Home About us Contact
|
Home About us Contact | ||
|
|
||
Cytokine Genes (cytokine + gene)
Terms modified by Cytokine Genes Selected AbstractsCombination Nonviral Interleukin-2 Gene Immunotherapy For Head and Neck Cancer: From Bench Top to BedsideTHE LARYNGOSCOPE, Issue 3 2005Bert W. O'Malley Jr MD Abstract Objective/Hypothesis: Intralesional delivery of cytokine genes has emerged as a promising therapeutic strategy for the treatment of cancer. In addition to the therapeutic effect of the delivered cytokine gene, the components of the gene delivery system also have been shown to induce beneficial immune responses. On the basis of these principles, we hypothesized that a molecular therapy could be developed that would provide synergistic antitumor activity by way of intralesional expression of interleukin (IL)-2 from a recombinant plasmid combined with induction of endogenous interferon (IFN)-, and IL-12 cytokines by immunostimulatory DNA. Our objective in these studies was to create and optimize a novel formulation of cationic lipid and DNA that generates local production of IL-2 protein within a targeted tumor environment with concomitant induction of the antitumor cytokines IFN-, and IL-12. Study Design: Prospective laboratory drug development plan that would produce human clinical trials. Materials and Methods: Engineered bacterial plasmids containing a cytomegalovirus promoter (CMV)-IL-2 expression cassette were specifically formulated with cationic lipids and optimized for antitumor effect in a floor of mouth murine tumor model. The treated tumors were assayed for local expression of IL-2 and concurrent expression of secondary cytokines IFN-, and IL-12. Established tumors in C3H/HeJ mice were treated with various IL-2 gene formulations, and clinical and immunologic responses were evaluated. Immunologic studies were performed and included cytolytic T-cell assays and cytokine expression profiles. For human clinical trials, a phase I 10 patient formulated IL-2 gene therapy study was completed. Subsequently, two large scale, phase II multi-institutional and multi-international studies were initiated comparing non-viral IL-2 gene therapy to palliative methotrexate chemotherapy or in combination with cisplatin. Results: In the preclinical stage, maximum tumor inhibition in animal models was obtained using IL-2 plasmid formulated with 1,2-dioleyloxypropyl-3-trimethyl ammonium chloride (DOTMA):cholesterol (1:1 mol:mol) at a plasmid:lipid charge ratio of 1:0.5 (,/+). Cationic lipid formulated IL-2 plasmid significantly inhibited tumor growth compared with formulated control plasmid (P < .01) or vehicle (lactose; P < .01). Consistent with previously reported studies of the immunostimulatory activity of DNA of bacterial origin, treatment of tumors with control plasmid in cationic lipid formulation induced production of endogenous IFN-, and IL-12 but not IL-2. Treatment of tumors with formulated IL-2 plasmid produced IL-2 protein levels that were 5-fold over background and increased IFN-, by 32-fold (P < .001) and IL-12 by 5.5-fold (P < .001) compared with control plasmid formulations. The phase I human trial demonstrated dose escalation safety, which was its primary objective, and there was one anecdotal reduction in tumor size. The phase II studies have been initiated and focus on either comparing the novel nonviral IL-2 gene immunotherapy formulation alone to methotrexate or comparing IL-2 gene therapy in combination with cisplatin in recurrent or unresectable patients with head and neck squamous cell carcinoma. Conclusions: The preclinical data provided proof of principle for matching a delivered IL-2 transgene with an immunostimulatory nonviral formulation to enhance intralesional production of therapeutic cytokines for the maximization of antitumor response. Human clinical trials have demonstrated this novel therapy to be safe in the human clinical setting. Phase II trials have been initiated to assess efficacy and feasibility as a single or combination therapy for head and neck cancer. [source] Interleukin-10 is associated with resistance to febrile seizures: Genetic association and experimental animal studiesEPILEPSIA, Issue 4 2009Yoshito Ishizaki Summary Purpose:, Febrile seizures (FS) are the most common form of childhood convulsions. Many reports have shown that a proinflammatory cytokine, interleukin-1 (IL-1) ,, may have a facilitatory effect on the development of FS. We have previously shown that the IL1B -511C/T single nucleotide polymorphism (SNP) is associated with simple FS of sporadic occurrence. The balance between pro- and antiinflammatory cytokines influences the regulation of infections and could, therefore, play a role in the pathogenesis of FS. Here, to determine whether pro- and antiinflammatory cytokine genes are responsible for the susceptibility to FS, we have performed an association study on functional SNPs of cytokine genes in FS patients and controls. Methods:, The promoter SNPs of four inflammatory cytokine genes (IL6 -572C/G, IL8 -251A/T, IL10 -592A/C and TNFA -1037C/T) were examined in 249 patients with FS (186 simple and 63 complex FS) and 225 controls. Because the IL10 -592 SNP showed a positive association with FS, two additional SNPs (IL10 -1082A/G and -819T/C) were subjected to haplotype analysis. Furthermore, we examined the in vivo role of IL-10 in hyperthermia-induced seizures using immature animal models. Results:, The frequencies of the IL10 -592C allele and -1082A/-819C/-592C haplotype were significantly decreased in FS as compared with in controls (p = 0.014 and 0.013, respectively). The seizure threshold temperature in the IL-10,administered rats was significantly higher than that in the saline-treated control ones (p = 0.027). Conclusions:, The present study suggests that IL-10 is genetically associated with FS and, contrary to IL-1,, confers resistance to FS. [source] Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004Susannah Abstract To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a ,-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-, during T helper cell differentiation. Instead, IFN-, was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves. [source] Analysis of allelic expression patterns of IL-2, IL-3, IL-4, and IL-13 in human CD4+ T,cell clonesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2003Jean-Pierre Bayley Abstract The occurrence of monoallelic expression of cytokine genes in single cells has been convincingly demonstrated, but there have been few reports of this phenomenon in T,cell clones. Here we describe studies on the expression of alleles of the human genes encoding IL-2, IL-3, IL-4, and IL-13 in human CD4+ T,cell clones. In contrast to the results reported in mouse T,cell clones andsingle human T,cells, we found no evidence for the monoallelic expression of the IL-2, IL-3, and IL-13 genes. The gene for IL-4 showed an imbalance in expression from each allele, indicating differential expression of IL-4 alleles within or between IL-4-expressing cells. [source] Helicobacter pylori Stimulates a Mixed Adaptive Immune Response with a Strong T-Regulatory Component in Human Gastric MucosaHELICOBACTER, Issue 3 2007Rasmus Goll Abstract Background:, Host factors play an important role in the pathophysiology of Helicobacter pylori infection and development of gastritis and related disease. The established opinion is that the T-cell-mediated immune response to H. pylori infection is of Th1 type. Our earlier immune cell phenotype studies indicate a mixed Th1,Th2 profile of the effector cells. Therefore, an extensive adaptive and regulatory cytokine gene expression profile was conducted by quantitative real-time polymerase chain reaction (qPCR). Materials and Methods:, Biopsies from gastric mucosa of 91 patients diagnosed as H. pylori negative, H. pylori positive with gastritis, or H. pylori positive with peptic ulcer were obtained by endoscopy. Gene expressions of nine cytokines and CagA status were measured by qPCR. Results:, All cytokine genes showed higher expression levels in the presence of H. pylori when compared to H. pylori- negative samples (fold increase: IL8: × 11.2; IL12A: × 2.4; TNF-,: × 5.2; IFN-,: × 4.3; IL4: × 3.6; IL6: × 14.7; and IL10: × 6.7). Patients infected with CagA-positive strains had higher expression of IL1-, and IL18 compared to patients infected with CagA-negative strains (× 1.6 for IL1-, and × 2.0 for IL18). Patients with duodenal ulcer had a lower antral Th1/Th2 ratio than other H. pylori -positive patients. Conclusions:, The cytokine profile of H. pylori -infected gastric mucosa shows a mixed Th1,Th2 profile. Furthermore, a high IL10 expression may indicate that also regulatory T cells play a role in the chronic phase of H. pylori infection. [source] Association of longevity with IL-10 ,1082 G/A and TNF-,,308 G/A polymorphismsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2010O. F. Khabour Summary Cytokines are crucial for the regulation of inflammation development in humans. Many studies have shown that variations in cytokine genes might play a role in determining human longevity. This study examined the changes in the gene pool relevant to the ,308 G/A polymorphism in the promoter region of the proinflammatory cytokine tumour necrosis factor (TNF)-, gene and the ,1082 G/A polymorphism in the promoter region of anti-inflammatory cytokine interleukin (IL)-10 gene with aging and survival selection occurs in the Jordanian population. IL-10 ,1028 G/A and TNF-,,308 G/A were genotyped in 119 randomly selected elderly subjects (41 women and 78 men) with a mean age of 90.2 years and young control subjects of 118 (46 women and 72 men) with a mean age of 31.9 years. No significant differences were found in the genotype and allele frequencies of TNF-, gene variants between the two groups (P > 0.05) while the IL-10 genotype and allele frequencies were significantly associated with longevity in men (P < 0.05) but not in women (P < 0.05). Thus, IL-10 ,1028 G/A polymorphism seems to play a role in the pathway to longevity in Jordanian men. [source] Single nucleotide polymorphisms of cytokine genes in the healthy Slovak populationINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2007J. Javor Summary Cytokines are molecules that control and modulate the activities of numerous target cells via binding to specific receptors. The observed differences in the cytokine production among individuals can be, at least partially, explained by gene polymorphisms. Several cytokine gene polymorphisms have been identified to play a role in susceptibility to various diseases, including autoimmune, infectious, allergic or cardiovascular diseases. The aim of the current study was to determine allele and genotype frequencies of 22 polymorphisms in 13 cytokine genes in the healthy Slovak population and to compare them with data available from six populations from Central and Southern Europe. A polymerase chain reaction with sequence-specific primers was used to genotype polymorphisms within genes encoding IL-1,, IL-1,, IL-1R, IL-1RA, IL-4R,, IL-12, IFN-,, TGF-,, TNF-,, IL-2, IL-4, IL-6 and IL-10 in a sample of 140 unrelated Slovak subjects. The allelic distribution of all polymorphisms in the Slovak population was very close to that in the geographically and historically closest populations in Central Europe , the Czech and the Polish. However, several differences were found between the Slovak and four populations from Southern Europe. The obtained data represent a basis for further studies on association of cytokine gene polymorphisms with some diseases. [source] Genotyping for cytokine polymorphisms: allele frequencies in the Italian populationINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 1 2003M. Uboldi de Capei Summary It has been demonstrated that many cytokine genes [e.g. tumour necrosis factor , (TNF-,) and interleukin 10 (IL-10)] show polymorphisms which may affect gene transcription, causing individual variations in cytokine production. The majority of polymorphisms described are single nucleotide polymorphisms (SNPs). In 140 healthy Italian subjects, the allelic and genotype frequencies were determined for the cytokine genes IL-1, (T/C ,889), IL-1, (C/T ,511, T/C +3962), IL-12 (C/A ,1188), interferon (IFN)-, (A/T UTR 5644), transforming growth factor (TGF)-, (C/T codon 10, G/C codon 25), TNF-, (G/A ,308, G/A ,238), IL-2 (T/G ,330, G/T +166), IL-4 (T/G ,1098, T/C ,590, T/C ,33), IL-6 (G/C ,174, G/A nt565), IL-10 (G/A ,1082, C/T ,819, C/A ,592), IL-1R (C/T pst11970), IL-1RA (T/C mspa111100) and IL-4RA (G/A +1902). All typings were performed with PCR-SSP assays. Allele and genotype frequencies and linkage disequilibria were calculated and compared with those of other populations. [source] Frequencies of the -330 (T , G) IL-2 and -590 (T , C) IL-4 gene polymorphisms in a population from south-eastern BrazilINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2002R. M. Scarel-Caminaga Summary Polymorphisms in the promoter regions of cytokine genes may affect their transcription. A T/G substitution at position ,330 of the interleukin-2 (IL-2) gene and a T/C substitution at position ,590 of the interleukin-4 (IL-4) gene have been described previously. The ,590 (T , C) IL-4 gene polymorphism was associated with asthma and atopy in US and Japanese populations. Population genetics is a useful tool for determination of the biological significance of genetic polymorphisms. The aim of this study was to investigate the frequencies of polymorphisms in the promoter regions of the IL-2 and IL-4 genes in a population from south-eastern Brazil and to compare them with those published for other populations. Allele frequencies were estimated in 114 unrelated individuals from São Paulo State. These subjects had an average age of 41.2 years (± 12.4 years) and the ethnic composition of the sample was: 78.07% Caucasian, 11.4% Black and 10.53% Mulatto. DNA from subjects was extracted from epithelial buccal cells, and the PCR-RFLP technique was employed to investigate the ,330 (T , G) IL-2 and ,590 (T , C) IL-4 gene polymorphisms. The allele frequency of the IL-2 gene polymorphism obtained in our study was similar to that found in UK Caucasoid groups. The T allele frequency of the IL-4 gene polymorphism observed in the Caucasian Brazilian group was similar to that found in UK and Australian populations, while the frequency observed for the Black Brazilian group was similar to that found in Japanese and Kuwaiti Arab populations. The results for the ,330 (T , G) IL-2 and ,590 (T , C) IL-4 polymorphisms are consistent with the high contribution of European lineages to the population in south-eastern Brazil. [source] Different effects of polymorphisms of tumor necrosis factor-alpha and interleukin-1 beta on development of peptic ulcer and gastric cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 1 2007Mitsushige Sugimoto Abstract Background and Aim:, In Western countries, polymorphism of pro-inflammatory cytokine genes is associated with the development of gastric cancer and duodenal ulcer. The aim of this study was to clarify the association of polymorphisms of interleukin (IL) -1, and tumor necrosis factor (TNF) -, with susceptibility to peptic ulcer diseases and gastric cancer in Japan. Methods:, The IL-1, -511/-31 and TNF-, -308/-857/-863/-1031 genotypes were determined in Helicobacter pylori -positive patients with gastritis only (n = 164), gastric ulcers (n = 110), duodenal ulcers (n = 94), or gastric cancers (n = 105), and in H. pylori -negative controls (n = 172). Results:, Carriage of the alleles TNF-,- 857 T (odd ratio [OR], 1.826; 95% confidence interval [CI], 1.097,3.039), TNF-,- 863 A (OR, 1.788; 95% CI, 1.079,2.905) and TNF-, -1031 C (OR, 1.912; 95% CI, 1.152,3.171) was associated with increased risk for gastric ulcer development. Carriage of the alleles TNF-,- 857 T (OR, 1.686; 95% CI, 1.003,2.832), TNF-,- 863 A (OR, 1.863; 95% CI, 1.118,3.107) and TNF-, -1031 C (OR 2.074; 95% CI, 1.244,3.457) was also associated with increased risk of gastric cancer development. There was no relationship between the development of H. pylori -related diseases and polymorphisms of IL-1, -511/-31 and TNF-, -308. The simultaneous carriage of three different high-producer alleles of TNF-, -857/-863/-1031 significantly increased the risk of gastric ulcer (OR, 6.57; 95% CI, 2.34,18.40) and gastric cancer (OR, 5.20; 95% CI, 1.83,14.78). Conclusions:, Polymorphisms in TNF-, rather than IL-1, are associated with increased risk for gastric ulcers and gastric cancer in Japan. The simultaneous carriage of more than one high-producer allele of TNF-, further increased the risks for gastric ulcer and cancer. [source] Statins enhance toll-like receptor 4-mediated cytokine gene expression in astrocytes: Implication of Rho proteins in negative feedback regulationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2008Gregory W. Konat Abstract Toll-like receptors (TLRs) are sentinels of innate immunity that recognize pathogenic molecules and trigger inflammatory response. Because inflammatory mediators are detrimental to the host, the TLR response is regulated by feedback inhibition. Statins, the inhibitors of isoprenoid biosynthesis, have been shown to be potent modulators of TLR activity, and this modulation may provide insight regarding mechanisms of the feedback inhibition. In the present study, we examined feedback mechanisms that regulate TLR4 activity in astrocytes using statins to perturb postligational signaling. Astrocytic cultures established from newborn rat brains were exposed to lipopolysaccharide (LPS), the ligand for TLR4. The up-regulation of expression of genes encoding interleukin (IL)-1,, IL-6, and tumor necrosis factor-, (TNF,) was determined by real-time RT-PCR. Pretreatment of the cells with either atorvastatin or simvastatin enhanced the LPS-induced up-regulation of cytokine gene expression. The most profound enhancement of approximately 17-fold was observed for the Il-6 gene. The enhancements for the Tnfa and Il-1b genes were approximately 5- and 3.5-fold, respectively. Mevalonate fully reversed the effects of statins, indicating that these drugs act through the inhibition of isoprenoid synthesis. The inhibition of protein geranylgeranylation, but not protein farnesylation, mimicked the effects of statins, strongly indicating that the enhancement is mediated by the Rho proteins. In support of this notion, pretreatment of cells with toxin B, a specific inhibitor of the Rho proteins, also enhanced LPS-triggered up-regulation of the cytokine genes. These results indicate that the Rho proteins are involved in the activation of negative feedback inhibition of TLR4 signaling in astrocytes. © 2007 Wiley-Liss, Inc. [source] Interleukin-21 triggers both cellular and humoral immune responses leading to therapeutic antitumor effects against head and neck squamous cell carcinomaTHE JOURNAL OF GENE MEDICINE, Issue 1 2006Hiroshi Nakano Abstract Background Interleukin-21 (IL-21) plays important roles in the regulation of T, B, and natural killer (NK) cells. We hypothesized that the cytokine may provide a novel immunotherapy strategy for cancer by stimulating both Th1 and Th2 immune responses. In this context, antitumor immunity induced by IL-21 was examined in mice bearing subcutaneous head and neck squamous cell carcinomas (HNSCC). Methods A plasmid vector encoding murine IL-21 was injected intravenously into mice with pre-established HNSCC tumors, either alone or in combination with a vector construct expressing IL-15. Cytotoxic T lymphocyte (CTL) and NK killing activities were evaluated by chrome release assays, while HNSCC-specific antibody was examined by flow cytometry and ELISA. Results Significant antitumor effects were obtained by repeated transfection with either the IL-21 or the IL-15 gene. Co-administration of both cytokine genes resulted in increased suppression of tumor growth, significantly prolonging the survival periods of the animals. Thirty percent of the tumor-bearing mice that received the combination therapy survived for more than 300 days, completely rejecting rechallenge with the tumor at a distant site. IL-21 induced significant elevation of HNSCC-specific CTL activity, while IL-21 and IL-15 augmented NK activity in an additive manner. IL-21 gene transfer also promoted the production of tumor-specific IgG. Conclusions In vivo transduction of the IL-21 gene elicits powerful antitumor immunity, including both humoral and cellular arms of the immune response, and results in significant suppression of pre-established HNSCC. Co-transfer of the IL-15 gene further improved the therapeutic outcome, mainly by augmenting NK tumoricidal activity. The biological effects of IL-21 may be in sharp contrast to those of conventional Th1 and Th2 cytokines, suggesting intriguing implications of this cytokine for the classical concept of Th1 vs. Th2 paradigm. Copyright © 2005 John Wiley & Sons, Ltd. [source] DNA vaccination against tumorsTHE JOURNAL OF GENE MEDICINE, Issue 1 2005Gérald J. Prud'homme Abstract DNA vaccines have been used to generate protective immunity against tumors in a variety of experimental models. The favorite target antigens have been those that are frequently expressed by human tumors, such as carcinoembryonic antigen (CEA), ErbB2/neu, and melanoma-associated antigens. DNA vaccines have the advantage of being simple to construct, produce and deliver. They can activate all arms of the immune system, and allow substantial flexibility in modifying the type of immune response generated through codelivery of cytokine genes. DNA vaccines can be applied by intramuscular, dermal/epidermal, oral, respiratory and other routes, and pose relatively few safety concerns. Compared to other nucleic acid vectors, they are usually devoid of viral or bacterial antigens and can be designed to deliver only the target tumor antigen(s). This is likely to be important when priming a response against weak tumor antigens. DNA vaccines have been more effective in rodents than in larger mammals or humans. However, a large number of methods that might be applied clinically have been shown to ameliorate these vaccines. This includes in vivo electroporation, and/or inclusion of various immunostimulatory molecules, xenoantigens (or their epitopes), antigen-cytokine fusion genes, agents that improve antigen uptake or presentation, and molecules that activate innate immunity mechanisms. In addition, CpG motifs carried by plasmids can overcome the negative effects of regulatory T cells. There have been few studies in humans, but recent clinical trials suggest that plasmid/virus, or plasmid/antigen-adjuvant, prime-boost strategies generate strong immune responses, and confirm the usefulness of plasmid-based vaccination. Copyright © 2004 John Wiley & Sons, Ltd. [source] Combination Nonviral Interleukin-2 Gene Immunotherapy For Head and Neck Cancer: From Bench Top to BedsideTHE LARYNGOSCOPE, Issue 3 2005Bert W. O'Malley Jr MD Abstract Objective/Hypothesis: Intralesional delivery of cytokine genes has emerged as a promising therapeutic strategy for the treatment of cancer. In addition to the therapeutic effect of the delivered cytokine gene, the components of the gene delivery system also have been shown to induce beneficial immune responses. On the basis of these principles, we hypothesized that a molecular therapy could be developed that would provide synergistic antitumor activity by way of intralesional expression of interleukin (IL)-2 from a recombinant plasmid combined with induction of endogenous interferon (IFN)-, and IL-12 cytokines by immunostimulatory DNA. Our objective in these studies was to create and optimize a novel formulation of cationic lipid and DNA that generates local production of IL-2 protein within a targeted tumor environment with concomitant induction of the antitumor cytokines IFN-, and IL-12. Study Design: Prospective laboratory drug development plan that would produce human clinical trials. Materials and Methods: Engineered bacterial plasmids containing a cytomegalovirus promoter (CMV)-IL-2 expression cassette were specifically formulated with cationic lipids and optimized for antitumor effect in a floor of mouth murine tumor model. The treated tumors were assayed for local expression of IL-2 and concurrent expression of secondary cytokines IFN-, and IL-12. Established tumors in C3H/HeJ mice were treated with various IL-2 gene formulations, and clinical and immunologic responses were evaluated. Immunologic studies were performed and included cytolytic T-cell assays and cytokine expression profiles. For human clinical trials, a phase I 10 patient formulated IL-2 gene therapy study was completed. Subsequently, two large scale, phase II multi-institutional and multi-international studies were initiated comparing non-viral IL-2 gene therapy to palliative methotrexate chemotherapy or in combination with cisplatin. Results: In the preclinical stage, maximum tumor inhibition in animal models was obtained using IL-2 plasmid formulated with 1,2-dioleyloxypropyl-3-trimethyl ammonium chloride (DOTMA):cholesterol (1:1 mol:mol) at a plasmid:lipid charge ratio of 1:0.5 (,/+). Cationic lipid formulated IL-2 plasmid significantly inhibited tumor growth compared with formulated control plasmid (P < .01) or vehicle (lactose; P < .01). Consistent with previously reported studies of the immunostimulatory activity of DNA of bacterial origin, treatment of tumors with control plasmid in cationic lipid formulation induced production of endogenous IFN-, and IL-12 but not IL-2. Treatment of tumors with formulated IL-2 plasmid produced IL-2 protein levels that were 5-fold over background and increased IFN-, by 32-fold (P < .001) and IL-12 by 5.5-fold (P < .001) compared with control plasmid formulations. The phase I human trial demonstrated dose escalation safety, which was its primary objective, and there was one anecdotal reduction in tumor size. The phase II studies have been initiated and focus on either comparing the novel nonviral IL-2 gene immunotherapy formulation alone to methotrexate or comparing IL-2 gene therapy in combination with cisplatin in recurrent or unresectable patients with head and neck squamous cell carcinoma. Conclusions: The preclinical data provided proof of principle for matching a delivered IL-2 transgene with an immunostimulatory nonviral formulation to enhance intralesional production of therapeutic cytokines for the maximization of antitumor response. Human clinical trials have demonstrated this novel therapy to be safe in the human clinical setting. Phase II trials have been initiated to assess efficacy and feasibility as a single or combination therapy for head and neck cancer. [source] Combination Nonviral Cytokine Gene Therapy for Head and Neck Cancer,THE LARYNGOSCOPE, Issue 5 2001Daqing Li MD Abstract Objective To establish the feasibility and efficacy of combination nonviral murine interferon-, (mIFN-,) and murine interleukin-2 (mIL-2) or murine interleukin-12 (mIL-12) gene therapy for head and neck squamous cell carcinoma in a murine model. Study Design Randomized controlled studies in a murine head and neck cancer model were performed to assess antitumor responses, secondary cytokine expression, and both natural killer (NK) cell and cytolytic T-cell (CTL) activity. Methods Tumors were established in the floor of mouth in C3H/HeJ immunocompetent mice. Established tumors were directly injected with polymer-formulated murine interferon-, (mIFN-,), lipid-formulated mIL-2, and polymer-formulated mIL-12 alone or in combination. Primary and secondary cytokine expression, NK cell activity, and CTL activity were assayed. Results The use of mIFN-, gene therapy in combination with either mIL-2 or mIL-12 resulted in significant antitumor effects as compared with each of the single cytokine and control treatment groups (P = .002). Increased levels of NK cell activity and tumor specific CD8+ cytotoxic T-lymphocyte activity were found in the combination mIFN-, and mIL-2 or mIL-12 groups. Augmented immune responses correlated with clinical antitumor effects. Conclusions The present study demonstrates that mIL-2 or mIL-12 augments tumor inhibition from mIFN-, and increases activation of NK and CD8+ T cells. These data support further investigation of polymer and lipid mediated delivery of cytokine genes for head and neck cancer. [source] Mapping of seven bovine cytokine genes involved in T-lymphocyte growth, differentiation and immune responseANIMAL GENETICS, Issue 6 2000T S Sonstegard No abstract is available for this article. [source] Inflammatory cytokine gene expression in the urinary sediment of patients with lupus nephritisARTHRITIS & RHEUMATISM, Issue 5 2003Rebecca Wing-Yan Chan Objective Lupus nephritis is characterized by intrarenal inflammation and lymphocyte activation. In the present study, the expression of cytokine genes in the urinary sediment of patients with systemic lupus erythematosus (SLE) was examined. Methods We studied 3 SLE patient groups (25 with active lupus nephritis [active group], 25 with inactive SLE and previous renal involvement [remission group], 20 with inactive SLE and no history of renal involvement [nonrenal SLE group]) and 2 control groups (10 patients with noninflammatory renal diseases [non-SLE group] and 10 healthy volunteers [healthy group]). Cytokine gene expression in the urinary sediment was studied by real-time quantitative polymerase chain reaction. Results Expression of interferon-, (IFN,) in urinary sediment was significantly higher in the active group than in all other groups (P < 0.001 by Kruskal-Wallis test). Among the SLE patient groups, there was a close correlation between IFN, expression and the overall SLE Disease Activity Index (SLEDAI) score (Spearman's r = 0.590, P < 0.001) and the SLEDAI renal score (r = 0.642, P < 0.001). Urinary expression of interleukin-2 (IL-2) in the active group was significantly higher than that in the healthy group (P = 0.046) but not in the remission or nonrenal SLE groups. There was no difference in the levels of IL-4 expression among the SLE groups. Conclusion We found a predominance of Th1 cytokine in the urinary sediment of patients with active lupus nephritis. Measurement of cytokine gene expression in urinary sediment may be a useful noninvasive tool for assessing the severity of renal involvement in SLE. [source] In this issue: Biotechnology Journal 9/2010BIOTECHNOLOGY JOURNAL, Issue 9 2010Article first published online: 10 SEP 2010 Linking obesity and colorectal cancer Sung and Bae, Biotechnol. J. 2010, 5, 930,941 Obesity is known as one of the most closely related risk factors of colorectal cancer (CRC). However, due to the complicated nature of the diet, it has been very difficult to provide clear explanations and molecular mechanisms for the role of dietary components in carcinogenesis. Nutrigenomics has become a powerful tool to study the relationships between food components and genes. It includes nutrigenetics (dealing with genetic variations related to phenotypic changes in response to diet), nutritional epigenomics and nutritional transcriptomics/proteomics/metabolomics. This review summarizes data on genes, proteins and metabolites that are related to either obesity or CRC and candidate molecules that may link obesity and CRC. The application of bioinformatics helps to perform large-scale network analysis to study cause-effect relationships between dietary components and CRC in the future. Hepatoprotective effects of oleuropein Kim et al., Biotechnol. J. 2010, 5, 950,960 Oleuropein, an active constituent of olive leaf, has a variety of pharmacological activities associated with its capacity to scavenge reactive oxygen species and has a protective effect against non-alcoholic fatty liver disease (NAFLD) in vivo. To gain insights into the molecular mechanisms of its hepatoprotective action the group of Taesun Park (Seoul, Korea) fed mice with a high fat diet supplemented with oleuropein. Then, liver tissue was subjected to DNA microarray analysis. Oleuropein in high fat diet reduced the mRNA level of regulators of hepatic fatty acid uptake and transport. The expression of a number of genes involved in oxidative stress responses, detoxification of lipid peroxidation products and proinflammatory cytokine genes were reduced, while highly regulated transcription factors were implicated in the lipogenesis, inflammation, insulin resistance and fibrosis, underlying the multifactorial effect of oleuropein on NAFLD. Genetic variations in obesity and diabetes Varma et al., Biotechnol. J. 2010, 5, 942,949 Obesity is a state of metabolic deregulation and a leading cause for development of type 2 diabetes, which are complex polygenic diseases. Here, authors from the National Centre of Toxicological Research at the FDA (Jefferson, Arizona, USA) used a data mining approach to evaluate the role of carbohydrate metabolic pathway genes in the development of obesity and type 2 diabetes. Data from public databases were used to map the position of these genes to known quantitative trait loci (QTL) and to find sequence and structural genetic variants such as single nucleotide polymorphisms (SNPs). The results demonstrated that a majority of carbohydrate metabolic pathways genes are associated with QTL for obesity and many for type 2 diabetes. This data mining approach can establish a strategy for interpreting an individual's risk factor for disease development, instead of population attributable risks. [source] Hepatoprotective effect of oleuropein in mice: Mechanisms uncovered by gene expression profilingBIOTECHNOLOGY JOURNAL, Issue 9 2010Yunjung Kim Abstract Oleuropein, an active constituent of olive leaf, has a variety of pharmacological activities associated with its capacity to scavenge reactive oxygen species. Oleuropein is also reported to have protective effects against non-alcoholic fatty liver disease (NAFLD) in vivo. In this study, gene expression profiling of hepatic tissues was examined, and transcription factors (TFs) with target genes that were modulated by oleuropein were identified to gain insights into the molecular mechanisms for the hepatoprotective action of this compound. C57BL/6N mice were fed either a high-fat diet (HFD) or 0.03% oleuropein-supplemented HFD for 10 weeks, after which their livers were subjected to oligo DNA microarray analysis. The oleuropein with which the HFD was supplemented reduced the hepatic mRNA level of the genes that encoded the key regulators of the hepatic fatty acid uptake and transport. In addition, the oleuropein reduced the expression of a number of hepatic genes involved in the oxidative stress responses and detoxification of lipid peroxidation products and proinflammatory cytokine genes. The (putative) candidate TFs that bound to the promoters of the genes regulated at least threefold (both up and down) by oleuropein were implicated in the lipogenesis, inflammation, insulin resistance, fibrosis, and cell proliferation and differentiation, which implies that the mechanisms that underlie the beneficial effects of oleuropein on NAFLD may be multifactorial. [source] Single nucleotide polymorphisms of the inflammatory cytokine genes in adults with chronic immune thrombocytopenic purpuraBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2004Takashi Satoh Summary Single nucleotide polymorphisms (SNPs) of inflammatory cytokine genes were examined in 84 adult Japanese patients with chronic immune thrombocytopenic purpura (ITP) and 56 race-matched healthy controls. The SNPs examined were within the genes encoding tumour necrosis factor (TNF)- , (,238 G/A and ,308 G/A), TNF- , (+252 G/A), and interleukin (IL)-1, (,511 C/T and +3953 T/C). Of these SNPs, the frequency of the TNF- , (+252) G/G phenotype was significantly higher in ITP patients than in healthy controls (21% vs. 7%, P = 0·04, odds ratio = 3·6, 95% confidence interval 1·1,11·1), while no significant association was detected for the other SNPs. The distribution of the TNF- , (+252) phenotype was not associated with human leucocyte antigen class II alleles or the therapeutic response in ITP patients. The frequency of circulating anti-glycoprotein IIb/IIIa antibody-producing B cells was significantly higher in ITP patients with the TNF- , (+252) G/G phenotype than in those with the G/A or A/A phenotype (11·9 ± 4·9 vs. 6·8 ± 4·9 and 3·7 ± 2·8 per 105 peripheral blood mononuclear cells; P = 0·02 and P < 0·001, respectively). These findings suggest that the SNP located at TNF- , (+252) contributes to susceptibility to chronic ITP by controlling the autoreactive B-cell responses to platelet membrane glycoproteins. [source] The combinations of TNF,,308 and IL-6 ,174 or IL-10 ,1082 genes polymorphisms suggest an association with susceptibility to sporadic late-onset Alzheimer's diseaseACTA NEUROLOGICA SCANDINAVICA, Issue 6 2009P. Vural Objective,,, Single nucleotide polymorphisms in the regulatory regions of the cytokine genes for tumor necrosis factor , (TNF,), interleukin (IL)-6 and IL-10 have been suggested to influence the risk of Alzheimer's disease (AD) with conflicting results. Aim,,, To investigate the TNF,,308, IL-6 ,174 and IL-10 ,1082 gene polymorphisms as susceptibility factors for AD. Methods,,, We analyzed genotype and allele distributions of these polymorphisms in 101 sporadic AD patients and 138 healthy controls. Results,,, Heterozygotes (AG) or combined genotype (AG+AA) for IL-10 ,1082 were associated with approximately two-fold increase in the risk of AD. Carriers of A alleles of both TNF,,308 and IL-10 ,1082 had 6.5 times higher risk for AD in comparison with non-carriers. Concomitant presence of both mutant TNF,,308 A and IL-6 ,174 C alleles raised three-fold the AD risk, whereas there was no notable risk for AD afflicted by IL-6 ,174 polymorphism alone. Conclusion,,, Our results suggest that TNF, and IL-10 promoter polymorphism might be a risk factor for AD. The combined effects of TNF,,308, IL-6 ,174 and IL-10 ,1082 variant alleles may be more decisive to induce functional differences and modify the risk for AD. [source] Promotion of stem cell proliferation by vegetable peptoneCELL PROLIFERATION, Issue 5 2009J. Lee Objectives:, Technical limitations and evolution of therapeutic applications for cell culture-derived products have accelerated elimination of animal-derived constituents from such products to minimize inadvertent introduction of microbial contaminants, such as fungi, bacteria or viruses. The study described here was conducted to investigate the proliferative effect of vegetable peptone on adult stem cells in the absence of serum, and its possible mechanisms of action. Materials and methods:, Cell viability and proliferation were determined using the MTT assay and Click-iTÔ EdU flow cytometry, respectively. In addition, changes in expression of cytokine genes were analysed using MILLIPLEXÔ human cytokine enzyme-linked immunosorbent assay kit. Results:, Viability of cord blood-derived mesenchymal stem cells (CB-MSC) and adipose tissue-derived stem cells (ADSC) increased significantly when treated with the peptone. In addition, median value of the group treated with peptone shifted to the right when compared to the untreated control group. Furthermore, quantitative analysis of the cytokines revealed that production of vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-,1), and interleukin-6 (IL-6) increased significantly in response to treatment with our vegetable peptone in both CB-MSCs and ADSCs. Conclusions:, Our findings revealed that the vegetable peptone promotes proliferation of CB-MSCs and ADSCs. In addition, results of this study suggest that induction of stem cell proliferation by vegetable peptone is likely to be related to its induction of VEGF, TGF-,1, and IL-6 expression. [source] Cytokine gene polymorphisms and sudden infant death syndromeACTA PAEDIATRICA, Issue 3 2010L Ferrante Abstract Aim:, Several studies indicate that the mucosal immune system is stimulated in cases of sudden infant death syndrome (SIDS), and our hypothesis is that this immune reaction is because of an unfavourable combination of functional polymorphisms in the cytokine genes. Methods:, Thus, in this study, single nucleotide polymorphisms (SNPs) in the genes encoding IL-6, IL-8, IL-12, IL-13, IL-16, IL-18 and IFN, were investigated in 148 SIDS cases, 56 borderline SIDS cases, 41 cases of infectious death and 131 controls. Results:, Regarding genotype distribution, no differences between the investigated groups were found. However, in the SIDS group, the genotypes IL-8 ,251AA/AT and IL-8 ,781CT/TT were significantly more frequent in the SIDS cases found dead in a prone sleeping position, compared with SIDS cases found dead in other sleeping positions. In addition, there was an association between fever prior to death and the genotype IL-13 +4464GG in the cases of infectious death. Conclusion:, This study indicates that specific interleukin genotypes are a part of a genetic make up that make infants sleeping prone at risk for SIDS. [source] Expression and function of the purinergic receptor P2X7 in patients with pulmonary tuberculosisCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2006S. Franco-Martínez Summary P2X7 is a channel receptor gated by adenosine triphosphate (ATP) that is involved in the killing of intracellular mycobacteria. To explore further the role of P2X7 in immunity against Mycobacterium tuberculosis, we studied its expression and function in 19 patients with pulmonary tuberculosis (TB) and 19 healthy contacts. Flow cytometry analysis showed a similar and variable expression of P2X7 in TB patients and healthy subjects. In contrast, P2X7 mARN levels were significantly higher in TB patients. When the function of the P2X7 receptor in peripheral blood mononuclear cells (PBMC) was assessed by the effect of exogenous ATP on apoptosis, the uptake of the fluorescent marker Lucifer yellow or extracellular signal regulated kinase (ERK) phosphorylation, no significant differences were detected in patients and controls. However, mRNA macroarray analysis showed that upon stimulation with ATP, the PBMC from TB patients showed a significant induction of a higher number of cytokine genes (27 of 96), and a lower number of apoptosis genes (20 of 96) compared to healthy controls (17 and 76 genes, respectively). These results suggest that although the PBMC from TB patients do not show apparent abnormalities in the expression of P2X7, and the intracellular signals generated through it, the pattern of gene expression induced by ATP in these cells is different from that found in healthy contacts. This phenomenon suggests a defective function of P2X7 in the immune cells from TB patients, a condition that may contribute to the inability of these patients to eliminate the mycobacteria. [source] | ||||||||||||||||||||||||||||