RESUMEN
Because human epidermal growth factor-like receptor (HER) 2 is expressed on the surface of human pancreatic carcinoma cells to varying degrees, trastuzumab, an anti-HER2 monoclonal antibody (mAb), is expected to exert antibody-dependent, natural killer (NK) cell-mediated cytotoxicity (ADCC) against the cells. However, some reports found that the effect of trastuzumab against human pancreatic carcinoma cells was limited because most express only limited HER2. We examined whether anti-CD137 stimulating mAb could enhance trastuzumab-mediated ADCC against Panc-1, a human pancreatic cancer cell line with low HER2 expression, in vitro. Supplementation of anti-CD137 mAb could improve trastuzumab-mediated ADCC against Panc-1 which was insufficient without this stimulating antibody. The ADCC differed in individual cells, and this was related to the expression of CD137 on the surface of NK cells after trastuzumab stimulation in association with the Fcγ-RIIIA polymorphism. NK cells with Fcγ-RIIIA-VV/VF showed high levels of ADCC against Panc-1, but those with Fcγ-RIIIA-FF did not show optimal ADCC. In addition, trastuzumab-mediated ADCC against the human pancreatic cancer cell line Capan-1 with high HER2 expression was generally high and not affected by the Fcγ-RIIIA polymorphism. These results demonstrated that in Fcγ-RIIIA-VV/VF-carrying healthy individuals, trastuzumab plus αCD137 mAb could induce effective ADCC against HER2-low-expressing pancreatic cancer cell lines, and that such an approach may result in similar findings in patients with pancreatic cancer.
Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Células Asesinas Naturales/inmunología , Neoplasias Pancreáticas/inmunología , Receptor ErbB-2/inmunología , Trastuzumab/farmacología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/antagonistas & inhibidores , Antineoplásicos Inmunológicos/inmunología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Células Asesinas Naturales/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Polimorfismo Genético , Receptor ErbB-2/genética , Receptores de IgG/genética , Receptores de IgG/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
Cancer immunosurveillance failure is largely attributed to the insufficient activation of tumor-specific class I major histocompatibility complex (MHC) molecule (MHC-I)-restricted CD8⺠cytotoxic T lymphocytes (CTLs). DEC-205⺠dendritic cells (DCs), having the ability to cross-present, can present captured tumor antigens on MHC-I alongside costimulatory molecules, inducing the priming and activation of tumor-specific CD8⺠CTLs. It has been suggested that reduced levels of costimulatory molecules on DCs may be a cause of impaired CTL induction and that some tumors may induce the downregulation of costimulatory molecules on tolerogenic DCs. To examine such possibilities, we established two distinct types of murine hepatoma cell lines, named Hepa1-6-1 and Hepa1-6-2 (derived from Hepa1-6 cells), and confirmed that they display similar antigenicities, as well as identical surface expression of MHC-I. We found that Hepa1-6-1 had the ability to grow continuously after subcutaneous implantation into syngeneic C57BL/6 mice and did not prime CD8⺠CTLs. In contrast, Hepa1-6-2 cells, which display reduced levels of adhesion molecules, such as Intercellular Adhesion Molecule 1 (ICAM-1), failed to grow in vivo and efficiently primed CTLs. Moreover, Hepa1-6-1-derived factors, such as transforming growth factor (TGF)-ß1, vascular endothelial growth factor (VEGF) and α-fetoprotein (AFP), converted CD11c(high) MHC-II(high) DEC-205⺠DC subsets into tolerogenic cells, displaying downregulated costimulatory molecules and having impaired cross-presenting capacities. These immunosuppressive tolerogenic DCs appeared to inhibit the induction of tumor-specific CD8⺠CTLs and suppress their cytotoxic functions within the tumor. Together, the findings presented here provide a new method of cancer immunotherapy using the selective suppression, depletion or alteration of immunosuppressive tolerogenic DCs within tumors.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/inmunología , Células Dendríticas/inmunología , Animales , Antígenos CD/metabolismo , Antígenos de Neoplasias/inmunología , Antígeno CD11c/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Reactividad Cruzada , Citotoxicidad Inmunológica , Regulación Neoplásica de la Expresión Génica , Tolerancia Inmunológica , Terapia de Inmunosupresión , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Lectinas Tipo C/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Antígenos de Histocompatibilidad Menor , Trasplante de Neoplasias , Receptores de Superficie Celular/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Carga Tumoral , Escape del Tumor , Factor A de Crecimiento Endotelial Vascular/metabolismo , alfa-Fetoproteínas/metabolismoRESUMEN
Because regulatory T (Treg) cells play an important role in modulating the immune system response against both endogenous and exogenous antigens, their control is critical to establish immunotherapy against autoimmune disorders, chronic viral infections and tumours. Ribavirin (RBV), an antiviral reagent used with interferon, is known to polarize the T helper (Th) 1/2 cell balance toward Th1 cells. Although the immunoregulatory mechanisms of RBV are not fully understood, it has been expected that RBV would affect T reg cells to modulate the Th1/2 cell balance. To confirm this hypothesis, we investigated whether RBV modulates the inhibitory activity of human peripheral CD4(+) CD25(+) CD127(-) T cells in vitro. CD4(+) CD25(+) CD127(-) T cells pre-incubated with RBV lose their ability to inhibit the proliferation of CD4(+) CD25(-) T cells. Expression of Forkhead box P3 (FOXP3) in CD4(+) CD25(-) T cells was down-modulated when they were incubated with CD4(+) CD25(+) CD127(-) T cells pre-incubated with RBV without down-modulating CD45RO on their surface. In addition, transwell assays and cytokine-neutralizing assays revealed that this effect depended mainly on the inhibition of interleukin-10 (IL-10) produced from CD4(+) CD25(+) CD127(-) T cells. These results indicated that RBV might inhibit the conversion of CD4(+) CD25(-) FOXP3(-) naive T cells into CD4(+) CD25(+) FOXP3(+) adaptive Treg cells by down-modulating the IL-10-producing Treg 1 cells to prevent these effector T cells from entering anergy and to maintain Th1 cell activity. Taken together, our findings suggest that RBV would be useful for both elimination of long-term viral infections such as hepatitis C virus infection and for up-regulation of tumour-specific cellular immune responses to prevent carcinogenesis, especially hepatocellular carcinoma.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Interleucina-10/inmunología , Ribavirina/farmacología , Linfocitos T Reguladores/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Células Cultivadas , Factores de Transcripción Forkhead/inmunología , Humanos , Interleucina-10/biosíntesis , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-7/inmunologíaRESUMEN
BACKGROUND AND AIM: The immunological mechanism by which ribavirin (RBV) polarizes the T-helper (Th) 1/2 balance toward Th1 predominancy is not fully understood. We therefore examined whether RBV affects costimulatory signaling, which is known to be essential for regulating the Th1/2 balance. METHODS: The expression of costimulatory molecules and their ligands, and levels of various cytokines, released from CD4(+) T cells obtained from healthy individuals or patients with chronic hepatitis C virus (HCV) infection were analyzed. RESULTS: In CD4(+) T cells, RBV selectively downmodulates the expression of inducible costimulator (ICOS), a ligand for B7-H2 on dendritic cells, which mainly differentiates Th0 into Th2 cells. Moreover, the levels of interleukin-10 (IL-10) released from RBV-stimulated CD4(+) T cells also decreased, indicating that the downmodulation of ICOS induced by RBV might be correlated with the decrease in IL-10 released from Th cells, leading to the inhibition of Th2 activity. An analysis of the association between ICOS kinetics and hepatitis C virus (HCV) elimination in hepatitis C patients receiving combined pegylated interferon and RBV indicated that HCV elimination tended to occur more frequently in patients showing ICOS downmodulation with RBV treatment. A decrease in IL-10 production by CD4(+) T cells was also observed in association with ICOS downregulation in patients who succeeded in HCV elimination. CONCLUSIONS: The downmodulation of ICOS in correlation with a reduction in IL-10 produced by CD4(+) T cells is possibly the immunological mechanism of action of RBV, which polarizes the Th1/2 balance toward a Th1 cytokine profile, thus contributing to the elimination of cells chronically infected with HCV.
Asunto(s)
Antivirales/farmacología , Linfocitos T CD4-Positivos/metabolismo , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Interleucina-10/metabolismo , Ribavirina/farmacología , Adulto , Anciano , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Células Dendríticas/metabolismo , Regulación hacia Abajo , Femenino , Hepacivirus , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Humanos , Ligando Coestimulador de Linfocitos T Inducibles/efectos de los fármacos , Proteína Coestimuladora de Linfocitos T Inducibles/efectos de los fármacos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Transducción de Señal , Carga ViralRESUMEN
BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) has recently been reported to be effective in the treatment of cirrhotic patients with refractory ascites. However, the clinical utility of TIPS in the subset of refractory ascitic patients with good hepatic and renal function is uncertain. The aim of this study was to compare the efficacy of TIPS to that of large-volume paracentesis in cirrhotic patients with refractory ascites who have good hepatic and renal function. METHODS: Sixty cirrhotic patients with refractory ascites who presented with a Child-Pugh score of <11, serum bilirubin of <3 mg/dl and creatinine of <1.9 mg/dl were assigned randomly to TIPS (n = 30) or large-volume paracentesis plus albumin (n = 30). The primary endpoint was survival. The secondary endpoints were response to treatment and development of hepatic encephalopathy. RESULTS: The baseline characteristics were similar in the two groups. Seventeen patients treated with TIPS and 21 treated with paracentesis died during the study period. The cumulative probabilities of survival at 1 and 2 years were 80 and 64% in the TIPS group and 49 and 35% in the paracentesis group (p < 0.005). TIPS was significantly superior to paracentesis in the control of ascites (p < 0.005). Treatment failure was more frequent in the paracentesis group, whereas the frequency of hepatic encephalopathy was greater in the TIPS group. CONCLUSIONS: In cirrhotic patients with refractory ascites who have good hepatic and renal function, TIPS improves survival and provides better control of ascites than large-volume paracentesis.
Asunto(s)
Ascitis/cirugía , Cirrosis Hepática/cirugía , Paracentesis , Derivación Portosistémica Intrahepática Transyugular , Anciano , Albúminas/uso terapéutico , Ascitis/mortalidad , Ascitis/fisiopatología , Ascitis/prevención & control , Terapia Combinada , Diuréticos/uso terapéutico , Femenino , Encefalopatía Hepática/etiología , Encefalopatía Hepática/fisiopatología , Humanos , Cirrosis Hepática/mortalidad , Cirrosis Hepática/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Resultado del Tratamiento , Ultrasonografía Doppler en ColorRESUMEN
BACKGROUND AND AIM: Terlipressin has been shown to be effective in the management of hepatorenal syndrome. However, how terlipressin exerts its effect on the renal artery is unknown. The aim of the present study was to assess the effects of terlipressin on systemic, hepatic and renal hemodynamics in cirrhosis. METHODS: Twenty-eight patients with cirrhosis and portal hypertension were studied. Systemic and hepatic hemodynamics, hepatic and renal arterial resistive indices and neurohumoral factors were measured prior to and 30 min after intravenous administration of 1 mg terlipressin (n = 19) or placebo (n = 9). RESULTS: After terlipressin, there were significant increases in both mean arterial pressure (P < 0.001) and systemic vascular resistance (P < 0.001), whereas heart rate (P < 0.001) and cardiac output (P < 0.001) decreased significantly. There was a significant decrease in the hepatic venous pressure gradient (P < 0.001). Portal venous blood flow also decreased significantly (P < 0.001). The mean hepatic arterial velocity increased significantly (P < 0.001). Although there was a significant decrease in the hepatic arterial resistive index (0.72 +/- 0.08 to 0.69 +/- 0.08, P < 0.001) and renal arterial resistive index (0.74 +/- 0.07 to 0.68 +/- 0.07, P < 0.001), portal vascular resistance was unchanged (P = 0.231). Plasma renin activity decreased significantly (P < 0.005), and there was a significant correlation between this decline and the decrease in renal arterial resistive index (r = 0.764, P < 0.005). The effects of terlipressin on systemic, hepatic and renal hemodynamics were observed similarly in patients with and without ascites. Placebo caused no significant effects. CONCLUSION: Terlipressin decreases hepatic and renal arterial resistance in patients with cirrhosis.
Asunto(s)
Hemodinámica/efectos de los fármacos , Síndrome Hepatorrenal/tratamiento farmacológico , Hipertensión Portal/tratamiento farmacológico , Circulación Hepática/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Lipresina/análogos & derivados , Circulación Renal/efectos de los fármacos , Vasoconstrictores/uso terapéutico , Anciano , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Síndrome Hepatorrenal/diagnóstico por imagen , Síndrome Hepatorrenal/etiología , Síndrome Hepatorrenal/fisiopatología , Humanos , Hipertensión Portal/diagnóstico por imagen , Hipertensión Portal/etiología , Hipertensión Portal/fisiopatología , Inyecciones Intravenosas , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/fisiopatología , Lipresina/administración & dosificación , Lipresina/efectos adversos , Lipresina/uso terapéutico , Masculino , Persona de Mediana Edad , Neurotransmisores/sangre , Efecto Placebo , Terlipresina , Resultado del Tratamiento , Ultrasonografía Doppler , Resistencia Vascular/efectos de los fármacos , Vasoconstrictores/administración & dosificación , Vasoconstrictores/efectos adversosRESUMEN
In this prospective cohort study, we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 50 patients with refractory ascites and a Child-Pugh score of 9.8. The mean duration of follow-up was 592 days. Ascites improved in 96% at 1 year and in 93% at 2 years. The cumulative survival rate was 71%, 52% and 18% at 1, 2 and 5 years. The Child-Pugh score and the performance status score improved significantly after TIPS. Thirty six patients required shunt revision during follow-up, due to shunt stenosis. Hepatic encephalopathy which was able to be controlled medically occurred in 26 patients. Our results suggest that although shunt revision may be needed, TIPS can control refractory ascites in most survival cases and improve QOL. However, the 5-year survival rate is still low in our TIPS-treated patients with refractory ascites.