Schmitz, V. (Volker)
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- An anti-ICAM-2 (CD102) monoclonal antibody induces immune-mediated regressions of transplanted ICAM-2-negative colon carcinomas(American Association for Cancer Research, 2002) Albar, J.P. (Juan P.); Mazzolini, G. (Guillermo); Gabari, I. (Izaskun); Melero, I. (Ignacio); Prieto, J. (Jesús); Tirapu, I. (Íñigo); Camafeita, E. (Emilio); Relloso, M. (Miguel); Schmitz, V. (Volker); Rodriguez-Calvillo, M. (Mercedes); Corbi, A.L. (Angel L.)Monoclonal antibodies (mAbs) can mediate antitumor effects by indirect mechanisms involving antiangiogenesis and up-regulation of the cellular immune response rather than by direct tumor cell destruction. From mAbs raised by immunization of rats with transformed murine endothelial cells, a mAb (EOL4G8) was selected for its ability to eradicate a fraction of established colon carcinomas that did not express the EOL4G8-recognized antigen. The antigen was found to be ICAM-2 (CD102). Antitumor effects of EOL4G8, which required a functional T-cell compartment, were abrogated by depletion of CD8(+) cells and correlated with antitumor CTL activity, whereas only a mild inhibition of angiogenesis was observed. Interestingly, we found that EOL4G8 acting on endothelial ICAM-2 markedly enhances leukotactic factor activity-1-independent adhesion of immature dendritic cells to endothelium-an effect that is at least in part mediated by DC-SIGN (CD209).
- Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12(Wiley Blackwell, 2001) Mazzolini, G. (Guillermo); Genove, G. (Guillem); Qian, C. (Cheng); Sangro, B. (Bruno); Barajas, M. (Miguel); Bilbao, R. (Roberto); Melero, I. (Ignacio); Narvaiza, I. (Íñigo); Prieto, J. (Jesús); Schmitz, V. (Volker)The use of gene therapy to enhance antitumor immunity has emerged as a promising procedure to fight cancer. In this study we have tested the ability of an adenovirus carrying interleukin 12 (IL-12) gene (AdCMVIL-12) to eliminate tumoral lesions in 3 animal models of orthotopic hepatocellular carcinoma (HCC). Intratumoral injection of AdCMVIL-12 in animals with a single big tumor nodule implanted in the liver resulted in significant inhibition of tumor growth in a dose-dependent manner. Fifty percent of animals that received a dose of 5 x 10(9) plaque-forming units, showed complete regression of the tumor 2 weeks after treatment. In animals with 2 independent tumor nodules in the left liver lobe, injection in only one of them of 5 x 10(9) pfu AdCMVIL-12 induced, 15 days after therapy, complete regression of 50% of treated tumors and also of 50% of untreated lesions, with 60% long-term survival. Rats that were tumor free after therapy with AdCMVIL-12 showed protection against tumor rechallenge. A group of rats received the carcinogen diethylnitrosamine and developed multiple hepatic dysplasic nodules of 1 to 5 mm in diameter. These animals were treated by intrahepatic artery injection of either AdCMVIL-12 (5 x 10(9) pfu) or control vector. In this model AdCMVIL-12 induced complete tumor regression in 20% of treated rats and inhibited tumor growth in 60% of cases with an increase in rat survival. Activation of natural killer (NK) cells and inhibition of angiogenesis were found to be antitumor mechanisms set in motion by AdCMVIL-12. Our data indicate that experimental HCC can be efficiently treated by intratumoral or intravascular injection of adenovirus expressing IL-12.
- Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells(Elsevier, 2011) Berasain, C. (Carmen); D'Avola, D. (Delia); Kawa, M. (Milosz); Qian, C. (Cheng); Sangro, B. (Bruno); Iñarrairaegui, M. (Mercedes); Prieto, J. (Jesús); Herrero, J.I. (José Ignacio); Quiroga, J. (Jorge); Schmitz, V. (Volker); Iñiguez, M. (María); Fernandez-Ruiz, V. (Verónica); Martinez-Anso, E. (Eduardo)BACKGROUND & AIMS: Cell therapy has been used to attenuate liver injury. Here we evaluated whether genetic engineering of either bone marrow-derived mononuclear cells (MNC) or endothelial progenitor cells (EPC) many enhance their hepatoprotective properties. METHODS: Mice with ConA-induced hepatitis or with lethal fulminant hepatitis resulting from administration of an adenovirus encoding CD40L (AdCD40L) received an intra-splenic injection of saline or 2 × 10(6) unmodified MNC or EPC or the same cells transduced ex vivo with an adenovirus expressing luciferase (MNCLUC and EPCLUC) or encoding the hepatoprotective cytokine cardiotrophin-1 (CT-1) (MNCCT-1 and EPCCT-1). We analyzed the extent of liver damage, the intensity of inflammatory reaction, and animal survival. RESULTS: Luciferase immunohistochemistry showed that after injection into the spleen, the engineered cells migrated efficiently to the damaged liver. In mice with ConA hepatitis EPCCT-1, but not other forms of cell therapy, significantly decreased serum transaminases and induced more intense histological improvement than other treatments. This superior therapeutic effect was associated with upregulation of cytoprotective molecules including IGF-I and EGF, lower expression of proinflammatory cytokines, IL-1b and TNFα, and decreased granzyme B levels. In AdCD40L-induced lethal fulminant hepatitis, EPCCT-1 also exceeded other cell therapies in attenuating the expression of proinflammatory mediators and hepatic injury enabling 35.7% survival while mortality was 100% in the other treatment groups. CONCLUSIONS: Genetic engineering of EPC to overexpress CT-1 enhances the hepatoprotective properties of EPC and constitutes a therapy that deserves consideration for acute liver failure. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
- Gene therapy for liver diseases: recent strategies for treatment of viral hepatitis and liver malignancies(British Society of Gastroenterology, 2002) Mazzolini, G. (Guillermo); Qian, C. (Cheng); Sangro, B. (Bruno); Melero, I. (Ignacio); Narvaiza, I. (Íñigo); Prieto, J. (Jesús); Schmitz, V. (Volker); Ruiz, J. (Juan)Gene therapy has emerged as a powerful and very plastic tool to regulate biological functions in diseased tissues with application in virtually all medical fields. An increasing number of experimental and clinical studies underline the importance of genes as curative agents in the future. However, intense research is needed to evaluate the potential of gene therapy to improve efficacy and minimise the toxicity of the procedure.