RESUMEN
Dendritic cell (DC)-based vaccines have been applied clinically in the setting of advanced-stage cancer. To date, the clinical efficacy of these vaccines has been limited, possibly owing to the impairment of transferred DC function in cancer-bearing patients. In this study, we examined the therapeutic efficacy of interleukin-12 (IL-12) gene-transfected DCs isolated from tumor-bearing hosts against liver tumor. The endogenous DCs isolated from subcutaneous (s.c.) CMS4 tumor-bearing mice (CMS4DC) exhibited decreased expression levels of antigen-presenting molecules and low-allostimulatory capacity. CMS4DC produced less IL-12p70 than DCs isolated from normal mice. Adenoviral transfection of IL-12 gene into CMS4DC (AdIL12DC) restored the expression of antigen-presenting molecules and allostimulatory capacity. Intratumoral (i.t.) delivery of AdIL12DC resulted in complete rejection of intrahepatic CMS4 tumors and activation of innate and acquired immune cells. Antibody depletion studies revealed that both CD4(+) and CD8(+) T cells as well as natural killer cells play critical roles in mediating liver tumor rejection. I.t. treatment of AdIL12DC resulted in long-term protection against s.c. rechallenge with CMS4 tumor cells. These results revealed that IL-12 gene transfer is capable of improving the impaired functions of DC isolated from tumor-bearing hosts, and support the preclinical therapeutic efficacy of intrahepatic injection of AdIL12DC.
Asunto(s)
Vacunas contra el Cáncer/administración & dosificación , Células Dendríticas/inmunología , Terapia Genética/métodos , Inmunoterapia Adoptiva/métodos , Interleucina-12/inmunología , Neoplasias Hepáticas/terapia , Adenoviridae/genética , Animales , Vacunas contra el Cáncer/inmunología , Pruebas Inmunológicas de Citotoxicidad/métodos , Femenino , Citometría de Flujo , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Inyecciones Intralesiones , Interleucina-12/genética , Células Asesinas Naturales/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/prevención & control , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales , Linfocitos T Citotóxicos/inmunología , Factores de Tiempo , Transducción Genética/métodosRESUMEN
PURPOSE: To assess the utility of secretin-stimulated dynamic MR cholangiopancreatography (MRCP) for the visualization of pancreaticobiliary reflux in patients with anomalous pancreaticobiliary junction (PBJ). MATERIAL AND METHODS: Ten controls and seven patients diagnosed as having anomalous PBJ were prospectively examined by dynamic MRCP after secretin injection using a breath-hold, single-shot turbo spin-echo T2-weighted sequence. The optimal MRCP section was repeated 35 times at approx. 10-second interval after secretin injection; the acquisition time was 4 s per image. The signal intensity (SI) changes of the extrahepatic and intrahepatic bile ducts, presence or absence of intraluminal signal void, caliber change of the bile duct, duodenal filling, and peak time of the SI ratio of the extrahepatic bile duct after secretin injection were compared between the controls and patients. RESULTS: In the controls, the extrahepatic and intrahepatic bile ducts showed neither enhancement nor caliber change over the observation period, providing no apparent peak time. Of the seven patients, the extrahepatic bile duct showed retrograde enhancement and sequential delay in occurrence of the peak time from its distal third to its proximal third (n = 6) with a signal void in its distal part (n =4); its caliber increased subsequently to pancreatic secretion (n = 5); the intrahepatic bile ducts showed a slight enhancement following SI increase of the proximal extrahepatic bile duct (n = 6); duodenal filling grade tended to be lower in the patients than volunteers (P<.005). CONCLUSION: In patients with anomalous PBJ pancreaticobiliary reflux were demonstrated by dynamic secretin-stimulated MRCP.
