RESUMEN
Overcoming immune tolerance of tumor angiogenesis should be useful for adjuvant therapy of cancer. We hypothesized that vaccination with autologous endothelium would induce an autoimmune response targeting tumor angiogenesis. To test this concept, we immunized BALB/c mice with a vaccine of glutaraldehyde-fixed murine hepatic sinusoidal endothelial cells (HSEs) in a lung metastasis model of Colon-26 cancer. Vaccination with autologous HSEs induced both preventive and therapeutic anti-tumor immunity that significantly inhibited the development of metastases. ELISA revealed an immunoglobulin response involving IgM and IgG subclasses. These antibodies had a strong affinity for antigens of both murine and human endothelium, and lyzed endothelial cells in the CDC assay. Flow-cytometry and chromium-release cytotoxicity assay revealed a specific CTL response against endothelial cells, which were lyzed in an effector: target ratio-dependent manner. Neither antibodies nor CTLs reacted with Colon-26. The effect of autologous HSEs was more pronounced than that of xenogeneic human umbilical vein endothelial cells (HUVECs), which were tested in the same experimental setting. Our results suggest that vaccination with autologous endothelium can overcome peripheral tolerance of self-angiogenic antigens and therefore should be useful for adjuvant immunotherapy of cancer.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Endotelio/inmunología , Neoplasias Pulmonares/secundario , Neovascularización Patológica/tratamiento farmacológico , Animales , Autoantígenos/inmunología , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Pruebas Inmunológicas de Citotoxicidad , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Invasividad Neoplásica , Linfocitos T Citotóxicos/inmunología , Venas Umbilicales/citologíaRESUMEN
Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.