CARs can be engineered using VH and VL chains derived from different CD123-specific mAbs to generate a panel of CAR+ T cells. While all CARs exhibited specificity to CD123, one VH and VL combination had reduced lysis of normal hematopoietic stem cells. This CAR's in vivo anti-tumor activity was similar whether signaling occurred via chimeric CD28 or CD137, prolonging survival in both AML and ALL models. Co-expression of inducible caspase 9 eliminated CAR+ T cells. These data help support the use of CD123-specific CARs for treatment of CD123+ hematologic malignancies.
[Mh] Termos MeSH primário: Engenharia Genética/métodos
Imunoterapia Adotiva/métodos
Subunidade alfa de Receptor de Interleucina-3/imunologia
Leucemia Mieloide Aguda/terapia
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
Proteínas Recombinantes de Fusão/imunologia
Linfócitos T/transplante
[Mh] Termos MeSH secundário: Animais
Linfócitos B/imunologia
Linfócitos B/patologia
Antígenos CD28/genética
Antígenos CD28/imunologia
Caspase 9/genética
Caspase 9/imunologia
Citotoxicidade Imunológica
Modelos Animais de Doenças
Expressão Gênica
Células-Tronco Hematopoéticas/imunologia
Células-Tronco Hematopoéticas/patologia
Seres Humanos
Subunidade alfa de Receptor de Interleucina-3/genética
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/imunologia
Leucemia Mieloide Aguda/patologia
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Terapia de Alvo Molecular
Plasmídeos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia
Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
Proteínas Recombinantes de Fusão/genética
Anticorpos de Domínio Único/genética
Linfócitos T/citologia
Linfócitos T/imunologia
Transfecção
Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD28 Antigens); 0 (Interleukin-3 Receptor alpha Subunit); 0 (Recombinant Fusion Proteins); 0 (Single-Domain Antibodies); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9); EC 3.4.22.- (CASP9 protein, human); EC 3.4.22.- (Caspase 9)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160823
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0159477


  9 / 276 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27513213
[Au] Autor:Finotti G; Tamassia N; Cassatella MA
[Ad] Endereço:Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy.
[Ti] Título:Synergistic production of TNFα and IFNα by human pDCs incubated with IFNλ3 and IL-3.
[So] Source:Cytokine;86:124-131, 2016 Oct.
[Is] ISSN:1096-0023
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In this study, we investigated whether IFNλ3 and IL-3 reciprocally influence their capacity to activate various functions of human plasmacytoid dendritic cells (pDCs). In fact, we preliminarily observed that IFNλ3 upregulates the expression of the IL-3Rα (CD123), while IL-3 augments the expression of IFNλR1 in pDCs. As a result, we found that combination of IFNλ3 and IL-3 induces a strong potentiation in the production of TNFα, IFNα, as well as in the expression of Interferon-Stimulated Gene (ISG) mRNAs by pDCs, as compared to either IFNλ3 or IL-3 alone. In such regard, we found that endogenous IFNα autocrinally promotes the expression of ISG mRNAs in IL-3-, but not in IFNλ3 plus IL-3-, treated pDCs. Moreover, we uncovered that the production of IFNα by IFNλ3 plus IL-3-treated pDCs is mostly dependent on endogenously produced TNFα. Altogether, our data demonstrate that IFNλ3 and IL-3 collaborate to promote, at maximal levels, discrete functional responses of human pDCs.
[Mh] Termos MeSH primário: Células Dendríticas/imunologia
Interferon-alfa/biossíntese
Interleucina-3/farmacologia
Interleucinas/farmacologia
Fator de Necrose Tumoral alfa/biossíntese
[Mh] Termos MeSH secundário: Células Cultivadas
Células Dendríticas/metabolismo
Citometria de Fluxo
Seres Humanos
Imunidade Inata
Interferon-alfa/imunologia
Subunidade alfa de Receptor de Interleucina-3/genética
Fator de Necrose Tumoral alfa/imunologia
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL28B protein, human); 0 (IL3RA protein, human); 0 (Interferon-alpha); 0 (Interleukin-3); 0 (Interleukin-3 Receptor alpha Subunit); 0 (Interleukins); 0 (Tumor Necrosis Factor-alpha)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160812
[St] Status:MEDLINE


  10 / 276 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27401038
[Au] Autor:Bonifant CL; Szoor A; Torres D; Joseph N; Velasquez MP; Iwahori K; Gaikwad A; Nguyen P; Arber C; Song XT; Redell M; Gottschalk S
[Ad] Endereço:Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA.
[Ti] Título:CD123-Engager T Cells as a Novel Immunotherapeutic for Acute Myeloid Leukemia.
[So] Source:Mol Ther;24(9):1615-26, 2016 Sep 29.
[Is] ISSN:1525-0024
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Immunotherapy with CD123-specific T-cell engager proteins or with T cells expressing CD123-specific chimeric antigen receptors is actively being pursued for acute myeloid leukemia. T cells secreting bispecific engager molecules (ENG-T cells) may present a promising alternative to these approaches. To evaluate therapeutic potential, we generated T cells to secrete CD123/CD3-bispecific engager molecules. CD123-ENG T cells recognized primary acute myeloid leukemia (AML) cells and cell lines in an antigen-dependent manner as judged by cytokine production and/or tumor killing, and redirected bystander T cells to AML cells. Infusion of CD123-ENG T cells resulted in regression of AML in xenograft models conferring a significant survival advantage of treated mice in comparison to mice that received control T cells. At high effector to target ratios, CD123-ENG T cells recognized normal hematopoietic stem and progenitor cells (HSPCs) with preferential recognition of HSPCs from cord blood compared to bone marrow. We therefore introduced the CD20 suicide gene that can be targeted in vivo with rituximab into CD123-ENG T cells. The expression of CD20 did not diminish the anti-AML activity of CD123-ENG T cells, but allowed for rituximab-mediated ENG-T cell elimination. Thus, ENG-T cells coexpressing CD20 suicide and CD123 engager molecules may present a promising immunotherapeutic approach for AML.
[Mh] Termos MeSH primário: Imunoterapia
Subunidade alfa de Receptor de Interleucina-3/metabolismo
Leucemia Mieloide Aguda/imunologia
Leucemia Mieloide Aguda/terapia
Linfócitos T/imunologia
Linfócitos T/metabolismo
[Mh] Termos MeSH secundário: Animais
Antígenos CD20/genética
Antígenos CD20/metabolismo
Complexo CD3/genética
Complexo CD3/metabolismo
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Proteínas do Sistema Complemento/imunologia
Proteínas do Sistema Complemento/metabolismo
Citocinas/secreção
Citotoxicidade Imunológica
Modelos Animais de Doenças
Genes Transgênicos Suicidas/genética
Vetores Genéticos/genética
Células-Tronco Hematopoéticas/imunologia
Células-Tronco Hematopoéticas/metabolismo
Seres Humanos
Imunoterapia/métodos
Subunidade alfa de Receptor de Interleucina-3/genética
Leucemia Mieloide Aguda/genética
Camundongos
Retroviridae/genética
Rituximab/farmacologia
Transdução Genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD20); 0 (CD3 Complex); 0 (Cytokines); 0 (Interleukin-3 Receptor alpha Subunit); 4F4X42SYQ6 (Rituximab); 9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160713
[St] Status:MEDLINE
[do] DOI:10.1038/mt.2016.116



página 1 de 28 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde