RESUMEN
Recently, we showed that baculovirus (BV)-infected dendritic cells (DCs) (BV-DCs) induced antitumor immunity against established tumors in mice. These antitumor effects were CD8(+) T-cell and natural killer (NK) cell dependent but CD4(+) T-cell independent. In the current study, we examined the antitumor effect of BV-DCs on human pancreatic cancer cells (AsPC-1). After treatment with BV-infected bone marrow-derived dendritic cells (BMDCs), human pancreatic tumors caused by AsPC-1 cells in a nude mouse model were significantly reduced in size, and the survival of the mice was improved compared with that of non-immature BMDC (iDC)- and BV-DC-immunized mice. We also found that wild-type BV could activate human DCs (HDCs) and that NK cells were activated by BV-infected HDCs (BHDCs). Our findings show that BV-DCs can induce antitumor immunity, which paves the way for the use of this technique as an effective tool for DC immunotherapy against malignancies.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Dendríticas/virología , Células Asesinas Naturales/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Animales , Baculoviridae/fisiología , Células Cultivadas , Células Dendríticas/inmunología , Femenino , Humanos , Inmunoterapia , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Pancreáticas/patología , Análisis de Supervivencia , Neoplasias PancreáticasRESUMEN
The importance of natural killer (NK) cells in innate immune responses against tumors or viral infections enhances the appeal of NK cell-based immunotherapeutic approaches. We have recently reported that baculovirus (BV)-infected dendritic cells (DCs; BV-DCs) induce antitumor immunity against established tumors in mice. These antitumor effects were CD8+ T-cell and NK cell dependent; however, they were found to be CD4+ T-cell independent. In this study, we investigated the involvement of Toll-like receptor 9 (TLR9) in the process of BV recognition by NK cells. We found that BV directly stimulated NK cells, induced the expression of the activation marker CD69 and promoted interferon-gamma (IFN-γ) production and cytotoxicity. Moreover, TLR9 knockout in mice (tlr9-/- NK cells) inhibited NK cell responses to BV, indicating that TLR9 may have a relevant role in the BV-induced upregulation of NK cell functions. Our data demonstrated for the first time that NK cells directly recognize BV via TLR9, which provides opportunities for the use of this technique as an effective tool for BV-based immunotherapies against malignancies.
Asunto(s)
Baculoviridae/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Receptor Toll-Like 9/inmunología , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Femenino , Inmunoterapia , Interferón gamma/genética , Interferón gamma/inmunología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Activación de Linfocitos/genética , Ratones , Ratones Noqueados , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/terapia , Receptor Toll-Like 9/genéticaRESUMEN
In order to define the effect of Type 2 (non-insulin-dependent) diabetes mellitus on the ability of insulin to regulate plasma-free fatty acid (FFA) concentrations, we determined the plasma FFA response to the intravenous infusion of various amounts of insulin. Plasma FFA concentrations were higher in patients with Type 2 diabetes (two way analysis of variance, p less than 0.001) over a plasma insulin concentration which ranged from approximately 5 to 55 mU/l of insulin. Although plasma FFA concentrations were higher in patients with Type 2 diabetes at any given insulin concentration, the relative ability of insulin to suppress plasma FFA concentration to half the initial value was comparable in normal individuals and patients with Type 2 diabetes, occurring at a plasma insulin concentration of approximately 20 mU/l. These data demonstrate that plasma FFA levels are regulated over a narrow range of plasma insulin concentrations in humans, and that plasma concentrations are higher than normal in patients with Type 2 diabetes throughout this range.