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Cytotherapy ; 21(3): 327-340, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30685216


Clinical trials of adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have delivered unprecedented responses in patients with relapsed refractory B-cell malignancy. These results have prompted Food and Drug Administration (FDA) approval of two CAR T-cell products in this high-risk patient population. The widening range of indications for CAR T-cell therapy and increasing patient numbers present a significant logistical challenge to manufacturers aiming for reproducible delivery systems for high-quality clinical CAR T-cell products. This review discusses current and novel CAR T-cell processing methodologies and the quality control systems needed to meet the increasing clinical demand for these exciting new therapies.

Imunoterapia Adotiva/métodos , Instalações Industriais e de Manufatura/normas , Neoplasias/terapia , Controle de Qualidade , Receptores de Antígenos Quiméricos , Antígenos CD19/imunologia , Remoção de Componentes Sanguíneos/métodos , Sobrevivência Celular , Criopreservação/métodos , Endotoxinas/análise , Humanos , Imunoterapia Adotiva/efeitos adversos , Ativação Linfocitária , Mycoplasma , Linfócitos T/imunologia , Transdução Genética/métodos
Mol Med ; 21(1): 46-57, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25611435


Chronic lymphocytic leukemia (CLL) development and progression are thought to be driven by unknown antigens/autoantigens through the B cell receptor (BCR) and environmental signals for survival and expansion including toll-like receptor (TLR) ligands. CD180/RP105, a membrane-associated orphan receptor of the TLR family, induces normal B cell activation and proliferation and is expressed by approximately 60% of CLL samples. Half of these respond to ligation with anti-CD180 antibody by increased activation/phosphorylation of protein kinases associated with BCR signaling. Hence CLL cells expressing both CD180 and the BCR could receive signals via both receptors. Here we investigated cross-talk between BCR and CD180-mediated signaling on CLL cell survival and apoptosis. Our data indicate that ligation of CD180 on responsive CLL cells leads to activation of either prosurvival Bruton tyrosine kinase (BTK)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT-mediated, or proapoptotic p38 mitogen-activated protein kinase (p38MAPK)-mediated signaling pathways, while selective immunoglobulin M (sIgM) ligation predominantly engages the BTK/PI3K/AKT pathway. Furthermore, pretreatment of CLL cells with anti-CD180 redirects IgM-mediated signaling from the prosurvival BTK/PI3K/AKT toward the proapoptotic p38MAPK pathway. Thus preengaging CD180 could prevent further prosurvival signaling mediated via the BCR and, instead, induce CLL cell apoptosis, opening the door to therapeutic profiling and new strategies for the treatment of a substantial cohort of CLL patients.

Br J Haematol ; 153(4): 486-98, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21443749


We previously showed that approximately 60% of B chronic lymphocytic leukaemia (B-CLL) cells express surface CD180, an orphan receptor of the Toll-like receptor family. Here we investigated the ability of anti-CD180 monoclonal antibody (mAb) to induce activation, cell cycling, survival and signalling in B-CLL cells and normal B cells. Upon addition of anti-CD180 mAb, alone or in combination with anti-CD40 mAb or recombinant IL-4 (rIL-4), expression of CD86, Ki-67, uptake of DiOC(6) , phosphorylation of signalling protein kinases and Ca(2+) flux were measured in B-CLL cells from untreated patients and normal B cells from age-matched volunteers. Normal B cells and approximately 50% of CD180(+) B-CLL clones responded to CD180 ligation by activation, cycling and increased survival comparable with, or superior to, those induced by anti-CD40 mAb or rIL-4 (Responder B-CLL). Non-responder CD180(+) B-CLL clones failed to respond to CD180 mAb and responded poorly to CD40 mAb and rIL-4. Anti-CD180 mAb induced phosphorylation of ZAP70/Syk, Erk, p38MAPK and Akt in normal B cells and Responder B-CLL cells. In contrast, Erk, p38MAPK and Akt were not phosphorylated in Non-responder B-CLL cells indicating a block in signalling and possible anergy. CD180 may provide powerful expansion and survival signals for Responder B-CLL cells and have an important prognostic value.

Antígenos CD/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Idoso , Idoso de 80 Anos ou mais , Apoptose/imunologia , Linfócitos B/imunologia , Antígenos CD40/imunologia , Ciclo Celular/imunologia , Proliferação de Células , Sobrevivência Celular/imunologia , Células Cultivadas , Sinergismo Farmacológico , Humanos , Imunofenotipagem , Interleucina-4/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Fosforilação , Proteínas Recombinantes/imunologia , Transdução de Sinais/imunologia