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Neoplasia ; 14(8): 757-70, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22952428

RESUMO

Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.


Assuntos
Neoplasias Encefálicas/imunologia , Células Dendríticas/imunologia , Glioblastoma/imunologia , Interferon-alfa/imunologia , Microambiente Tumoral , Adenoviridae/genética , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Terapia Genética , Glioblastoma/patologia , Glioblastoma/terapia , Imunoterapia , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Membrana/genética , Ratos , Linfócitos T/imunologia , Timidina Quinase/genética
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