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PubMed1995

Genotype, slow decrease in virus titer during interferon treatment and high degree of sequence variability of hypervariable region are indicative of poor response to interferon treatment in patients with chronic hepatitis type C.

In a study assessing factors associated with a good or a poor response to interferon treatment in patients with chronic hepatitis type C, we analyzed serum samples taken from 26 interferon-treated patients and found further evidence that infection with genotype II is associated with a poor response. Whereas all seven patients with group III genotype tested showed a good response (normalization of alanine aminotransferase level for more than 6 months), only 10 of 19 (53%) patients infected with group II genotype showed a good response. We also observed that 16 of 17 (94%) patients who exhibited a rapid virus titer decrease during the first 2 weeks of treatment later showed a good response. In contrast, only three of nine (33%) patients with an initially slow viral decrease eventually showed a good response (p<0.04). None of the 26 control patients exhibited a marked virus decrease or normalization of serum alanine aminotransferase level. Interestingly, high degrees of sequence variability were seen in three patients with group II hepatitis C virus who responded poorly to the therapy. All three showed slow decreases in virus titer during the first 2 weeks of treatment. In contrast, patients with genotype II who showed a good response to treatment were seen to have very few mutations. In three patients with genotype III who had responded well to interferon treatment, all showed very little amino acid sequence variability in the hypervariable region compared with patients with genotype II who had responded poorly to interferon treatment. These data suggest that a slow decrease in virus titer during the beginning of interferon treatment and a high degree of sequence variability, both of which are often seen in patients with group II genotype, are associated with poor response to interferon treatment.

Adult↗
PubMed1987

Endogenous gamma interferon production may protect against hepatic cirrhosis and administration of exogenous gamma interferon may protect individuals prone to cirrhosis.

Hepatic cirrhosis is characterized by the replacement of normal liver parenchyma by collagenous fibrous tissue. Although hepatocytes in the adult retain the ability to divide, under certain circumstances hepatocyte death leads to replacement with fibroblasts and collagen. Whether a particular form of hepatocyte injury leads to cirrhosis is dependent upon the stimulus for the injury and is also highly variable between individuals. It has recently been shown that gamma interferon inhibits collagen synthesis in vitro and fibrosis in vivo. I suggest that individuals who are prone to hepatic cirrhosis from a given stimulus are low producers of gamma interferon while high gamma interferon producers are relatively protected from cirrhosis. I also hypothesize that exogenous gamma interferon administration may halt or slow the progression of cirrhosis in patients with early progressive cirrhosis. Alternatively, endogenous gamma interferon production could be stimulated in these patients with progressive cirrhosis. One agent which may be useful for inducing endogenous gamma interferon is GE-132, an organogermanium.

Humans↗
PubMed2005

The duration of in vitro stimulation with recall antigens determines the subset distribution of interferon-gamma-producing lymphoid cells: a kinetic analysis using the Interferon-gamma Secretion Assay.

Analyses of cellular immune responses during natural infections and following vaccination with established or candidate vaccines are becoming increasingly important and so are the research tools used to achieve this goal. During a recent evaluation of the analytical performance characteristics of one of these techniques, the interferon-gamma secretion assay, we noticed that following overnight incubation of PBMC with recall antigens (varicella-zoster antigen, Candida albicans antigen or hepatitis B surface antigen) NK cells are frequently the most predominant interferon-gamma-producing cell population. In this study, we monitored the subset distribution of interferon-gamma-producing cells following more extended in vitro culture periods and found that, irrespective of the antigen applied, the contribution of NK cells decreased whereas the importance of T cells and NKT cells rose. Analysis of the subset distribution showed that HBsAg stimulated CD4 cells predominantly whereas Candida antigen and varicella-zoster antigen were better inducers of CD8 responses. No correlation was found between the kinetics of total number of interferon-gamma-producing cells and the changes of concentrations of interferon-gamma in the culture supernatants. Interferon-gamma levels in culture supernatants correlated strongly with the kinetics of T(H) lymphocytes (CD3+, CD4+), CTL (CD3+, CD8+), and NKT cells (CD3+, CD56+). These observations lead us to conclude that methods that enumerate cytokine-secreting cells without determining their phenotype should be interpreted with great care and that an 'elispot' should not be directly considered as the footprint of a T lymphocyte.

Antigens↗
PubMed1993

Treatment of chronic hepatitis B with recombinant interferon alpha versus recombinant interferon alpha plus levamisole.

To compare the efficacy and tolerance of the simultaneous administration of levamisole plus IFN versus treatment with IFN alone in chronic hepatitis B, 39 patients were randomly assigned into two groups. Nineteen patients received 15 million units of recombinant alpha interferon 2b (rIFN-alpha 2b) 3 times a week for 4 months. The other 20 patients were treated with the same dose and schedule of rIFN-alpha 2b and 150 mg of levamisole simultaneously given during the first 6 weeks of treatment. At the end of the study (thirteenth month), serum HBV-DNA was negative in 59% of patients treated with interferon alone and in 37% of those treated with interferon and levamisole. HBeAg was negative in a similar percentage in the two groups (41% vs. 37%). Serum alanine aminotransferase levels decreased in patients who lost viral DNA. These data demonstrate that the combination of alpha interferon and levamisole, at the doses and under the schedule used in this study, does not achieve better results than the treatment with alpha interferon alone. Although tolerance to the simultaneous administration of alpha interferon and levamisole is good, secondary effects may be hazardous.

Adolescent↗
PubMed1998

Treatment of chronic hepatitis C with alpha-interferon plus ofloxacin in patients not responding to alpha-interferon alone.

BACKGROUND/AIMS: Ofloxacin, a quinolone antibiotic, was recently shown to increase the primary response rate to alpha-interferon treatment of chronic hepatitis C. METHODS: Fifty-five patients with chronic hepatitis C were scheduled to receive 3 MU of a-interferon, three times a week, for 1 year. After 3 months of therapy, patients who were still HCV RNA-positive in serum started receiving a combined regimen with 3 MU of alpha-interferon, three times a week, plus ofloxacin, 600 mg daily, per os. After 3 months of combined therapy, patients with undetectable serum HCV RNA continued the combined regimen for another 6 months, whereas patients who were still HCV RNA-positive were definitively considered as non-responders and withdrawn from the study. Serum HCV RNA levels were quantitatively evaluated after 3 months of therapy with a-interferon alone and compared with those detected after 3 months of combined regimen. RESULTS: Among the 54 patients who completed the first 3 months of treatment, 32 (59.3%) still had HCV RNA detectable in serum and started receiving the ofloxacin/alpha-interferon therapy. Among the 26 patients who completed the 3 additional months of combined regimen, only one showed a virological response: this patient maintained a complete response to the end of combined treatment, but relapsed thereafter. The combination therapy had no effect on the serum HCV RNA or alanine aminotransferase levels. CONCLUSIONS: The combined administration of alpha-interferon and ofloxacin to patients with chronic hepatitis C who have not responded to alpha-interferon alone does not increase the primary virological response rate.

Adult↗
PubMed2001

Interferon-associated retinopathy in a uniform regimen of natural interferon-alpha therapy for chronic hepatitis C.

BACKGROUND/AIMS: The development of retinal lesions induced by a uniform regimen of interferon-alpha therapy for chronic hepatitis C was prospectively investigated. METHODS: Eighty-one patients received 6 mega units of natural interferon-alpha intramuscularly daily for 2 weeks and then 3 times a week for 22 weeks. The total dose of interferon-alpha administered was uniformly 478 mega units per patient. Two expert ophthalmologists prospectively examined the patients for retinal lesions before, during and after the therapy. RESULTS: Retinopathy was not found in comparison groups or any of the patients before treatment. In total 34.6% (28/81) of the patients showed cotton-wool spots or minor retinal hemorrhage, or both lesions, during therapy, but these lesions were reversed during or after interferon therapy. The occurrence rates of cotton-wool spots alone, retinal hemorrhage alone and both lesions were 13.6% (11/81), 6.2% (5/81), and 14.8% (12/81), respectively. The appearance of retinopathy did not correlate with patients' background including viral loads and response to the therapy, but was more frequently found in older patients and patients with hypertension and/or diabetes mellitus; disappearance of retinopathy was more prolonged than in patients without these complications. Almost all the lesions appeared 2-4 months after the start of the therapy, and the severity of the lesions did not differ between patients with and without hypertension and/or diabetes mellitus. CONCLUSION: Although it is not clear if interferon-associated retinopathy occurs in a dose-dependent manner, the present study shows a standard pattern of the occurrence of retinopathy in patients with chronic hepatitis C receiving a uniform dosage of natural interferon-alpha.

Age Distribution↗
PubMed1999

Sustained response to interferon-alpha or to interferon-alpha plus ribavirin in hepatitis C virus-associated symptomatic mixed cryoglobulinaemia.

BACKGROUND: Hepatitis C virus (HCV) infection has been associated with mixed cryoglobulinaemia. AIM: To investigate the efficacy of anti-viral therapy on the eradication of HCV and its clinical manifestations in patients with HCV-associated symptomatic mixed cryoglobulinaemia. PATIENTS AND METHODS: 18 out of 32 patients with symptomatic mixed cryoglobulinaemia (MC group) received a 12-month course of interferon (3 MU three times a week, subcutaneously). Nonresponders or relapsers to this therapy were treated with interferon plus ribavirin (1200 mg/day, orally) for 12-months. 226 patients with HCV infection and without cryoglobulins were studied in comparison (Hepatitis C group). Serial quantification of serum HCV-RNA and cryoglobulins were performed. RESULTS: In the MC group, 10 out of 18 patients (55%) receiving interferon showed an end of treatment response, but at the end of follow-up, only five (28%) patients had a sustained response. In the hepatitis C group, 91 patients (47%) showed an end of treatment response but only 42 (20%) a sustained response. In the MC group alanine transaminase, cryocrit and rheumatoid factor decreased significantly in responders, with an improvement or disappearance of the MC-associated clinical manifestations. Alanine transaminase, cryocrit and rheumatoid factor increased in the relapsers and the clinical manifestations reappeared. Nonresponders and relapsers to interferon in the MC group were retreated with interferon plus ribavirin. Five out of eight nonresponders showed a end of treatment response but it was sustained in three of them. In the relapsers, treatment with combined therapy achieved a sustained response in four out of the five patients (80%). CONCLUSIONS: Interferon as monotherapy or combined with ribavirin is a safe and effective treatment in patients with HCV-associated MC. The presence of cryoglobulins does not affect the response to anti-viral treatment in patients with HCV infection. The eradication of HCV is associated with an improvement or disappearance of MC-associated clinical manifestations.

Antiviral Agents↗
PubMed2002

Early viral clearance and sustained response in chronic hepatitis C: a controlled trial of interferon and ribavirin after high-dose interferon induction.

High-dose induction with alpha-interferon induces early viral clearance of hepatitis C and combined with ribavirin enhances sustained response. We assess whether adding ribavirin after viral clearance obtained by alpha-interferon induction increased the rate of viral eradication.Forty-one naïve patients with chronic hepatitis C were randomised to receive, after 4 weeks of 10 mU daily of alpha-interferon (induction), 3 mU daily for 22 weeks and 3 mU thrice weekly for 26 weeks of either interferon alone (monotherapy) or interferon plus 1000-1200 mg daily of ribavirin (combination therapy). At the end of the induction phase, 23 (56%) subjects had cleared HCV-RNA. During therapy, breakthrough was observed in four patients on monotherapy, but never in patients on combination therapy. The rate of clearance of HCV-RNA was different between monotherapy and combination therapy at the end of treatment (40% vs. 76.1%, P=0.02) and at the end of follow-up (5% vs. 57.1%, P=0.001). Twelve of the 23 patients who cleared HCV-RNA during induction, but only one of the 18 still HCV-RNA-positive after 4 weeks of therapy, had a sustained response (52.2% vs. 5.6%, P=0.001). Clearance of HCV-RNA at 1 week had a high positive predictive value for sustained response in combination therapy (PPV=0.75), but not in monotherapy (PPV=0.33). Induction with high daily doses of alpha-interferon obtains suppression of hepatitis C in more than half of patients, but ribavirin is needed to maintain a sustained response. The rate of sustained response is a function of the time to HCV-RNA clearance. In patients not responding to induction therapy addition of ribavirin does not obtain a sustained virological response.

Adolescent↗
PubMed1975

Interferon action II. Membrane-bound alkaline ribonuclease activity in chick embryo cells manifesting interferon-mediated interference.

Membrane fractions from chick embryo cells manifesting viral interference mediated by interferon or poly(I)-poly(C) contain high levels of an alkaline ribonuclease. Enhanced RNase activity is not observed when inhibitors of cell protein or RNA synthesis are present during interferon treatment, or when heterologous interferon is used. The RNase associated with comparable membrane fractions from cells treated with mock-interferon is about 1/10 as active, and shows qualitative differences. In principle, divergent views of interferon action may be reconciled to a common mode of action by postulating that viral interference results from a newly induced or activated RNase of cellular origin and proper specificity that acts to reduce the accumulation and functional capacity of newly synthesized viral RNAs, particularly mRNA. Previous data in support of interferon's acting to inhibit virion-derived transcription in vivo are now interpreted as demonstrating enhanced degradation of viral transcripts (mRNA).

Animals↗
PubMed1979

Interferon action: induction of specific proteins in mouse and human cells by homologous interferons.

Treatment of mouse (Ehrlich ascites tumor and L929) and human (FS4, GM258, etc.) cells with homologous interferons results in the induction of several proteins. Extracts obtained from cells labeled with [35S]methionine in the absence or presence of interferon were fractionated on poly(I) . poly(C)-agarose columns. The proteins retained on the columns revealed, upon sodium dodecyl sulfate/polyacrylamide gel electrophoresis, three protein bands in mouse cells (Mr 120,000; 80,000; and 67,000) and two in human cells (Mr 120,000 and 80,000) which were detected in the extracts of interferon-treated but not of untreated cells. These proteins were retained on double-stranded RNA [poly(I) . poly(C)-agarose] columns but very poorly, if at all, on single-stranded RNA [poly(I)- or poly(C)-agarose] columns, suggesting that they have an affinity for double-stranded RNA. In addition, interferon treatment of human fibroblasts greatly increased the labeling of three other protein bands (Mr 88,000; 67,000; and 56,000) which were detected in whole extracts but were not appreciably retained on poly(I) . poly(C)-agarose columns. The appearance of the induced proteins was blocked by actinomycin D if added together with interferon, indicating that transcription of certain genetic information is required. The possible correlation between the induced proteins described here and the elevated levels of certain enzymes in interferon-treated cells (a protein kinase and 2'-5'-oligoadenylate synthetase) is at present unclear.

Animals↗
PubMed2000

RNase-L-dependent destabilization of interferon-induced mRNAs. A role for the 2-5A system in attenuation of the interferon response.

The 2-5A system is an interferon-regulated RNA degradation pathway with antiviral, growth-inhibitory, and pro-apoptotic activities. RNase-L mediates the antiviral activity through the degradation of viral RNAs, and the anticellular effects of the 2-5A system are thought to be similarly mediated through the degradation of cellular transcripts. However, specific RNase-L-regulated cellular RNAs have not been identified. To isolate candidate RNase-L substrates, differential display was used to identify mRNAs that exhibited increased expression in RNase-L-deficient N1E-115 cells as compared with RNase-L-transfected cells. A novel interferon-stimulated gene encoding a 43-kDa ubiquitin-specific protease, designated ISG43, was identified in this screen. ISG43 expression is induced by interferon and negatively regulated by RNase-L. ISG43 induction is a primary response to interferon treatment and requires a functional JAK/STAT signaling pathway. The kinetics of ISG43 induction were identical in wild type and RNase-L knock-out fibroblasts; however, the decline in ISG43 mRNA following interferon treatment was markedly attenuated in RNase-L knock-out fibroblasts. The delayed shut-off kinetics of ISG43 mRNA corresponded to an increase in its half-life in RNase-L-deficient cells. ISG15 mRNA also displayed RNase-L-dependent regulation. These findings identify a novel role for the 2-5A system in the attenuation of the interferon response.

Amino Acid Sequence↗
PubMed1992

Interferon action: nucleolar and nucleoplasmic localization of the interferon-inducible 72-kD protein that is encoded by the Ifi 204 gene from the gene 200 cluster.

The interferons are cytokines with antiviral, cell growth regulatory, and immunomodulatory activities. These activities are mediated by the proteins induced by the interferons. Earlier we described a gene cluster (the 200 cluster) consisting of at least six adjacent, interferon-activatable genes located next to the erythroid alpha-spectrin locus on murine chromosome 1. The genes of the cluster arose by repeated gene duplication and they specify proteins with pronounced sequence similarity. We have now raised polyclonal antibodies against a segment from one of these proteins (the 204 protein of 72 kD). Using these, we established that the 204 protein is a phosphoprotein whose level in cells from various murine lines can be increased up to 75-fold upon treatment with alpha interferon. Experiments involving fractionation of cell lysates and indirect immunofluorescence microscopy of control and interferon-treated cells revealed that the 204 protein is nucleolar and nucleoplasmic. This conclusion was confirmed by co-localization with B23, a known nucleolar protein. The 204 protein is the first interferon-induced protein found to be located in the nucleoli, the subcellular organelles of ribosomal RNA production and ribosome assembly. It remains to be seen whether the 204 protein affects any of these processes. Studies on 204 protein function should be facilitated by the availability of complete cDNA clones and the finding of cell lines in which the expression of this protein is impaired.

Amino Acid Sequence↗
PubMed1982

Interferon production in human hematopoietic cell lines: response to chemicals and characterization of interferons.

We have surveyed interferon production and its modulation by 5-bromodeoxyuridine, butyrate, dexamethasone, dimethylsulfoxide and tetradecanoylphorbolacetate in 20 human hematopoietic cell lines derived from leukemias, lymphomas, myelomas and normal leukocytes, representing various maturation stages of lymphoid and myeloid cells. Sendai virus-induced interferon production was enhanced by at least one of the chemicals in 13 out of 14 B-type lymphoid cell lines, whereas no enhancement was observed in any of the non-B, non-T-, T-lymphoid, or myeloid cell lines tested. Interferon produced by 11 cell lines was partially characterized using antisera specific for HuIFN-alpha and HuIFN-beta. Six cell lines produced both IFN-alpha and IFN-beta, two lines produced by IFN-alpha and three lines (including both T-cell lines tested) produced only IFN-beta. In all cases examined, enhancement by chemicals of total interferon yields was due to selective stimulation of production of IFN-alpha. Poly (I):(C) induction of interferon was studied in a number of B-cell lines. In general, a similar pattern of IFN-alpha and -beta synthesis was observed as in virus-induced cells, but the proportion of IFN-beta was relatively smaller. Treatment with butyrate enhanced interferon production to a similar extent accompanied by a similar shift in composition as in virus-induced cells. Our results demonstrate that even in closely related cell types, production of IFN-alpha and IFN-beta can be regulated differently in response to the same inducer. In a single cell type in response to a single inducer, expression of IFN-alpha and IFN-beta can be differentially affected by chemicals.

Bromodeoxyuridine↗
PubMed1980

Interferon induction by viruses. III. Vesicular stomatitis virus: interferon-inducing particle activity requires partial transcription of gene N.

We have measured the interferon-inducing particle (i.f.p.) activity of a ts mutant, GII (I), of vesicular stomatitis virus (VSV) and a non-ts revertant, RI (T1026) in "aged" chick embryo cells and mouse (L(Y) cells at 40.5 and 37.5 degrees C, respectively. Our results suggest that a single i.f.p. suffices to induce a quantum yield of interferon and that there are several times more i.f.p. than plaque-forming particles (p.f.p.) in stock preparations of VSV. Furthermore, while virus replication or amplified RNA synthesis is not required for a particle of VSV to induce interferon, there is a requirement for primary transcription. About one-tenth of the genome must remain intact and be transcribed to synthesize an interferon-inducer moiety. (This represents transcription of about two-thirds of the N protein gene.) We conclude that VSV does not contain a pre-formed inducer of interferon and propose a model for its formation. We suggest that there is a cumulative loss of N (and/or NS and L) protein from the ribonucleoprotein complex during primary transcription, leading ultimately to extensive base-pairing between the genome RNA and its complementary transcript. We suggest that the dsRNA thus formed constitutes the interferon inducer moiety of VSV.

Animals↗
PubMed1991

Perturbation of metabolism and disposition of cyclophosphamide by interferon and poly I:C, an interferon inducer, in mice.

The effects of interferon and poly I:C on the metabolism and disposition of cyclophosphamide were investigated in mice. Elimination of cyclophosphamide from the blood was decreased in mice treated 24 hr previously with interferon (2.5 x 10(6) U/kg, intraperitoneally) or poly I:C (10 mg/kg, intraperitoneally). The blood half-life of cyclophosphamide in interferon or poly I:C-pretreated mice was prolonged to a first order of disappearance of 29.3 and 41.6 min., respectively, compared to 19.0 min. in control mice. Also, the rate of formation of activated cyclophosphamide was delayed and the peak blood level of activated cyclophosphamide was not as high in poly I:C-pretreated and interferon-pretreated mice as in control mice. The decreased elimination and elevated blood levels of activated cyclophosphamide were reflected by changes in its antitumour activity and toxicity in the mice. In 9,000 x g supernatants prepared from the liver homogenate of mice treated with interferon or poly I:C, the oxidation of cyclophosphamide in vitro has decreased by 29 and 37%, respectively. However, the addition of these agents to normal 9,000 x g supernatant suspensions had no effect on cyclophosphamide oxidation. Modulation of the metabolism and disposition resulted from depressed levels of cytochrome P-450 in the hepatic microsomes of the mice administered interferon or poly I:C.

Animals↗
PubMed1982

Modulation of natural killer cell activity in mice after interferon induction: depression of activity and depression of in vitro enhancement by interferon.

Splenic natural killer (NK) cell activity of BALB/c and C3H mice was assayed after administration of the interferon inducers Escherichia coli endotoxin or Newcastle disease virus (NDV). As expected, the NK cell activity rose early in response to the interferon inducers. At 1 to 3 days after an injection of endotoxin, NK activity was hyperesponsive to interferon stimulation. At 5 to 9 days after injection of either endotoxin or NDV, splenic NK activity was depressed, and the spleen cells showed a relative refractoriness to in vitro interferon stimulation. It is postulated that this phenomenon may be related to hyporeactivity, the inability to reinduce interferon after an initial period of interferon production.

Animals↗
PubMed1966

Effect of mycoplasma on interferon production and interferon assay in cell cultures.

Armstrong, D. (The Children's Hospital of Philadelphia, Philadelphia, Pa.), and K. Paucker. Effect of mycoplasma on interferon production and interferon assay in cell cultures. J. Bacteriol. 92:97-101. 1966.-The influence of mycoplasma on the production and action of interferon was studied in cultures of both L and human embryonic kidney (HEK) cells. Mycoplasma hominis 1, the Negroni agent, and the F12 mycoplasma were used for infection of L cells, and M. hominis 1 and M. pneumoniae for inoculation of HEK cells. All strains were capable of multiplication in the culture systems employed. None produced detectable levels of interferon, and responsiveness of the cells to induction of interferon by virus remained unaltered. Infection with mycoplasma did not impair the sensitivity of the cells to the action of interferon, nor was the replication of vesicular stomatitis virus noticeably diminished.

Animals↗
PubMed1972

Cellular alteration by interferon: a virus-free system for assaying interferon.

A system is described for assaying mouse interferon without using a viral "challenge" agent. Interferon-treated L cells were destroyed by exposure to polyriboinosinic.polyribocytidylic acid [poly(I).poly(C)], and the amount of destruction was dependent on both the concentration of interferon to which the cells were exposed and the amount of poly(I).poly(C) used as the "challenge" material. If the amount of poly(I).poly(C) was constant, the concentration of interferon could be determined by quantitating cell destruction 6 hr after addition of the double-stranded ribonucleic acid. In addition to eliminating the necessity for employing infectious virus for interferon assays, this system has the advantages of being quicker, easier, and more sensitive than other interferon assays. The sensitivity of the assay is related directly to the amount of poly(I).poly(C) applied to the cells, with each fivefold increase of poly(I).poly(C) giving about a fivefold increase of sensitivity.

Animals↗