- Klíčová slova
- aktivační znaky, genová exprese,
- MeSH
- alergie genetika imunologie MeSH
- cytokiny MeSH
- dendritické buňky imunologie MeSH
- dítě MeSH
- fetální krev cytologie imunologie MeSH
- financování organizované MeSH
- interleukin-12 genetika imunologie MeSH
- lidé MeSH
- novorozenec MeSH
- odběr fetální krve MeSH
- regulace genové exprese genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
Oncolytic virotherapy is a novel approach to cancer treatment. In the present study we tested the ability of reovirus type 3, strain Dearing, to suppress the growth of tumors induced in mice by HPV16-transformed TC-1 cells. In vitro, these cells are highly susceptible to the virus. In repeated in vivo tests the intratumoral inoculation of the virus resulted in only a minor slow-down of tumor growth, never in a complete cure. The effect of the treatment was not enhanced by the simultaneous administration of non-oncogenic, genetically modified TC-1 cells expressing either IL-2, IL-12 or GM-CSF, and, in fact, the oncolytic effect of the virus was even less expressed in some instances. When cyclophosphamide was used in combination with the viral treatment, a synergistic effect resulting in tumor suppression was observed. In most instances the tumor regression was transitory, however, and was followed by tumor progression. The outcome of these experiments was dependent on the timing of the two treatments.
- MeSH
- cyklofosfamid aplikace a dávkování MeSH
- experimentální nádory terapie virologie MeSH
- faktor stimulující granulocyto-makrofágové kolonie genetika MeSH
- financování organizované MeSH
- genetická terapie metody MeSH
- interleukin-12 genetika MeSH
- interleukin-2 genetika MeSH
- kombinovaná terapie MeSH
- lidský papilomavirus 16 MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- onkolytická viroterapie metody MeSH
- protinádorové látky aplikace a dávkování MeSH
- protinádorové vakcíny aplikace a dávkování MeSH
- savčí orthoreovirus 3 MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a serious disease with unknown cause and the influence of cytokine gene polymorphisms is presumed in the etiology and pathogenesis of the disease. We used high-resolution computed tomography (HRCT) as a marker of disease stage and progression and compared the alveolar and interstitial score with IL-1, IL-4, IL-12, IL-1RA and IL-4RA cytokine gene polymorphisms. SUBJECTS AND METHODS: The IPF patients were all Caucasians from the Czech Republic and consisted of 20 females and 10 males, with a mean age of 65 years, range 36-85. The HRCT results were evaluated by an experienced viewer using the interstitial and alveolar score scales, which were based on the IPF HRCT description system from Gay SE, Kazerooni EA, Tows GB, Lynch JP, Gross BH, Cascade PN, et al. [Idiopathic pulmonary fibrosis. Predicting response to therapy and survival. Am J Respir Crit Care Med 1998;157:1063-72]. We evaluated the polymorphisms of cytokine genes utilizing a PCR with sequence-specific primers method. RESULTS: The HRCT alveolar score was more pronounced in IL-4 RA (+1902) AG heterozygotes. The HRCT interstitial score was less severe in the IL-12 (-1188) AA homozygotes. According to progression of the HRCT interstitial score, the CC homozygosity at IL-1 RA (mspa 111100), the AA homozygosity at IL-4 RA (+1902) and CC homozygosity at IL-4(+33) positions were more frequent in patients with stable disease compared to those with progressive disease. CONCLUSIONS: We assume from our data that the polymorphisms of IL-4, IL-4RA, IL-1RA and IL-12 genes (genes of cytokines with regulatory activity) might influence the phenotype of IPF as shown by measurable changes in HRCT investigations.
- MeSH
- antagonista receptoru pro interleukin 1 genetika MeSH
- dospělí MeSH
- fenotyp MeSH
- financování organizované MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- interleukin-12 genetika MeSH
- interleukin-4 genetika MeSH
- interleukiny chemická syntéza MeSH
- lidé středního věku MeSH
- lidé MeSH
- plicní alveoly radiografie MeSH
- plicní fibróza genetika radiografie MeSH
- počítačová rentgenová tomografie MeSH
- polymorfismus genetický MeSH
- progrese nemoci MeSH
- receptor interleukinu-4 - alfa-podjednotka genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- MeSH
- autoimunitní nemoci genetika MeSH
- cytokiny fyziologie genetika klasifikace MeSH
- interleukin-1 genetika imunologie MeSH
- interleukin-10 genetika imunologie MeSH
- interleukin-12 genetika imunologie MeSH
- interleukin-6 genetika imunologie MeSH
- lidé MeSH
- polymorfismus genetický genetika imunologie MeSH
- tumor nekrotizující faktory genetika imunologie MeSH
- Check Tag
- lidé MeSH
Moderately immunogenic HPV 16-associated murine tumour cell line mimicking human HPV 16-associated neoplasms TC-1 (MHC class I(+)) and its variants, TC-1/P3C10 and TC-1/A9, with a marked down-regulation of MHC I molecules, were used to examine the effect of local interleukin 12 (IL-12) gene therapy for the treatment of early tumour transplants and minimal residual tumour disease obtained after cytoreductive chemotherapy (CMRTD). Experiments were designed to examine whether down-regulation of MHC class I molecules plays a role during chemotherapy and gene therapy of early tumour transplants. It was found that peritumoral administration of IL-12-producing tumour cell vaccines (single dose, day 8 after tumour cell administration) inhibited the growth of both TC-1 (MHC class I positive) tumours and their MHC class I-deficient variants. To investigate the antitumour effects in a clinically relevant setting, IL-12 gene therapy was utilised for the treatment of minimal residual tumour disease after cytoreductive chemotherapy. Intra-peritoneal treatment of tumour-bearing mice with ifosfamide derivative, CBM-4A, produced a significant tumour-inhibitory effect. This treatment was followed by peritumoral s.c. administration of genetically modified TC-1 (MHC class I positive) or MK16/I/IIIABC (MHC class I negative) vaccines producing IL-12 (single dose, day 7 after chemotherapy) or with recombinant interleukin 12 (rIL-12) in two cycles of 5 daily doses (days 8-19) after chemotherapy. This combined therapy significantly inhibited the growth of TC-1 and TC-1/A9 (MHC class I-) tumours. When the combined therapy of TC-1 (MHC class I positive) tumours was followed by peritumoral administration of bone marrow dendritic cell (BMDC) vaccines, the IL-12-mediated inhibitory effect was significantly boosted. In the next set of experiments, the impacts of chemotherapy and IL-12 adjuvant therapy on MHC class I surface expression were assessed. Chemotherapy and gene therapy of tumours led to the up-regulation of MHC I expression on MHC class I-deficient tumours (TC-1/A9 and TC-1/P3C10) and to down-regulation on MHC I-proficient tumours (TC-1). These findings indicate that the MHC I phenotype is not stable during tumour progression and treatment. Collectively, these results illustrate the efficacy of IL-12 gene therapy in combination with chemotherapy on HPV-associated tumours regardless of the level of MHC class I expression on the tumour cells.
- MeSH
- down regulace MeSH
- experimentální nádory virologie MeSH
- financování organizované MeSH
- genetická terapie MeSH
- geny MHC třídy I MeSH
- HLA antigeny biosyntéza MeSH
- ifosfamid analogy a deriváty farmakologie MeSH
- imunoterapie MeSH
- interleukin-12 fyziologie genetika MeSH
- lidé MeSH
- lidský papilomavirus 16 patogenita MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- protinádorové vakcíny MeSH
- reziduální nádor MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
