α-Fetoprotein and Interleukin-18 Gene–Modified Dendritic Cells Effectively Stimulate Specific Type-1 CD4- and CD8-Mediated T-Cell Response from Hepatocellular Carcinoma Patients in Vitro
Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Shaanxi Province, China.Human Immunology (Impact Factor: 2.14). 06/2007; 68(5):334-41. DOI: 10.1016/j.humimm.2007.01.008
The T-helper 1 (Th1) immune reaction is most important in dendritic cell (DC)-based immunotherapy. Interleukin (IL)-18, a Th1-biasing cytokine, plays a pivotal role in inducing cytotoxic T lymphocyte (CTL) responses. In this study, we analyzed whether dendritic cells (DCs) from patients with hepatocellular carcinoma (HCC) can be transduced with the IL-18 gene and/or alpha-fetoprotein (AFP) gene, and we examined whether vaccinations using these genetically engineered DC can induce stronger therapeutic antitumor immunity. The results showed that DC transfected with AdIL-18/AFP can expressed IL-18 and AFP by reverse transcriptase-polymerase chain reaction and enzyme-linked immunoassay. Compared with those before transfection, the expressions of membrane molecules were increased dramatically. Specific T cells generated by DC transfected with AdIL-18/AFP recognized HLA-matched HepG2 cell lines specifically. Most importantly, The cytotoxic activity of CTLs against HepG2 with DC expressing AFP(AFP-DC) was significantly augmented by co-transduction with the IL-18 gene. Administration with such vaccine also significantly increased the production of interleukin-12p70 and interferon-gamma. These results indicate that a vaccination therapy using DC co-transduced with the TAA gene and IL-18 genes is effective strategy for immunotherapy in terms of the activation of DCs, CD4+ T, cells and CD8+ T cells, and may be useful in the clinical application of a cancer vaccine therapy.
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ABSTRACT: ObjectiveTo determine serum interleukin-18 (IL-18) levels and their clinical significance in patients with prostate cancer. MethodsPeripheral blood samples were obtained from 38 nonmetastatic and 18 metastatic prostate cancer patients who underwent curative surgery and from 25 healthy volunteers. The serum IL-18 level was determined in each sample with the enzyme-linked immunosorbent assay. ResultsThe levels of serum IL-18 were increased significantly in prostate cancer patients compared with control subjects (P < 0.05). Serum IL-18 levels were significantly higher in the metastatic patients compared with the nonmetastatic patients (P < 0.01). Patients with bone metastasis had higher serum IL-18 levels compared with patients with liver and lung metastasis (P < 0.01). When the patients were subdivided into groups, it was found that the serum IL-18 levels in patients with T2, T3 and T4 stage were significantly higher than that of T1 stage patients (P < 0.01). Patients with IL-18 levels ≥ 316 pg/ml experienced a significantly lower survival rate compared with the patients who had IL-18 levels < 316 pg/mL after undergoing surgery (P < 0.05). The serum IL-18 level was identified as an independent postoperative prognostic factor in multivariate survival analysis using a Cox proportional hazards model (hazard ratio, 4.21; P = 0.02). ConclusionThe serum IL-18 level may be a useful marker in monitoring prostate cancer patients. IL-18 activity in prostate cancer patients with bone metastasis may be more valuable in the follow-up.The Chinese-German Journal of Clinical Oncology 01/2007; 6(6):574-578. DOI:10.1007/s10330-007-0134-0
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ABSTRACT: In the present study, we analyzed differential composition of blood serum from Ehrlich carcinoma-bearing and healthy male C57Bl/6 mice by isolating complexes of hemoglobin and other serum proteins by a proteomic approach (gel filtration, gel electrophoresis, and mass spectrometry). The hemoglobin fractions isolated from the serum of mice- bearing tumors contained several proteins with molecular weights of 15, 65, 68, and 100 kDa, while hemoglobin fractions isolated from the serum of healthy mice did not contain additional protein bands. These bands were identified by MALDI-TOF as haptoglobin, serum albumin, a homologue of alpha-fetoprotein, and hemoglobin-alpha. Ion exchange chromatography indicated complex formation of these proteins. Injection of hemoglobin-associated blood serum proteins (HAP) isolated from tumor-bearing animals, leads to tumor regression. Intraperitoneally injected HAP-induced apoptosis in Ehrlich carcinoma cells but not normal peritoneal cells and led to a complete regression of the ascitic or solid Ehrlich carcinoma. A one-year follow up of the animals did not reveal any signs of tumor growth. In conclusion, HAP might be a novel principle of tumor regression. The clinical relevance of these findings with Ehrlich carcinoma should be investigated in the future.International Journal of Oncology 05/2008; 32(4):885-93. DOI:10.3892/ijo.32.4.885 · 3.03 Impact Factor
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ABSTRACT: Gene therapy involves the transfer of genetic sequences to tissues to obtain a curative effect. Effective gene transfer can be achieved by introducing the therapeutic gene into virus-like particles that facilitate the penetration of the transgene into the cells. However, direct injection of viral vectors may activate innate immunity leading to toxic effects. On the other hand, viral vectors frequently induce neutralizing antibodies, which limit the efficacy of repeated vector administration. Moreover, targeting of the transgene to the desired tissue is a goal that not always can be attained with current vectors. The use of cells as vehicles for therapeutic genes may offer solutions for these issues. Ex vivo transduction of specific cells with vectors encoding therapeutic genes followed by injection of the engineered cells to the patient will reduce the inherent toxicity of the vector while preventing the development of neutralizing antibodies. At the same time, this therapeutic approach can take advantage of the homing properties of the transduced cells to target transgene expression to the sites of interest. Thus, it has been shown that administration of dendritic cells engineered ex vivo with vectors encoding selected antigenic determinants or immunostimulatory molecules is an efficient means to elicit protective immune responses. Similarly, since endothelial progenitor cells (EPC) move to inflammed, ischemic or neoplastic tissues, the injection of EPC transduced ex vivo with appropriate therapeutic genes is an effective method to direct transgene expression to the lesions to be treated. Promising data in animal models of disease point to a future clinical application of this therapeutic strategy.Gene therapy 06/2008; 15(10):765-71. DOI:10.1038/gt.2008.44 · 3.10 Impact Factor
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