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At least 739 records · Page 41Linked to original sources
PubMed2003

[Generation of neutralizing anti-interferon antibodies and factors influencing their production in chronic hepatitis B patients receiving recombinant interferon-alpha treatment].

OBJECTIVE: To investigate the generation of neutralizing anti-interferon-alpha antibodies (NA) in patients with chronic hepatitis B in the course of interferon-alpha treatment, and analyze the factors influencing the production of the antibodies. METHODS: A total of 181 patients with histologically confirmed chronic hepatitis B were enrolled in this study. Recombinant interferon-alpha 1b (rIFN-alpha 1b) was given subcutaneously 3 times a week (5 MU once) in a treatment course lasting for 6 to 37 months (median 10.0 months). In each case, serum NA was detected with antiviral neutralization bioassay, HBeAg with enzyme-linked immunoassay (EIA) and hepatitis B virus DNA with fluorescent quantitative PCR every 1 to 3 months starting from 3 months after the initiation of the treatment. RESULTS: Of the 181 patients, 61 were positive for NA during the treatment course, resulting in an overall NA occurrence rate of 33.7%. The overall incidence rate, as well as the overall prevalence rate, was significantly higher in male than in female patients (39.1% vs 20.8%, (2)=5.622, P=0.018), and no correlations of NA generation was observed with age, pretreatment serum ALT level, serum HBeAg, serum HBV DNA level, liver histological findings or treatment course. Binary logistic regression analysis showed that the only factor in relation with NA production was gender. The prevalence rates of NA varied significantly with the treatment courses ( (2)=98.051, P=0.000). Bivariate correlation analysis showed that the prevalence rate of NA, but not the incidence of NA, was strongly related with the treatment course (r=0.855, P<0.001). CONCLUSIONS: In chronic hepatitis B patients treated with rIFN-alpha 1b, the prevalence rate of NA, instead of the incidence of NA, is significantly related to the treatment course. NA was more likely to develop in male patients to contribute to their poorer antiviral response in comparison with the female patients.

Adolescent↗
PubMed2004

[Clinical significance of neutralizing anti-interferon antibodies in chronic hepatitis B patients treated with recombinant interferon-alpha].

OBJECTIVE: To investigate the clinical significance of neutralizing anti-interferon-alpha antibodies (NA) in chronic hepatitis B patients treated with recombinant interferon-alpha(rIFN-alpha). METHODS: One hundred and eighty-one patients (128 male and 53 female) with histological proven chronic hepatitis B were treated with 5 MU recombinant interferon-alpha 1b (rIFN-alpha 1b) subcutaneously thrice weekly for 6 to 37 (median 10) months. For each patient, Specific detection of serum HBV DNA level with fluorescent-quantitative PCR, HBeAg with enzymoimmunoassay and NA with an antiviral neutralizing biological assay were performed during therapy. RESULTS: NA was found in 61 (33.7%) of 181 patients. At the end of treatment, complete-response was achieved in 17 (27.9%) of 61 patients with NA and in 54 (45.0%) of 120 patients without NA, respectively (chi2=4.979). For NA positive patients, the complete-response rate was significantly lower in those who had not achieved partial-response prior to or at the same time as NA occurred than in those who did (3.8%, 1/26, vs. 45.7%, 16/35, chi2 = 7.457). Moreover, it was lower in patients who either had 20pg/ml of serum HBV DNA or above or HBV DNA had being reduced by less than 60% recent 3 months, but higher in those who had less than 20pg/ml of HBV DNA and HBV DNA had being reduced by 60% or above (20.0%, 9/45, vs. 56.3%, 9/16, chi2 = 11.009). CONCLUSION: NA may negate the antiviral effects of rIFN-alpha in chronic hepatitis B patients treated with rIFN-alpha, especially if they appear before partial-response or at the occasion at which serum HBV DNA level was not below 20pg/ml or HBV DNA had being reduced by less than 60% recent 3 months.

Antibodies↗
PubMed2004

Correlation of the response of recurrent malignant gliomas treated with interferon alpha with tumor interferon alpha gene content.

Malignant gliomas are treated by combining surgery and radiation with chemotherapy. Cure is rare and utilizing information arising from our improved understanding of brain tumor biology may be of value. Interferon alpha (IFNalpha) treatment as restorative immunotherapy has been utilized in malignant gliomas in the past. Interferon alpha/beta gene presence is variable in these tumors. The relationship between response to IFNalpha therapy and gene status has not been assessed prospectively. Patients with recurrent malignant gliomas were treated with 8-week courses of IFNalpha. Clinical and laboratory toxicity was assessed and response determined by MRI scans. Tumor interferon alpha/beta gene content was measured. Toxicities included fourteen grade 3/4 neuro-motor events, and eleven grade 3 neuro-cortical events. Rapid tolerance developed and with dose reductions few doses were missed. Three individuals with glioblastoma multiforme demonstrated a partial response. Median time to progression was 24.6 (+/-17.6) weeks for all glioblastomas. The correlation between longer time to progression and lower tumor IFNalpha gene content as measured here was significant. A minority of patients with recurrent malignant gliomas will respond to IFNalpha therapy at starting doses of 20 Mu/m(2) and above. These doses are associated with significant toxicity. A relationship between the tumor IFNalpha gene status and tumor response to therapy may be present. With current improved understanding of IFNalpha toxicities and ability to measure tumor IFNalpha function, this therapy warrants further evaluation for identifying patients whose tumors are likely to be responsive to IFNalpha therapy.

Adult↗
PubMed1989

Interferons as gene activators. Indications for repeated gene duplication during the evolution of a cluster of interferon-activatable genes on murine chromosome 1.

We have described earlier a gene cluster, including at least six interferon-activatable genes closely linked to the erythroid alpha spectrin locus and the serum amyloid P-component locus on murine chromosome 1. Here, we report that sequences of three genes from the cluster (the 201, 202, and 204 genes) are very similar in a segment extending from at least 550 nucleotides upstream of the 3' end of the transcription initiation region to beyond the first exon intron border (96% similarity between the 202 and 204 genes and 89% similarity between the 201 and 204 genes). This region contains the following two types of interferon-responsive enhancers: a GA box and a Friedman Stark sequence. The proteins coded for by the 202 gene (51 kDa) and the 204 gene (72 kDa) are hydrophilic. The amino acids have been conserved in the two proteins in 47% of the sequence. Each protein includes two apparently contiguous, approximately 200-amino acid long segments with much sequence similarity (27% in the 202 protein and 34% in the 204 protein). These segments are preceded in the 204 protein only by a segment including four perfect and three imperfect repeats of a 7 amino acid sequence. These and other data suggest that the evolution of the gene cluster involved the duplication of a DNA segment generating a double length transcription unit and subsequent divergence and duplication of this unit giving rise to at least two interferon-activatable genes (the 202 and 204 genes).

Amino Acid Sequence↗
PubMed1989

Enhanced in vivo therapeutic response to interferon in mice with an in vitro interferon-resistant B-cell lymphoma.

A stable subline of 38C13 B-cell lymphoma (SIR-1) resistant to the antiproliferative effects of alpha-interferon (IFN) was isolated. In addition to defects in antiproliferative effects of IFN, SIR-1 is defective in IFN-mediated antiviral activity against both encephalomyocarditis virus and vesicularstomatitis virus. It is also defective in the induction of 2'-5'-oligoadenylate synthetase mRNA and enzyme activity, enhancement of H-2 antigen expression, and transient induction and subsequent repression of c-myc by IFN. SIR-1, although completely resistant to IFN in vitro, is more sensitive to IFN than the parental cell line in vivo. IFN treatment at 10(4) units, three times weekly, resulted in a 28% increase in mean survival time and a 1.4% long term survival rate in the IFN-sensitive 38C13 cell line but resulted in a 275% increase in mean survival rate and a 27% long term survival rate in the interferon-resistant SIR-1 mutant. Statistical analysis of 38C13 and SIR-1 with and without IFN treatment demonstrate that: a) the SIR-1 mutant remains sensitive to the cytotoxic effects of IFN in vivo (P less than 0.0001); and b) the mean survival and long term survival of animals with the SIR-1 mutant is significantly greater than for animals with the IFN-sensitive 38C13 cell line (P less than 0.0001). Two additional independently isolated IFN-resistant cell lines (SIR-111 and SIR-E102) also demonstrate significantly enhanced in vivo response to IFN compared to the interferon-sensitive parental (38C13) cells. These results indicate that, for this cell line, the antitumor effects of IFN are mediated by activation of host defenses and that resistance to the in vitro cytotoxic effects of IFN results in a tumor phenotype that is more readily recognized by host defenses and eliminated.

2',5'-Oligoadenylate Synthetase↗
PubMed1987

[Phase II study of natural interferon-gamma. Natural Interferon-gamma Cooperative Study Group].

Naturally produced interferon-gamma was evaluated in 187 cases with advanced cancer. Interferon was given by the i.v. routes in doses ranging from 1 X 10(5) IU to 2 X 10(5) IU/day daily or every other day for more than 2 months. Overall, clinical anticancer spectrum, effectiveness, toxicities, and pharmacokinetics were similar to that seen with preparations of interferon-alpha, and beta.

Drug Evaluation↗
PubMed1977

Antiviral action of interferon in man: use of interferon in varicella - zoster infections in man.

The effect of human leukocyte interferon on varicella-zoster infections was compared in a placebo controlled study. Thirty-six patients were treated with interferon and 26 with placebo. In the interferon treated group the duration of pain was shortened, the development of crust formation was enhanced and the viral clearance from lesions was accelerated, compared with the control group.

Antiviral Agents↗
PubMed1978

The protective effect of endogenous interferon in mouse malaria, as demonstrated by the use of anti-interferon globulins.

Both death rate and percentage of parasitized erythrocytes in mice infected with Plasmodium berghei were enhanced by injections of anti-interferon globulins. As, in the same time, parasite-induced interferon was neutralized by these globulins, it can be concluded that endogenous interferon plays an important inhibiting role during parasitic diseases, such as malaria, as it has been previously demonstrated in many virus infections.

Animals↗
PubMed1986

Treatment of soft tissue sarcoma with fibroblast interferon (beta-interferon): an American Cancer Society/Illinois Cancer Council Study.

Twenty patients with soft tissue sarcoma were treated with iv human fibroblast interferon (beta-interferon). Each cycle of treatment involved 5 X 10(6) units over 10 minutes, then 5 X 10(6) units iv over 3 hours daily X 10 with cycles repeated every 20 days X 3. Maintenance therapy was given twice weekly if disease was stable or responsive after three therapy periods. One patient had a partial response to treatment and six patients experienced stable disease for variable periods of time. Toxicity (fever, fatigue, leukopenia, hepatic enzyme elevations) was moderate and tolerable; therapy (except in one case of profound granulocytopenia) was neither interrupted nor discontinued because of toxicity. We conclude that beta-interferon in the dose and schedule used has limited value for soft tissue sarcoma.

Adult↗
PubMed1985

Mechanism of interferon action. Purification and substrate specificities of the double-stranded RNA-dependent protein kinase from untreated and interferon-treated mouse fibroblasts.

The double-stranded RNA (dsRNA)-dependent protein kinase which catalyzes the phosphorylation of ribosome-associated protein P1 and the alpha subunit of eukaryotic protein synthesis initiation factor 2 (eIF-2) was purified and characterized from mouse fibroblast L929 cells treated with either natural or recombinant interferon and from untreated cells. The dsRNA-dependent P1/eIF-2 alpha kinase was purified at least 1,500-fold from interferon-treated cells; the kinase activity that catalyzed the phosphorylation of eIF-2 alpha copurified with protein P1. The yield of P1/eIF-2 alpha protein kinase activity obtained following purification from cells treated with interferon was about 5-10 times greater than the yield from an equivalent number of untreated cells. The purified protein kinase remained dsRNA dependent. When P1 kinase was activated by dsRNA, a major phosphopeptide designated Xds was phosphorylated; Xds was not phosphorylated from P1 which had not been activated by dsRNA. The apparent native molecular weight of the purified mouse L929 dsRNA-dependent kinase as determined by sedimentation analysis was about 62,000, comparable to the molecular weight of 67,000 determined for denatured L929 phosphoprotein P1 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purified protein kinase was highly selective for the alpha subunit of protein synthesis initiation factor eIF-2 and endogenous protein P1. Kinase activity was dependent upon Mg2+, and the Km for ATP was determined to be 5 X 10(-6) M. Histones (H1, H2A-B, H3, and H4) and protein synthesis initiation factors other than eIF-2 (eIF-3, eIF-4A, eIF-4B, and eIF-5) were not substrates or were very poor substrates for the purified dsRNA-dependent protein kinase. N-Ethylmaleimide, ethylenediaminetetraacetic acid, AMP, pyrophosphate, spermine, spermidine, and high concentrations of potassium inhibited both P1 and eIF-2 alpha phosphorylation by the purified kinase, whereas ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and phenanthroline did not significantly affect the phosphorylation of either protein P1 or eIF-2 alpha.

Amnion↗
PubMed1979

Synthesis of spontaneous interferon by mouse peritoneal cells in vitro. II. Characteristics of the process of spontaneous interferon synthesis.

As it was shown previously that the peritoneal cells of mice were capable of producing interferon spontaneously. Spontaneous interferon appeared after 5 to 6 h of incubation of peritoneal cells at 26 degrees C and its highest level has been found after 12 h. The production of spontaneous interferon was inhibited by 4 h incubation of peritoneal cells at a temperature of 37 degrees C as well as by actinomycin D added at 0 to 4 h.

Animals↗
PubMed1994

[Efficacy of interferon combined glycyrrhizin therapy in patients with chronic hepatitis C resistant to interferon therapy].

To assess the efficacy of interferon (IFN) combined with a large dose of glycyrrhizin (SNMC) therapy in patients with chronic hepatitis C who were resistant to interferon therapy alone, we studied 8 patients with chronic hepatitis C who did not respond to the initial interferon therapy. Initially all of 8 patients received 6 million units of alpha-IFN intramuscularly, three times a week, for 3 months and their serum alanine transaminase (ALT) did not decrease more than 50% at the end of therapy and returned to pretreatment levels after therapy. Six months later, all of these patients received alpha-IFN (6 MU) combined with 80 ml of SNMC intravenously, three times a week for 6 months. Prior to the initial IFN therapy alone, all of the patients were positive for anti-HCV and HCV RNA in the serum. With IFN therapy, serum HCV RNA became negative in 4 of 8 patients and HAI score decreased significantly although their ALT levels did not decrease more than 50%, while with IFN combined with SNMC therapy, ALT levels decreased approximately 70% in all patients (one became normal), serum HCV RNA became negative in 2 and HAI scores did not change significantly. There was no significant differences in decrease of HCV RNA titers and HAI scores between two therapy except the ALT levels. These findings suggest that IFN combined SNMC therapy does not appear to be more beneficial than IFN therapy alone.

Adult↗
PubMed1996

Pilot study of a short course of ribavirin and alpha interferon in the treatment of chronic active hepatitis C not responding to alpha-interferon alone.

Chronic active hepatitis due to HCV represents a severe progressive disorder of the liver, At present, Interferon seems to be the most efficacious treatment available, however, only 20-25% of the patients treated achieve complete remission. The efficacy has, therefore, been evaluated of Ribavirin, a nucleoside analogue active both on DNA and RNA viruses, in the treatment of non responders to a previous course of interferon. Twenty patients were randomly assigned to two groups: A) received the association R (800 mg/day for 2 months)+interferon (9 Mu/week for 6 months); B) received IFN (9 Mu/week for 6 months). All patients completed the study without important side effects. Four patients in group A presented reduced ALT and loss of viraemia during treatment with Ribavirin. Only one patient in group B had reduced indices of cell lysis and was negative for HCV-RNA during the course of the study. However, viremia and an increase of ALT values were observed in all of these subjects once treatment was interrupted. The results emerging from this study indicate that Ribavirin therapy, at the dose and duration of treatment employed, is not sufficient to change the natural course of events of chronic active hepatitis from HCV.

Adult↗
PubMed2000

Functional significance of globotriaosyl ceramide in interferon-alpha(2)/type 1 interferon receptor-mediated antiviral activity.

The N-terminus of the type 1 interferon receptor subunit, IFNAR1, has high amino acid sequence similarity to the receptor binding B subunit of the Escherichia coli-derived verotoxin 1, VT1. The glycolipid, globotriaosyl ceramide (Gb(3): Gal alpha(1) --> 4 Gal beta 1 --> 4 Glu beta 1 --> 1 Cer) is the specific cell receptor for VT1. Gb(3)-deficient variant cells selected for VT resistance are cross-resistant to interferon-alpha (IFN-alpha)-mediated antiproliferative activity. The association of eIFNAR1 with Gal alpha 1 --> 4 Gal containing glycolipids has been previously shown to be important for the receptor-mediated IFN-alpha signal transduction for growth inhibition. The crucial role of Gb(3) for the signal transduction of IFN-alpha-mediated antiviral activity is now reported. IFN-alpha-mediated antiviral activity, nuclear translocation of activated Stat1, and increased expression of PKR were defective in Gb(3)-deficient vero mutant cells, although the surface expression of IFNAR1 was unaltered. The VT1B subunit was found to inhibit IFN-alpha-mediated antiviral activity, Stat1 nuclear translocation and PKR upregulation. Unlike VT1 cytotoxicity, IFN-alpha-induced Stat1 nuclear translocation was not inhibited when RME was prevented, suggesting that the accessory function of Gb(3) occurs at the plasma membrane. IFN-alpha antiviral activity was also studied in Gb(3)-positive MRC-5 cells, which are resistant to IFN-alpha growth inhibition, partially resistant to VT1 but still remain fully sensitive to IFN-alpha antiviral activity, and two astrocytoma cell lines expressing different Gb(3) fatty acid isoforms. In both systems, long chain fatty acid-containing Gb(3) isoforms, which are less effective to mediate VT1 cytotoxicity, were found to correlate with higher IFN-alpha-mediated antiviral activity. Inhibition of Gb(3) synthesis in toto prevented IFN-alpha antiviral activity in all cells. We propose that the long chain Gb(3) fatty isoforms preferentially remain in the plasma membrane, and by associating with IFNAR1, mediate IFN-alpha antiviral signaling, whereas short chain Gb(3) fatty acid isoforms are preferentially internalized to mediate VT1 cytotoxicity and IFNAR1-dependent IFN-alpha growth inhibition.

Animals↗
PubMed1996

Expression of interferon-alpha receptor mRNA in the liver in chronic liver diseases associated with hepatitis C virus: relation to effectiveness of interferon therapy.

To investigate whether interferon-alpha receptor (IFN-alpha Rc) expression was related to the effectiveness of interferon therapy in hepatitis C virus (HCV)-associated chronic liver disease (CLD). IFN-alpha Rc mRNA was investigated by reverse transcription polymerase chain reaction (RT-PCR) in liver biopsies and peripheral blood mononuclear cells (PBMCs) from 40 patients with HCV-associated CLD who subsequently received IFN-alpha therapy. IFN-alpha Rc mRNA in the liver was detected in 18 of 20 (90%) responders to IFN and in 5 of 20 (25%) non-responders (P < 0.01). In PBMCs, IFN-alpha Rc mRNA was detected in all patients regardless of response to IFN. Increased histological hepatitis activity and liver fibrosis were significantly related to the absence of IFN-alpha Rc mRNA. The HCV-RNA genotype showed no significant relationship to IFN-alpha Rc mRNA expression. Our results suggest that IFN-alpha Rc mRNA expression in the liver, but not in PBMCs, is closely associated with the effectiveness of IFN-alpha therapy in HCV-associated CLD.

Antiviral Agents↗
PubMed2006

Adjunctive treatment of disseminated Mycobacterium avium complex infection with interferon alpha-2b in a patient with complete interferon-gamma receptor R1 deficiency.

We report adjunct treatment of (interferon) IFN-alpha2b (Intron-A) in a patient with complete interferon-gamma receptor R1 (IFNGR1) deficiency suffering from disseminated infection with Mycobacterium avium complex (MAC) resistant to multiple anti-mycobacterial agents. A low dose of IFN-alpha2b (3 x 10(6) units/m(2) three times weekly subcutaneously) successfully attenuated progressive hepatosplenomegaly and abdominal/retroperitoneal/pelvic lymphadenopathy, although the patient continued to be mycobacteremic. This is the first report of a complete IFNGR1 deficiency treated with adjuvant IFN-alpha2b for disseminated MAC infection.

Child, Preschool↗
PubMed1997

Purification of an atypical bovine interferon induced in response to heat shock in bovine cultured cells. Characterization in comparison with the classical alpha, beta and gamma interferon.

Heat-shock induced factor (HSIF) was excreted by bovine MDBK cells during their recovery period after a heat shock. This factor has the capacity to induce 2',5' oligoadenylate synthetase activity, an enzyme generally by interferon treatment (J Biol Chem (1987) 262, 4806-4811). We have observed that an antiviral state was also produced in response to heat shock. HSIF was purified 10,000-fold and different techniques showed a copurification of both activities. Certain properties of HSIF were established, such as its molecular mass (45 kDa) and isoelectric point (6.8). This cytokine was acid-sensitive as IFN gamma (type II) and temperature labile contrarily to alpha, beta and gamma bovine IFN. Immunoprecipitation and comparative chromatography on lectines or polynucleotides established that HSIF was structurally different from the three classes of bovine IFN. Moreover, two-dimensional electrophoresis and comparative analysis of [35S] methionine-labeled proteins induced by HSIF alpha, beta or gamma bovine IFN showed that HSIF induces a specific set of proteins. Taken together, all these results strongly suggest that HSIF is a new atypical bovine interferon induced in response to heat shock.

2',5'-Oligoadenylate Synthetase↗