Prieto, J. (Jesús)
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- Induction of potent and long-lasting CD4 and CD8 T-cell responses against hepatitis C virus by immunization with viral antigens plus poly(I:C) and anti-CD40(Elsevier masson, 2007) Dotor, J. (Javier); Zabaleta, A. (Aintzane); Borras-Cuesta, F. (Francisco); Quer, J. (Josep); Esteban, J.I. (Juan Ignacio); Prieto, J. (Jesús); Llopiz, D. (Diana); Vayreda, F. (Francesc); Sarobe, P. (Pablo); Arribillaga, L. (Laura); Lasarte, J.J. (Juan José)Development of vaccination strategies against hepatitis C virus (HCV) is of paramount importance. With this aim, we tested the ability of dendritic cell-activating reagents polyinosinic-polycytidylic acid (poly(I:C)) and anti-CD40, as adjuvants to induce T-cell responses against HCV. Immunization of mice with these adjuvants induced dendritic cell maturation in vivo. Also, joint administration of poly(I:C) and anti-CD40 plus HCV antigens had a synergistic effect on the induction of anti-HCV T-cell responses. CD4 responses displayed a Th1 cytokine profile, and CD8 responses could be induced by immunization with a minimal CD8 epitope. Addition of a low amount of NS3 protein (as a source of Th epitopes) to the immunization mixture enhanced CD8 responses, whereas immunization with higher doses of NS3 induced both CD4 and CD8 responses. Surprisingly, immunization with NS3 protein but not with CD8 epitopes was able to induce CD8 responses and able to recognize cells expressing HCV antigens endogenously. Moreover, immunization with these adjuvants activated NK cells, which in turn helped to induce Th1 responses. Finally, this combined immunization protocol afforded long-lasting T-cell responses, suggesting that this strategy may prove to be useful in vaccination and/or treatment of HCV infection.
- An oncolytic adenovirus controlled by a modified telomerase promoter is attenuated in telomerase-negative cells, but shows reduced activity in cancer cells(Springer, 2005) Gomar, C. (Celia); Qian, C. (Cheng); Kramer, M.G. (María Gabriela); Farinati, F. (F.); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén)
- Risk factors for recurrence of hepatitis C after liver transplantation.(Wiley-Blackwell, 1998) Civeira, M.P. (María Pilar); Peña, A. (Andrés) de la; Álvarez-Cienfuegos, J. (Javier); Sola, J. (Josu); Sangro, B. (Bruno); Prieto, J. (Jesús); Herrero, J.I. (José Ignacio); Garcia, N. (Nicolás); Quiroga, J. (Jorge)Recurrent hepatitis C is a frequent complication after liver transplantation for hepatitis C virus– related cirrhosis, but risk factors related to its development remain ill defined. Twenty-three patients receiving a primary liver graft for hepatitis C virus–related cirrhosis and with an assessable biopsy performed at least 6 months after liver transplantation were studied retrospectively. The end point of this study was to look for risk factors associated with the development of histologic hepatitis C in the graft. Thirty-six major variables were studied, and those reaching significance by univariate analysis were included in a multivariate analysis. Eighteen patients (78%) developed posttransplant hepatitis C. On univariate analysis, six variables showed significant predictive value: increased immunosuppression for treatment of acute rejection; pretransplant hepatocellular carcinoma; cumulative doses of prednisone at 3, 6, and 12 months after transplantation; and mean blood trough levels of cyclosporine in the first 6 months posttransplantation. On multivariate analysis, two variables retained independent statistical significance as predictors of hepatitis C recurrence, namely receipt of antirejection therapy (P 5 .0087) and lower mean cyclosporine levels in the first 6 months after transplantation (P 5 .0134). Therefore, recurrence of hepatitis C after liver transplantation seems to be at least partially related to posttransplantation immunosuppressive therapy.
- The stilbene disulfonic acid DIDS stimulates the production of TNF-alpha in human lymphocytes(Elsevier, 1992) Civeira, M.P. (María Pilar); Arrazola, A. (Arantxa); Larrea, E. (Esther); Medina, J.F. (Juan Francisco); Diez-Martinez, J. (Javier); Qian, C. (Cheng); Prieto, J. (Jesús); Garciandia, A. (Ana)Exposure of human peripheral blood mononuclear cells (PBMC) to the stilbene derivative DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) (60 microM and above) significantly increased the release of tumor necrosis factor-alpha (TNF-alpha), as determined by TNF-alpha activity in the incubation media. When the TNF-alpha message was analyzed in PBMC by a reverse transcription/polymerase chain reaction (RT/PCR)-based procedure, it was found that incubation with DIDS (60 microM) was followed by a time-dependent accumulation of TNF-alpha mRNA. Measurements of intracellular pH showed that the presence of increasing concentrations of DIDS resulted in a progressive intracellular alkalinization of PBMC. It is suggested that the known DIDS effect of inhibiting transmembrane anion exchange, i.e., chloride/bicarbonate exchange, might play a role in the stimulation of TNF-alpha production by PBMC exposed to DIDS.
- Enhanced therapeutic effect using sequential administration of antigenically distinct oncolytic viruses expressing oncostatin M in a Syrian hamster orthotopic pancreatic cancer model(BioMed Central, 2015) González-Aseguinolaza, G. (Gloria); Bravo-Perez, C. (Carlos); Quetglas, J.I. (José Ignacio); Larrea, E. (Esther); Poutou, J. (Joanna); Nistal-Villan, E. (Estanislao); Prieto, J. (Jesús); Hernandez-Alcoceba, R. (Rubén); Buñuales, M. (María); Carte, B. (Beatriz); Gonzalez-Aparicio, M. (Manuela)The limited efficacy of current treatments against pancreatic cancer has prompted the search of new alternatives such as virotherapy. Activation of the immune response against cancer cells is emerging as one of the main mechanisms of action of oncolytic viruses (OV). Direct oncolysis releases tumor antigens, and viral replication within the tumor microenvironment is a potent danger signal. Arming OV with immunostimulatory transgenes further enhances their therapeutic effect. However, standard virotherapy protocols do not take full advantage of OV as cancer vaccines because repeated viral administrations may polarize immune responses against strong viral antigens, and the rapid onset of neutralizing antibodies limits the efficacy of redosing. An alternative paradigm based on sequential combination of antigenically distinct OV has been recently proposed.
- Gene therapy of cancer based on interleukin 12(Bentham Science Publishers, 2005) Qian, C. (Cheng); Sangro, B. (Bruno); Melero, I. (Ignacio); Prieto, J. (Jesús)Tumor formation and growth depends mainly on the inability of the organism to elicit a potent immune response, and on the formation of new blood vessels that enable tumor nutrition. Interleukin-12 (IL-12) therapy can target both processes. And IL-12-based gene therapy may restrict IL-12 production to the relevant site in order to obtain enhanced antitumor activity and reduced toxicity. In the clinical setting, IL-12 gene transfer can be used either to improve the pharmacokinetic/pharmacodynamic profile of the cytokine, to transduce dendritic cells or to enhance the efficiency of antitumor vaccination. It can also synergize with other procedures involving the simultaneous transfer of other transgenes or non-gene based strategies. The strong anti-tumoral power shown in many different animal models has not been found in early clinical trials in which cancer patients were treated by peritumoral injections of autologous fibroblasts producing IL-12, intratumoral injections of an adenoviral vector encoding human IL-12 genes, or intratumoral injection of autologous dendritic cells transduced ex vivo with this same adenoviral vector. However, these trials have set the proof-of-concept that local production of IL-12 inside a tumor can stimulate tumor infiltration by effector immune cells and that in some cases it is followed by tumor regression. From the many questions that arise after these disappointing results the most relevant concerns the duration and intensity of transgene expression and the capability to monitor this topics in vivo. New vectors that might achieve regulated, long-term production of this cytokine might have better results and merit clinical testing.
- Regulation of stathmin phosphorylation in mouse liver progenitor-29 cells during proteasome inhibition(Wiley-VCH Verlag Berlin, 2009) Mora, M.I. (María I.); Corrales, F.J. (Fernando José); Sanchez-Quiles, V. (Virginia); Fernandez-Irigoyen, J. (Joaquín); Prieto, J. (Jesús); Muñoz, J. (Javier); Santamaria, E. (Enrique)Proteasome inhibitors are potential therapeutic agents in the treatment of hepatocarcinoma and other liver diseases. The analysis of alternative protein phosphorylation states might contribute to elucidate the underlying mechanisms of proteasome inhibitor-induced apoptosis. We have investigated the response of mouse liver progenitor-29 (MLP-29) cells to MG132 using a combination of phosphoprotein affinity chromatography, DIGE, and nano LC-MS/MS. Thirteen unique deregulated phosphoproteins involved in chaperone activity, stress response, mRNA processing and cell cycle control were unambiguously identified. Alterations in NDRG1 and stathmin suggest new mechanisms associated to proteasome inhibitor-induced apoptosis in MLP-29 cells. Particularly, a transient modification of the phosphorylation state of Ser(16), Ser(25) and Ser(38), which are involved in the regulation of stathmin activity, was detected in three distinct isoforms upon proteasome inhibition. The parallel deregulation of calcium/calmodulin-activated protein kinase II, extracellular regulated kinase-1/2 and cyclin-dependent kinase-2, might explain the modified phosphorylation pattern of stathmin. Interestingly, stathmin phosphorylation profile was also modified in response to epoxomicin treatment, a more specific proteasome inhibitor. In summary, we report here data supporting that regulation of NDRG1 and stathmin by phosphorylation at specific Ser/Thr residues may participate in the cellular response induced by proteasome inhibitors.
- Combination of a TLR4 ligand and anaphylatoxin C5a for the induction of antigen-specific cytotoxic T cell responses(Elsevier, 2012) Leclerc, C. (Claude); Fayolle, C. (Catherine); Pio, R. (Rubén); Lozano-Moreda, T. (Teresa); Rudilla, F. (Francesc); Durantez, M. (Maika); Casares, N. (Noelia); Prieto, J. (Jesús); Sarobe, P. (Pablo); Villanueva, L. (Lorea); Arribillaga, L. (Laura); Lasarte, J.J. (Juan José)The complement system and Toll-like receptors (TLR) are key innate defense systems which might interact synergistically on dendritic cells (DC) to reinforce adaptive immunity. In a previous work, we found that the extra domain A from fibronectin EDA (an endogenous ligand for TLR4) can favour antigen delivery to DC and induce their maturation. Given the potential of anaphylatoxins to cause inflammation and activation of myeloid cells, we hypothesized that a fusion protein between EDA, and anaphylatoxins C3a, C4a or C5a together with an antigen might improve the immunogenicity of the antigen. Naked DNA immunization with a construct expressing the fusion protein between C5a, EDA and the cytotoxic T cell epitope SIINFEKL from ovalbumin, induced strong antigen specific T cell responses. The purified recombinant fusion protein EDA-SIINFEKL-C5a induced activation of dendritic cells, the production of proinflammatory cytokines/chemokines and stimulated antigen presenting cell migration and NK cell activation. As compared to EDA-SIINFEKL, the fusion protein EDA-SIINFEKL-C5a did not induce the production of the immunosuppressive molecules IL-10, CCL17, CCL1, CXCL12 or XCL1 by DC. Moreover, EDA-SIINFEKL-C5a induced strong specific T cell responses in vivo and protected mice against E.G7-OVA tumor growth more efficiently than EDA-SIINFEKL or SIINFEKL-C5a recombinant proteins. Our results suggest that fusion proteins containing EDA, the anaphylatoxin C5a and the antigen may serve as a suitable strategy for the development of anti-tumor or anti-viral vaccines.
- Liver transplantation in cirrhotic patients with diabetes mellitus: Midterm results, survival, and adverse events(Wiley-Blackwell, 2001) Pardo, F. (Fernando); Álvarez-Cienfuegos, J. (Javier); Gomez-Manero, N. (Noemí); Sangro, B. (Bruno); Prieto, J. (Jesús); Herrero, J.I. (José Ignacio); Quiroga, J. (Jorge); Blanco, J.J. (Jose J.)Liver cirrhosis is frequently associated with diabetes mellitus (DM), and this metabolic complication is also frequent after orthotopic liver transplantation (OLT). The aim of our study is to investigate which factors are associated with DM before and after OLT and their impact on post-OLT evolution. We evaluated the prevalence of DM among 115 liver transplant candidates with cirrhosis and assessed their evolution after OLT (median follow-up, 41 months). Sixteen candidates had DM requiring pharmacological therapy (group A), 45 candidates had DM controlled with diet (group B), and 54 candidates did not have DM (group C). One-year and 3-year actuarial survival rates were 100% and 100% for group A, 91% and 85% for group B, and 77% and 74% for group C, respectively (P <.03). Post-OLT DM was more frequent in group A. The incidence of other metabolic complications, major infections, rejection, and arterial hypertension; the need for hospitalization; and renal and graft function of patients in groups A, B, and C were similar. The only risk factor for DM 1 year after OLT on multivariate analysis was pre-OLT DM requiring pharmacological treatment. The incidence of complications, need for hospitalization, and renal and graft function 1 year after OLT for patients with post-OLT DM were similar to those of patients without post-OLT DM. In conclusion, patients with cirrhosis who have DM have a greater risk for post-OLT DM, but their midterm survival is not worse than the survival of those without DM.
- Blockade of Wnt signaling inhibits angiogenesis and tumor growth in hepatocellular carcinoma(American association for cancer research, 2009) Shan, J. (Juanjuan); Kawa, M. (Milosz); Qian, C. (Cheng); Dong, A. (Aiwen); Hu, J. (Jie); Prieto, J. (Jesús); Fernandez-Ruiz, V. (Verónica); Martinez-Anso, E. (Eduardo)Aberrant activation of Wnt signaling plays an important role in hepatocarcinogenesis. In addition to direct effects on tumor cells, Wnt signaling might be involved in the organization of tumor microenvironment. In this study, we have explored whether Wnt signaling blockade by exogenous expression of Wnt antagonists could inhibit tumor angiogenesis and control tumor growth. Human Wnt inhibitory factor 1 (WIF1) and secreted frizzled-related protein 1 (sFRP1) were each fused with Fc fragment of human IgG1 to construct fusion proteins WIF1-Fc and sFRP1-Fc. The recombinant adenoviral vectors carrying WIF1-Fc and sFRP1-Fc driven by cytomegalovirus promoter were constructed. Ad-WIF1-Fc or Ad-sFRP1-Fc induced the expression and correct conformation of WIF1-Fc and sFRP1-Fc fusion proteins. These molecules caused down-regulation of E2F1, cyclin D1, and c-myc and promoted cell apoptosis in hepatocellular carcinoma cells. Treatment of established hepatocellular carcinoma tumors with Ad-WIF1-Fc and/or Ad-sFRP1-Fc resulted in significant inhibition of tumor growth and prolonged animal survival. The antineoplastic effect was associated with increased apoptosis of tumor cells, reduced microvessel density, and decreased expression of vascular endothelial growth factor and stromal cell-derived factor-1. Tube formation and migration of human microvascular endothelial cells and mouse endothelial progenitor cells (EPC) were significantly inhibited by both WIF1-Fc and sFRP1-Fc. In addition, these molecules blocked EPC differentiation and caused EPC apoptosis. Our data indicate that Wnt antagonists WIF1-Fc and sFRP1-Fc inhibit Wnt signaling and exert potent antitumor activity by increasing the apoptosis rate in tumor cells and by impairing tumor vascularization.