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At least 901 records · Page 50Linked to original sources
PubMed2005

Treatment with pegylated interferon alpha-2b and ribavirin in patients unresponsive to previous treatments with standard interferon as monotherapy or combined with ribavirin.

BACKGROUND: Little information is available on the effect of pegylated interferon (PEG) and ribavirin (RBV) in patients with chronic hepatitis due to virus C (CHC) who were non-responders to previous treatment. OBJECTIVES: To evaluate response to treatment in patients who were non-responders to previous treatment. METHODS: One hundred and twenty-four patients who were non-responders to previous treatment were included. All patients were treated with PEG alpha 2b interferon (dose: 1.5 mg/kg body weight) and RBV (weight-dependent dosage). A qualitative PCR of virus C after six months was evaluated. In those in whom this was positive, treatment was discontinued; in those who were negative treatment was continued to the end of the year. RESULTS: Response following treatment (RFT) was 35.4% (44 patients), and sustained viral response (SVR) 29.8% (37 patients). No relation was observed between RFT, SVR and any previous treatment. RFT was dependent on low initial viremia and SVR was significantly and independently related to low serum hepatitis C RNA and a non-1 genotype. In general, treatment was well tolerated. Medication was discontinued in 5 patients, and doses reduced in 18. CONCLUSION: On retreatment with PEG and RBV a SVR of 29.8% was achieved in patients who had not responded to previous treatment, so its use in this group of patients is indicated.

Adult↗
PubMed1999

Induction of transcription factor interferon regulatory factor-1 by interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) in FRTL-5 cells.

While it is well known that interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) play a role in the regulation of thyroid growth and differentiated functions, the cellular and molecular mechanisms involved in mediating the effects of IFN gamma and TNF alpha on thyroid function are unknown. In the present study, we used FRTL-5 rat thyroid cells to examine the effects of IFN gamma and TNF alpha on gene expression of transcription factor interferon regulatory factor-1 (IRF-1), which is involved in mediating the effects of these cytokines in a number of cell types. Northern blot analysis of FRTL-5 mRNA showed a single IRF-1 mRNA at 2.2 Kb. In quiescent FRTL-5 cells, IRF-1 mRNA levels were low but detectable by Northern analysis. Incubation of FRTL-5 cells with IFN gamma or TNF alpha resulted in a dose- and time-dependent increase in IRF-1 mRNA levels. We have shown that TNF-alpha and IFN-gamma act synergistically to block the TSH-induced increase in type I 5'-deiodinase(5'D-I) activity and 5'D-I gene expression in FRTL-5 rat thyroid cells. Incubation of FRTL-5 cells with IFN gamma and TNF alpha in combination, however, did not synergistically increase IRF-1 mRNA levels. Electrophoretic mobility shift assay (EMSA) revealed that IFN gamma induced the formation of a single complex to a IFN gamma activation site (GAS) probe in a dose dependent manner. Several lines of evidence suggest that TNF alpha activates transcription factor nuclear factor-kappa B (NF kappa B) through activation of protein kinase C (PKC) or the hydrolysis of sphingomyelin to ceramide in a number of cell types. Here we demonstrate that hydrolysis of sphingomyelin to ceramide by sphingomyelinase (SMase), but not activation of PKC by 12-O-tetradecanoylphorbol 13-acetate (TPA), was involved in the activation of NF kappa B in FRTL-5 cells. Similarly, hydrolysis of sphingomyelin to ceramide, but not activation of PKC, resulted in an increased in IRF-1 mRNA levels in FRTL-5 cells. The present data demonstrate that IFN gamma and TNF alpha increase IRF-1 mRNA levels in FRTL-5 cells through activation of GAS and NF kappa B binding proteins, respectively. Thus, our results suggest that upregulation of IRF-1 may play a role in mediating the effects of IFN gamma and TNF alpha on thyroid function. Our results also suggest that the induction of IRF-1 mRNA by IFN gamma and TNF alpha is not the cellular mechanism involved in the synergistic effect of these cytokines on thyroid function.

Animals↗
PubMed2000

Tumour necrosis factor-alpha and interferon-gamma synergistically activate the RANTES promoter through nuclear factor kappaB and interferon regulatory factor 1 (IRF-1) transcription factors.

Inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) synergistically activate expression of the RANTES (regulated upon activation, normal T-cell expressed and secreted) gene, which plays a crucial role in the chemoattraction of leukocytes during the inflammatory response. To understand at the molecular level the mechanism by which the two cytokines activate RANTES gene expression, we determined the requirement of cis-acting elements in the RANTES promoter and trans-acting factors. The murine RANTES promoter contained one putative interferon regulatory factor, IRF, and three putative nuclear factor kappaB (NF-kappaB) binding sites. Specific destruction of the IRF binding site and one of the three NF-kappaB binding sites abolished the inducibility of promoter activity by IFN-gamma and TNF-alpha, respectively. In contrast, mutation of the other two putative NF-kappaB binding sites did not affect RANTES promoter activity significantly. In addition, the RANTES promoter was stimulated by co-transfection of plasmids that expressed either p65, an NF-kappaB family protein, or the IRF-1 transcription factor. RANTES promoters with mutations in the NF-kappaB or IRF binding sites were not stimulated by p65 or IRF-1 expression, respectively. In electrophoretic mobility-shift and immunologic assays, we showed that IRF-1 was induced after cells were treated with IFN-gamma and that NF-kappaB was activated by TNF-alpha treatment. These results demonstrate that both NF-kappaB and IRF-1 transcription factors mediate the induction of RANTES expression via their cognate cis-acting elements when cells are stimulated by TNF-alpha and IFN-gamma.

3T3 Cells↗
PubMed2003

Interferon plus ribavirin in patients with hepatitis C virus positive mixed cryoglobulinemia resistant to interferon.

OBJECTIVE: Only a small fraction of patients with hepatitis C virus (HCV) positive mixed cryoglobulinemia achieve longterm recovery after interferon (IFN) therapy; we evaluated the effectiveness and safety of combination therapy (interferon plus ribavirin) in nonresponders or those who relapsed after one or more courses of IFN. METHODS: Twenty-seven patients with HCV positive mixed cryoglobulinemia were studied. All were treated with IFN-a2b (3 MU 3 times weekly) for one year, plus daily oral ribavirin 1000 or 1200 mg. RESULTS: Five patients (18.5%) obtained complete recovery from viral infection and from all signs and symptoms of disease. During treatment, most patients (85%) improved clinically. All 5 responders were "relapsers" to the first treatment(s). CONCLUSION: Combination therapy of IFN plus ribavirin could be useful for patients with mixed cryoglobulinemia resistant to IFN as monotherapy.

Adult↗
PubMedDate not supplied

[An intensification of antiviral and interferon effects of ridostin (an interferon inducer) by cationic liposomes in vitro and in intranasal administration].

Combined application of ridostine with catonic liposomes was shown to essentially enhance the interferon-inducing and antiviral activity of the former in experiments with cell cultures L-929, which is apparently related with an improved efficiency of intracellular delivery of dsRNA. A comparative study demonstrated that ridostine, when combined with liposomes, is needed by 10(3)-10(4) times less as when it is used alone. A pretreatment of the cellular monolayer by cationic liposomes contributes also to enhancing the activity of ridostine, which can be explained by an enhanced permeability of cells for dsRNA holding on-for as long as 30 minutes after the removal of liposomes from the liquid culture. A separate successive administration of, first, liposomes and, then, of ridostine in BALB/c mice (20 mg/kg) leads to a more intensified induction of interferon in the upper respiratory tract tissues as compared with the administration of ridostine alone.

Administration, Intranasal↗
PubMed2003

[The assessment of development of binding antibodies to interferon beta during interferon beta 1a treatment of multiple sclerosis].

The importance of binding antibodies (BAb) that develop during the treatment of multiple sclerosis with interferon beta has not been fully explained yet. However, they are generally regarded as one of factors that may diminish treatment efficacy. The aim of the study was to evaluate firstly, BAb occurrence in interferon beta 1-a (IFN beta 1-a)-treated MS patients and secondly, BAb impact on clinical efficacy of this medication. In the 36-month study participants were 21 patients with relapsing-remitting multiple sclerosis, RR-MS, (14 women, 7 men, aged 29.6 +/- 8.5). All the patients were receiving intramuscular IFN beta-1a (Avonex) for 24 months, in the dose of 30 micrograms per week. Clinical parameters and serum BAb levels (the EIA method) were estimated every 3 months. Two control groups, examined only once, included 20 RR-MS patients without IFN-beta therapy and 20 healthy volunteers. While before treatment a high BAb level was found in 2 patients (9.5%), at 6 months of treatment it was found in 8 patients (38.1%). A similar number of patients with high BAb levels was seen throughout the study during the IFN-beta treatment. On therapy completion serum BAb levels decreased very rapidly. After 2 years of treatment, disability as measured by the EDSS scale was more pronounced in patients with serum BAb, but the differences were statistically not significant. No statistically significant relationship was found either between elevated BAb levels and the number of relapses during the IFN-beta treatment (including relapses that required steroid therapy).

Adjuvants, Immunologic↗
PubMed2006

[Interferon resistance and ISDR (interferon sensitivity determining region)].

A region associated with sensitivity to interferon has been identified in the nonstructural protein 5A(NS5A) of hepatitis C virus(HCV) genotype 1b. The region spans amino acid residues 2209 to 2248(NS5A2209-2248). While complete response was not obtained in the patients with HCV whose NS5A2209-2248 sequences were identical to that of HCV-J (wild type), all patients with HCV of 4 to 11 amino acid substitutions (mutant type) achieved complete response. We designed this region as the interferon sensitivity determining region(ISDR). Recently, a subgenomic HCV replicon system was established, and reported to replicate efficiently and continuously in human hepatoma Huh-7 cells. However, HCV replicon needs amino acid mutation, called as adaptive mutations, in NS5A for efficient replication. These findings demonstrate that the genetic structure of the NS5A domain is critical in HCV replication.

Amino Acid Substitution↗
PubMedDate not supplied

Tumor response to interferon inducer and radiation effect of serum interferon levels.

The effect of interferon inducing complex of polyriboinosinic, polyribocytidylic acid with poly-L-lysine and carboxymethylcellulose - Poly (ICLC) - on the response of Lewis lung carcinoma in C57B1 mice to radiation treatments was studied. Improved tumor response was obtained in mice receiving 1.5 mg/m2 or higher of Poly (ICLC). Such doses have induced more than 1000 mu/ml of serum interferon. The same doses of Poly (ICLC) potentiated the epilation effect of radiation. The injection of 0.15 mg/m2 of Poly (ICLC) led to protection of the tumor and the stimulation of it's growth. It also did not potentiate the epilation effect. In this study, one weekly administration of Poly (ICLC) was as effective as three times per week treatment. The cellular mechanism of the increased radiosensitivity caused by Poly (ICLC) was reflected in the reduction of the width of the shoulder on the cell survival curve, which was dependent on the dose of the drug. In cell cultures, doses of 100 micrograms/ml synchronized the cell division, thus contributing to the increase in radiosensitivity.

Animals↗
PubMed1988

Priming of Staphylococcus aureus-induced interferon production in human buffy coat leukocytes by human interferon-alpha pretreatment.

Human buffy coat leukocytes produced interferon (IFN) in response to induction with heat-killed Staphylococcus aureus. Pretreatment of cell with 150 IU/ml human interferon-alpha (HuIFN-alpha) for 3 h enhanced the IFN production by about four- to eight-fold. The simultaneous presence of HuIFN-alpha and gamma in the culture supernatants was indicated by parallel titrations on human embryo fibroblasts (HEF) and MadinDarby bovine kidney (MDBK) cells and also by the distribution of the peak IFN activities after Sephacryl S-200 gel filtration.

Humans↗
PubMed1989

Serum levels of alpha-interferon and gamma-interferon in patients with acute and chronic viral hepatitis.

We measured activities of alpha- and gamma-interferon simultaneously in 198 sera of 70 patients with acute and chronic viral hepatitis using specific and sensitive enzyme immunoassay and immunoradiometric assay. The results were compared with those in patients with influenza and in healthy controls. Twelve out of 28 patients with acute viral hepatitis showed positive alpha-IFN and/or gamma-IFN activities. alpha-IFN was detectable throughout the clinical course while gamma-IFN levels rose in the convalescent phase regardless of etiology. Conversely, in patients with influenza, both alpha-IFN and gamma-IFN levels of initial samples tended to be higher than those of late samples. Six out of 12 patients with chronic active type B hepatitis showed increased alpha-IFN and/or gamma-IFN values during acute deterioration with marked elevation of serum alanine aminotransferase. However, the two interferons did not always appear simultaneously, although either was detectable in both acute and chronic hepatitis. Enhanced alpha-IFN or gamma-IFN activity was not found in asymptomatic chronic hepatitis B carriers or in patients with chronic persistent hepatitis and liver cirrhosis with chronic hepatitis B virus infection, with the exception of 2 cases. Our results indicated that circulating multiple IFN species were present during the clinical course in some patients with acute and chronic viral hepatitis.

Acute Disease↗
PubMed1989

Heterogeneous response of human colon cancer cells to the cytostatic and cytotoxic effects of recombinant human cytokines: interferon-alpha, interferon-gamma, tumor necrosis factor, and interleukin-1.

We examined whether different human colorectal carcinomas (HCC) and cells populating a single neoplasm exhibit a heterogeneous response to the cytostatic and cytolytic effects of recombinant human cytokines used clinically for cancer therapy. The effects of interferon-alpha (IFN-alpha) hybrid BBDD, interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), interleukin-1 (IL-1), and the chemotherapeutic drug 5-fluorouracil (used as a positive control for cytostasis) were examined in six recently established HCC cell lines. One cell line was sensitive to the cytostatic and cytotoxic effects of IFN-alpha BBDD, whereas five cell lines were sensitive to IFN-gamma. Tumor cell sensitivity to IFN-alpha BBDD was independent of sensitivity to IFN-gamma. Only one cell line was somewhat sensitive to the cytostatic and cytotoxic effect of TNF, and none was sensitive to IL-1. The heterogeneous response to cytokines by a single neoplasm was demonstrated by analysis of multiple clones. Clonal populations exhibited different levels of susceptibility to cytostatic effects mediated by cytokines. The combination of IFN-gamma with IFN-alpha BBDD or with TNF produced additive or even synergistic cytostasis in HCC lines sensitive to the cytokines but not in cell lines that were resistant to either one or both agents. Collectively, these studies demonstrate intra- and intertumoral heterogeneity in sensitivity to recombinant cytokines, a finding that should receive consideration for clinical application.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Long-term killing of natural killer-resistant target cells by interferon-alpha-, interferon-gamma-, and interleukin-2-activated natural killer cells.

The sensitivity of target cells to natural killer (NK) cell-mediated cytotoxicity was investigated. Five target cell lines were examined for susceptibility to killing by activated NK cells in a 4-hour cytotoxicity assay: one of them (K562) was highly sensitive, while the other four were resistant. However, the four NK-resistant target cell lines were fully susceptible to lysis when the assay was extended to 24 h. The cytotoxic cells that killed the NK-resistant target cells in a 24-hour assay were plastic- and nylon wool-nonadherent human peripheral blood mononuclear cells (PBMC) and their cytotoxicity was increased by interferon-alpha, interferon-gamma, and interleukin-2. Further, the cytotoxic activity of PBMC in the long-term assay was associated with large granular lymphocytes purified on a Percoll gradient, that killed the NK-sensitive cell line K562 in a 4-hour assay. All of the above are general criteria to qualify the cytotoxic cells as NK cells. Thus, the NK-resistant phenotype may not reflect absolute immunity to NK-mediated lysis, but it may reflect the different rates at which various target cell lines can be killed.

Cell Line↗
PubMed1986

Preparation of 32P-labeled murine immune interferon and its binding to the mouse immune interferon receptor.

Murine immune interferon (Mu-IFN-gamma) can be radiolabeled with [gamma-32P]ATP by the catalytic subunit of cAMP-dependent protein kinase. The resulting 32P-labeled Mu-IFN-gamma (32P-Mu-IFN-gamma) with high radiological specific activity (60-260 muCi/micrograms) retains biological activity. Acid hydrolysis of 32P-Mu-IFN-gamma or 32P-labeled human IFN-gamma leads to the release of [32P]phosphoserine but not phosphothreonine or phosphotyrosine. With 32P-Mu-IFN-gamma, we have demonstrated that there are 5 X 10(3) to 1.5 X 10(4) receptors per-cell on several murine cell lines of diverse origin and that the Kd at 24 degrees C for these cells is in the range of 1 X 10(-10) to 1 X 10(-9) M. Covalent binding of 32P-Mu-IFN-gamma to its receptor results in the formation of several specific high-molecular weight products, the major one of which has an apparent molecular weight of 90,000-100,000. If this represents a 1:1 complex of Mu-IFN-gamma and its receptor (or its binding subunit), the murine interferon gamma receptor has a molecular weight of 75,000-85,000.

Adenosine Triphosphate↗
PubMed1987

[Combined effect of human recombinant interferon-beta and interferon-gamma against an experimental model of peritonitis carcinomatosa in nude mice].

The development of useful therapy for the peritonitis carcinomatosa of gastrointestinal cancer is an important theme in cancer therapy. We developed an experimental model of peritonitis carcinomatosa in nude mice transplanted intraperitoneally human colon cancer cells. In this study, we investigated combined effect of human recombinant interferon-beta (rIFN-beta) and recombinant interferon-gamma (rIFN-gamma) in vivo using this model. The result indicate that each rIFN-beta and rIFN-gamma showed a significant prolonged survival compared with the control group (mean survival days: 41.8 +/- 5.0 days). Furthermore, combined administration of rIFN-beta and rIFN-gamma showed a marked prolonged survival (mean survival days: 114.0 +/- 7.4 days) compared with rIFN-beta or rIFN-gamma alone. These results suggest that a combined treatment of rIFN-beta and rIFN-gamma may be useful against peritonitis carcinomatosa of gastrointestinal cancer.

Animals↗
PubMed1987

The capacity of blood lymphoid cells to produce alpha- and gamma-interferon is decreased during alpha-interferon therapy.

The influence of alpha-interferon (alpha-IFN) therapy on the capacity of blood lymphoid cells to produce alpha- and gamma-interferon (IFN) was studied in 21 patients with gynecological tumors, i.e., ovarian carcinoma (14 patients) or condylomata accuminata (7 patients). The mean capacity of the lymphoid cells to produce alpha-IFN in response to Sendai virus was increased, although not statistically significant, as compared to an age- and sex-matched control group, whereas the mean capacity of the patients' blood lymphoid cells to produce gamma-IFN in response to PHA or PWM was slightly decreased as compared to the control group. One day after the first injection of alpha-IFN there was a statistically significant decrease in the capacity of blood lymphoid cells to produce alpha-IFN and this decrease remained after 3 months of IFN therapy in most patients investigated. One week after initiation of alpha-IFN therapy there was a statistically significant decrease in the capacity of the cells to produce gamma-IFN in response to PHA or PWM and in most patients studied this decrease remained after 3 months of treatment. We conclude that the capacity of blood lymphoid cells to produce IFN is suppressed during exogenous alpha-IFN therapy.

Adult↗
PubMed1988

Overlapping polypeptide induction in human fibroblasts in response to treatment with interferon-alpha, interferon-gamma, interleukin 1 alpha, interleukin 1 beta, and tumor necrosis factor.

Cytokine-induced polypeptides were identified in whole cell lysates of human fibroblasts by computer-based analysis of two-dimensional gels with the use of the PDQuest System. Treatment with interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) enhanced the synthesis of 12 and 28 polypeptides, respectively. Exposure to interleukin 1 alpha (IL-1 alpha) or interleukin 1 beta (IL-1 beta) resulted in the increased synthesis of seven identical polypeptides. Treatment with tumor necrosis factor (TNF) at 100 U/ml led to enhanced expression of seven polypeptides, whereas exposure to TNF at 1000 U/ml increased the levels of these seven plus two additional polypeptides. The antiviral and antiproliferative effects of these cytokines in strain 153 fibroblasts were also assessed. Both IFN-alpha and IFN-gamma exhibited antiviral activity, whereas both IL-1 and TNF stimulated fibroblast growth. IFN-gamma was alone in inhibiting proliferation. Thus, although these cytokines exhibit low degrees of structural homology, they share some common functions, and a number of polypeptides were induced in common by two or more of these agents. The greatest similarities in polypeptide induction occur between IFN-alpha and IFN-gamma and between the IL-1s and TNF. However, polypeptides were also induced in common by IFN-alpha and TNF, IFN-gamma and IL-1, and IFN-gamma and TNF. These similarities in polypeptide induction may reflect the overlapping functions of these cytokines and may be indicative of common biochemical pathways in their mechanisms of action.

Biological Products↗
PubMed1983

[Effect of preliminary treatment with homologous interferon (priming) on the production of human immune interferon].

Pretreatment of the cultures of human peripheral blood leukocytes and splenocytes with the incubation medium of the mitogen-stimulated human lymphoid cells containing various concentrations of lymphokines (including 10 to 1280 units/ml of immune interferon) resulted in increased (by at least 4 times) production of interferon, induced by staphylococcal enterotoxin A, phytohemagglutinin and mitogen from Phytolacca americana (PWM), as well as in intensification of DNA synthesis in the producing cells. A more pronounced specific binding of the inductor labeled with radioactive iodine to the producing cells was also observed.

Cells, Cultured↗
PubMed1984

Inhibition of mouse bladder tumor proliferation by murine interferon-gamma and its synergism with interferon-beta.

We studied the effect of interferon-gamma (IFN-gamma) and mouse L-cell interferon (IFN-beta) on the proliferation of a mouse bladder tumor, MBT-2. A liquid culture clonogenic assay was used, and a linear relationship was obtained between the number of cells plated and the number of colonies formed. When the cells were assayed in the presence of various doses of murine IFN-gamma or IFN-beta, colony formation was inhibited in a dose-dependent manner. Partially purified IFN-gamma was more effective than IFN-beta in inhibiting MBT-2 colony formation in that IFN-beta exhibited a 50% inhibition dose of approximately 1000 units/ml, while the 50% inhibition dose for the partially purified IFN-gamma was approximately 70 units/ml. The 50% inhibition dose for recombinant IFN-gamma was 700 units/ml, suggesting that multiple lymphokines were active in the partially purified preparation. Further studies with partially purified IFN-gamma showed that the inhibitory effect was time dependent with the maximal effect observed after 48 hr of exposure in a 5-day assay. Treatment of partially purified IFN-gamma for 24 hr at pH 2.0 resulted in the abrogation of the antiproliferative effect. Studies in which partially purified IFN-gamma preparations were treated with a monoclonal antibody against IFN-gamma also resulted in abrogation of antiproliferative activity, confirming the nature of the antiproliferative agent to be IFN-gamma. Further studies showed that murine recombinant IFN-gamma also inhibited MBT-2 proliferation in a dose-dependent manner, confirming that IFN-gamma alone mediates antiproliferative activity. Combinations of IFN-beta and recombinant IFN-gamma acted synergistically in the inhibition of MBT-2 proliferation.

Animals↗