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PubMed1996

Anti-interferon-gamma antibodies in a patient undergoing interferon-gamma treatment for systemic mastocytosis.

An 81-year-old woman with systemic mastocytosis responded to subcutaneous recombinant interferon-gamma (rIFN-gamma) treatment for about 6 months, when intestinal symptoms gradually recurred. A serum sample obtained 3 months later was positive for specific rIFN-gamma-binding antibodies, which had been absent at the initiation of treatment. Cessation of IFN-gamma therapy was followed by a slow decline of IFN antibody titers. The IFN-gamma antibodies were of polyclonal or oligoclonal origin, with a predominance of IgG1 and IgG2 and small amounts of IgA and IgM. They neutralized the antiviral activity of both rIFN-gamma and, less efficiently, natural IFN-gamma in vitro. The time course of the neutralizing titers paralleled the IFN-binding activity of the antibodies. Thus, like other cytokines, rIFN-gamma may be immunogenic in rare patients and elicit the formation of neutralizing antibodies that may impair the therapeutic activity of the drug and interfere with the endogenous IFN-gamma system.

Aged↗

PubMed1996

Interferon-alpha 8b is the only variant of interferon-alpha 8 identified in a large human population.

Three variants of human interferon (IFN)-alpha 8a gene, that is, IFN-alpha 8b, and IFN-alpha 8c, have been reported previously. They differ from each other by changes in their coding region at nucleotide positions 359-360, 372, and 550. Human genomic DNA obtained from over 28,000 healthy blood donors and from 4 human cell lines was used in the polymerase chain reaction (PCR) designed for specific amplification of the IFN-alpha 8 gene fragments. The resulting PCR product was analyzed by (1) restriction endonuclease digestion, (2) DNA sequencing, and (3) allele-specific secondary PCR amplification. Only one sequence for IFN-alpha 8 was identified, and that was for IFN-alpha 8b. The sequences for IFN-alpha 8a and IFN-alpha 8c were not detected after PCR amplification either in the pooled leukocytes obtained from > 28,000 individuals or in cell lines tested. These data suggest that the naturally occurring variant or allele for IFN-alpha 8 in the population is IFN-alpha 8b. IFN-alpha 8a and IFN-alpha 8c variants were consistently below the level of detection of the assays and, if present at all in the population, are very rare.

Alleles↗

PubMed1996

Hypomutable potential accompanying interferon-alpha resistance in a human cell line, IFr, derived from interferon-alpha-sensitive and hypermutable RSa cells.

A human cell line, IFr, established from RSa cells, is a variant with increased resistance to cell proliferation inhibition (CPI) by human interferon (HuIFN)-alpha. The parent RSa cells are also hypermutable after irradiation with far-ultraviolet light (UV), as assessed by two different methods: cloning efficiency of ouabain-resistant (OuaR) mutants and K-ras codon 12 mutation in genomic DNA identified by polymerase chain reaction (PCR) following differential dot-blot hybridization. In the present study, IFr cells were found to be hypomutable: Less than 1 OuaR mutant per 10(4) surviving cells after UV (0-12 J/m2), in contrast to 1-53 OuaR mutants per 10(4) survivors in RSa cells, and no-detectable K-ras codon 12 mutation at any doses tested. However, IFr cells, when cultured with medium containing the protease inhibitor antipain after UV irradiation showed hypermutability to almost the same extent as RSa cells, as determined by both phenotypic and genetic mutation analyses. These results, together with the previous finding of antipain-sensitive protease induction in UV-irradiated or HuIFN-alpha-treated IFr cells, suggest that antipain-sensitive proteases or cellular functions or both may be involved in not only HuIFN-alpha resistance but also hypomutability of IFr cells.

Antipain↗

PubMed1996

Role of interferon-stimulated gene ISG-15 in the interferon-omega-mediated inhibition of human immunodeficiency virus replication.

Interferon-alpha (IFN-alpha) inhibits human immunodeficiency virus (HIV) replication in vivo and in vitro. In this study, we show that IFN-omega (IFN-omega) is also a potent inhibitor of HIV replication in vitro and that both laboratory and primary isolates of HIV-1 are more sensitive to IFN-omega than to IFN-alpha 2. Like IFN-alpha 2, IFN-omega inhibited proviral synthesis in acutely infected cells, but in contrast to IFN-alpha 2, IFN-omega did not alter the levels of HIV-1 unspliced messages. Yet, inhibition of HIV protein synthesis was greater in IFN-omega-treated than in IFN-alpha 2-treated cells. Whereas expression of IFN-stimulated genes was transient in IFN-alpha 2-treated cells, their expression was sustained in IFN-omega-treated cells. Expression of ISG-15 in particular was higher on treatment with IFN-omega than with IFN-alpha 2. Overexpression of ISG-15 in IFN-alpha 2-treated cells mimicked the effects of IFN-omega. In untreated cells, it resulted in the trapping of HIV unspliced RNA in the nucleus and a decrease in cytoplasmic HIV transcripts and HIV protein synthesis. These findings suggest that the sustained induction of IFN-stimulated genes by IFN-omega and that of ISG-15 in particular may confer a higher therapeutic index to IFN-omega in controlling HIV infection.

Antiviral Agents↗

PubMed1990

Modulation of the co-promoting activity of gamma interferon in SENCAR and C57BL/6 mouse skin by difluoromethylornithine and the scheduling and duration of interferon treatment.

The murine skin multistage carcinogenesis model was used to characterize the co-promoting and tumor progressing activities of i.p. administered recombinant DNA-derived murine gamma interferon (rMuIFN-gamma). The dorsal skins of female SENCAR mice were topically initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted twice a week for 20 weeks with 1 microgram of 12-O-tetradecanoylphorbol-13-acetate (TPA). Doses of rMuIFN-gamma that had no effect on papilloma multiplicities when administered 1 day prior to TPA treatment increased the numbers of papillomas per mouse by 33-38% when administered immediately prior (zero time) to TPA application. A minimum of 6 weeks of co-treatment with TPA and rMuIFN-gamma (zero time) were necessary for demonstration of rMuIFN-gamma-dependent co-promotion. The ad libitum administration of either 0.25 or 1% (w/v) solutions of alpha-difluoromethylornithine (DFMO) in the drinking water inhibited by 90% the TPA-dependent elevation of epidermal ornithine decarboxylase activity but had minimal effect on papilloma multiplicities in TPA-promoted mice. However, both doses of DFMO completely suppressed rMuIFN-gamma-dependent co-promotion. Carcinoma incidence and multiplicities by weeks 46-48 of the promotion-progression period were statistically indistinguishable for initiated mice treated with TPA, TPA + DFMO, TPA + IFN-gamma or TPA + DFMO + IFN-gamma. Similarly, i.p. administration of rMuIFN-gamma to papilloma-bearing mice in a tumor progression study, with and without simultaneous topical TPA treatment, did not affect carcinoma latency or carcinoma multiplicities. C57BL/6 mice initiated with DMBA developed few papillomas (0.2 paps/mouse) after 19 weeks of TPA promotion. The i.p. administration of rMuIFN-gamma to C57BL/6 mice at the time of TPA treatment, at doses that were co-promoting in SENCAR mice, did not increase papilloma multiplicities. Collectively, our studies suggest that the co-promoting activity of rMuIFN-gamma is exceptionally sensitive to inhibition by DFMO and dependent upon the scheduling and duration of rMuIFN-gamma treatment, and the mouse strain/stock employed for the studies.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways.

The interferon-inducible double-stranded RNA protein kinase PKR controls protein synthesis through the phosphorylation of eukaryotic translation initiation factor (eIF)-2. In addition to its demonstrated role in translational control, several reports have suggested a transcriptional role for PKR. Here we report that PKR is involved in IFN- and dsRNA-signaling pathways by modulating the function of the signal transducer and activator of transcription STAT1. We also show that PKR associates with STAT1 in mouse and human cells. The association is not a kinase-substrate interaction since STAT1 phosphorylation is not modified by PKR in vitro or in vivo. In addition, the formation of the PKR-STAT1 complex is not dependent upon the enzymatic activity of PKR but does require the dsRNA-binding domain of PKR. Moreover, there is a concomitant decrease in PKR-STAT1 interaction and increase in STAT1 DNA binding in response to IFNs or dsRNA. These findings suggest that PKR plays an important role in IFN and dsRNA-signaling pathways by modulating the transcriptional function of STAT1.

3T3 Cells↗

PubMed1992

Absence of neutralizing antibodies to interferon in condyloma acuminata and cancer patients treated with natural human leukocyte interferon.

Human leukocyte-derived interferon-alpha (IFN-alpha n3) was used to treat condyloma acuminata patients in a double-blind placebo-controlled clinical study. The incidence of antibody formation to IFN-alpha was evaluated in matched patient sera from the control placebo and the IFN-alpha n3 treatment groups. Sera from IFN-alpha n3-treated phase I cancer patients and untreated healthy donors were also evaluated. Three sensitive assay methods (ELISA, competitive immunoradiometric, and antiviral neutralization) were used in these evaluations. The overall levels of detectable binding anti-IFN-alpha antibodies in the patients were similar to those of the normal donors. No neutralizing antibodies were generated in the patients after repeated treatment with natural IFN-alpha n3.

Antibodies↗

PubMed1993

Interferon-alpha therapy with and without interferon-alpha priming in patients with chronic hepatitis B infection.

To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the efficacy of subsequent IFN-alpha therapy in the treatment of chronic hepatitis B, a randomized trial was conducted to compare IFN-alpha priming (IFN-alpha for one month; no treatment for one month) followed by IFN-alpha therapy for three months, with IFN-alpha therapy (10 MU thrice-weekly) given for three months. Thirty-seven patients seropositive for more than six months for HBsAg, HBeAg and HBV DNA, and with histological evidence of active liver inflammation, were recruited. Eight patients (40%) treated with a priming course of IFN-alpha responded to subsequent IFN-alpha therapy for three months with loss of HBV DNA and HBe seroconversion. This compared with five patients (29%), treated only with IFN-alpha therapy for three months, who lost HBV DNA and HBeAg (but only two [12%] developed anti-HBe). IFN-alpha was well tolerated, with only three patients withdrawing from the study because of 'flu'-like symptoms or inconvenience in the early phase. The better response, although not significant, may suggest a place for a short priming course of IFN-alpha in addition to the current IFN-alpha treatment regimen.

Adult↗

PubMed1989

Augmentation of antiproliferative activity of interferon alfa against human bladder tumor cell lines by encapsulation of interferon alfa within liposomes.

Present therapy for human bladder cancer includes the intravesical administration of antiproliferative agents, such as recombinant human interferon alfa (IFN-alpha). The administration of cytotoxic molecules encapsulated in liposomes could provide a more efficient method for such therapy. Therefore, we determined whether encapsulation of the recombinant human IFN-alpha hybrid BBDD within liposomes will produce antitumor effects against the human bladder cancer cell line 253J superior to those observed with free IFN-alpha. Adherent cells were cultured in medium alone, in medium containing different concentrations of IFN-alpha, or in medium containing multilamellar liposomes (phosphatidylcholine-phosphatidylserine at a molar ratio of 7:3) that encapsulated saline or IFN-alpha. Cell growth was determined 96-120 hours later. Additional control groups consisted of target cells cultured with free IFN-alpha or with IFN-alpha plus liposomes containing saline. Cytostasis mediated by free IFN-alpha alone or IFN-alpha in the presence of liposome-saline was identical and ranged from 0%-30% (10 IU/mL) to 45%-70% (1,000 IU/mL). Liposomes containing saline produced no effects. Liposome-encapsulated IFN-alpha produced significantly greater growth inhibition than free IFN-alpha: 40%-70% (10 IU/mL) and 80%-90% (1,000 IU/mL), respectively. Moreover, a 253J variant subline selected for resistance to free IFN-alpha was sensitive to IFN-alpha presented in liposomes. These data suggest that the encapsulation of antiproliferative agents such as IFN-alpha in liposomes can improve therapeutic results.

Carcinoma, Transitional Cell↗

PubMed1985

Characterization of a mouse interferon gene locus I. Isolation of a cluster of four alpha interferon genes.

A BALB/c mouse genomic library was screened with a murine interferon alpha 2 (MuIFN-alpha 2) cDNA coding region fragment. Eight clones were isolated which contain different mouse chromosomal segments related to the MuIFN-alpha 2 probe and a 28 kilobase (kb) region of mouse genomic DNA containing four different MuIFN-alpha genes (alpha 1, alpha 4, alpha 5 and alpha 6) was identified and characterized; an intergenic 1000 nucleotide long conserved sequence was found to be associated with three of these four alpha genes, indicating that this alpha-IFN gene cluster evolved through tandem duplications. Sequence analysis revealed the absence of a polyadenylation site in the 3' untranslated region of MuIFN-alpha 1, and showed that one of the genes (alpha 4) contains an internal deletion of 5 amino acids in the coding region.

Animals↗

PubMed1990

Endogenous IFN-gamma during human bone marrow transplantation. Analysis of serum levels of interferon and interferon-dependent secondary messages.

Serum levels of interferon-gamma and the IFN-dependent marker molecules neopterin and beta 2-microglobulin were assessed in BMT recipients. Concentrations of the latter two markers were corrected for creatinine levels in order to eliminate the impact of alteration of kidney function. Serum levels were assessed daily using commercially available radioimmunoassays. Twelve patients were studied during the early phase of allogeneic bone marrow transplantation and eleven additional patients during complications of BMT. Results indicated that both the conditioning regimen for BMT as well as major clinical complications such as infection and acute graft-versus-host disease strongly influence the endogenous patterns of the lymphokine and its secondary messages. During allogeneic BMT IFN-gamma and neopterin levels exhibited a biphasic pattern with a first peak during conditioning with high-dose cyclophosphamide and a second still higher peak at the time of hemopoietic regeneration. beta-2-microglobulin ratios increased during conditioning and remained elevated throughout observation. Serious infections of bacterial and viral origin as well as GvHD were accompanied by elevated levels of all three serum parameters studied. The kinetics of enhanced endogenous production, however, differed between infectious complications and GvHD. Increasing concentrations were observed during infections subsequent to clinical manifestation, whereas they preceded disease manifestation in GvHD.

Biopterins↗

PubMed2000

Efficacy of ursodeoxycholic acid in association with alpha-interferon for chronic hepatitis C in alpha-interferon non-responder patients.

BACKGROUND: The aim of the present study was to evaluate the effect of combined treatment with alpha-interferon (alpha-IFN) and ursodeoxycholic acid (UDCA) on liver function tests and serum HCV-RNA in patients with chronic hepatitis C who had not responded to alpha-IFN alone. METHOD: One hundred and three patients (60 men, 43 women, mean age 49 +/- 1.3 years) who had not responded (both HCV-RNA positive and increased serum ALT levels) to 4 consecutive months of treatment with alpha-IFN (3 MU three times weekly) were randomly assigned to receive UDCA (IFN-UDCA, 53 patients, 600 mg/day) in addition to the same alpha-IFN dose, or to continue alpha-IFN alone (IFN-controls, 50 patients). After stopping alpha-IFN, patients who had received UDCA continued to receive UDCA for an additional 6-month period. The two groups were comparable for sex, basal ALT, basal yGT, genotype distribution and liver histology, while mean age was lower in controls (53 +/- 1.8 vs 46 +/- 1.8 years; P< 0.01). RESULTS: Twenty (38%) out of 53 IFN-UDCA patients had normal ALT, compared with only six (12%) out of 50 IFN-control patients (P < 0.01). HCV-RNA became undetectable in four IFN-UDCA patients. Three months after withdrawal of alpha IFN, 15 IFN-UDCA responders, but none of the IFN-controls, had normal ALT values (P< 0.01); 6 months after withdrawal, nine IFN-UDCA responders still had normal ALT (P= NS) and HCV-RNA was still undetectable in four of them. Portal and periportal inflammation showed a statistically significant improvement (Fisher's exact test P< 0.01) in IFN-UDCA patients as compared with IFN-controls, while no effect was observed on portal fibrosis. CONCLUSIONS: These data demonstrate that UDCA improves the response rate to alpha-IFN. Furthermore, in 8% of IFN-UDCA patients the response rate was sustained and associated with HCV-RNA clearance.

Analysis of Variance↗

PubMed2004

Interferon-alpha and lamivudine combination therapy of children with chronic hepatitis b infection who were interferon-alpha nonresponders.

Greater than one-half of children with chronic hepatitis B infection are nonresponders to interferon-alpha (IFN-alpha). The aim of this study was to investigate the efficacy of lamivudine (LMV) and IFN-alpha combination therapy in these children. Nineteen children were given LMV alone for 3 months; then IFN-alpha was added to LMV for 6 months. Virologic response was achieved in seven (36.8%) patients. LMV and IFN-alpha combination therapy may represent an effective treatment option.

Adolescent↗

PubMed2005

Interferon-gamma up-regulates toll-like receptor 4 and cooperates with lipopolysaccharide to produce macrophage-derived chemokine and interferon-gamma inducible protein-10 in human bladder cancer cell line RT4.

PURPOSE: Previously we have reported that RT4, a well differentiated human bladder cancer line, increases the expression of macrophage derived chemokine (MDC) and interferon (IFN)-gamma-inducible protein-10 (IP-10) in response to IFN-gamma and tumor necrosis factor (TNF)-alpha. In this study we examined the signal mechanisms for inducting these 2 chemokines in RT4 cells by lipopolysaccharide (LPS), IFN-gamma and TNF-alpha. MATERIALS AND METHODS: MDC and IP-10 expression was evaluated by sandwich enzyme-linked immunosorbent assay. Signal molecule activation was examined by Western blotting and electrophoretic mobility shift assay. The expression of toll-like receptor (TLR)-4 was analyzed by reverse transcriptase-polymerase chain reaction and flow cytometry. RESULTS: LPS did not induce RT4 cells to produce IP-10 and MDC. However, LPS plus IFN-gamma synergized the productions of the 2 chemokines. IFN-gamma up-regulated the expression of TLR-4, which is an LPS binding receptor. Although LPS and IFN-gamma alone marginally activated nuclear factor (NF)-kappaB but not AP-1, LPS plus IFN-gamma augmented NF-kappaB and AP-1. Specific inhibition of NF-kappaB and AP-1 pathways decreased the production of MDC and IP-10. Extracellular regulated kinase (ERK)1/2, an upstream signal of AP-1, was also responsive to LPS and/or IFN-gamma. TNF-alpha also activated NF-kappaB, AP-1 and ERK1/2. However, TNF-alpha plus IFN- gamma was associated with the activation of NF-kappaB but not of AP-1/ERK1/2 for the induction of MDC and IP-10. CONCLUSIONS: IFN-gamma enhances LPS for the induction of MDC and IP-10 through up-regulation of TLR-4, and the signal pathways of NF-kappaB and AP-1/ERK1/2. This mechanism may help us understand inflammatory responses of the bladder to localized bacterial infection.

Cell Line, Tumor↗

PubMed1977

Metabolism of interferon: hepatic clearance of native and desialylated interferon.

The effect of removal of sialic acid on the survival of rabbit serum and urinary interferon (IF) has been investigated in isolate, perfused rabbit liver preparations. In contrast with native IF, which may be already partially desialylated. IF freed of 80 to 90% of its sialic acid was rapidly cleared from the perfusate of normal livers, or livers pre-treated with actinomycin D. The results suggest that the mechanism of IF catabolism by the liver is similar to that reported for several other circulating glycoproteins.

Animals↗

PubMed1983

Interferon induction by viruses. X. A model for interferon induction by Newcastle disease virus.

Unirradiated Newcastle disease virus (NDV, strain AV) induced high levels of interferon (IFN) in primary chick embryo cells if the cells were 'aged' in vitro for 6 to 7 days. Dose (multiplicity)-response (IFN yield) curves, carried out in the presence of anti-NDV serum to prevent cycling infection, revealed that stocks of NDV-AV contain about sevenfold more IFN-inducing particles (IFP) than infectious particles (PFP). These non-infectious IFP were responsible for nearly all IFN induction in 'aged' cells, since PFP were determined to be incapable of inducing IFN. In contrast, with mouse L(Y) cells as hosts, about one-third the number of particles as there are PFP appeared to score as IFP. Heat and u.v. radiation (254 nm) inactivated NDV IFP and PFP activity at the same rate whether tested in chick or mouse cells, implying that virion-associated transcription is required to induce IFN. A model is proposed to account for the generation of IFN-inducing particles from infectious NDV following u.v. irradiation, and their subsequent inactivation at high doses of radiation. The model defines a series of u.v. targets in the NDV genome that regulate the expression of IFN-inducing particle activity in 'unaged' chick embryo cells.

Animals↗

PubMed1987

Selection and characterization of interferon-sensitive cells derived from an interferon-resistant NIH 3T3 line.

We have developed a selection protocol to isolate interferon (IFN)-sensitive subclones directly from an IFN-resistant cell population. The protocol uses encephalomyocarditis virus (EMCV) as a selection agent in combination with pretreatment with low doses of IFN and subsequent growth in the presence of virus-neutralizing antiserum. We have applied this protocol to the partially IFN-resistant NIH 3T3 clone 1 line and have obtained a number of IFN-sensitive subclones. Sensitivity to IFN was restricted to protection against EMCV. Replication of vesicular stomatitis virus as well as cell growth were resistant to IFN treatment as in the original clone 1 line. We have compared levels of 2',5'-oligoadenylate (2-5A) synthetase, dsRNA-activated protein kinase and 2-5A-dependent RNase in some IFN-sensitive subclones and found no difference from the resistant clone 1 cells. Markedly decreased levels of 2-5A-dependent RNase and thus a defective 2-5A pathway have been implicated as a possible cause for the partial resistance of clone 1 cells to IFN. Since the selected IFN-sensitive subclones are of the same phenotype in this respect as the clone 1 line we suggest that inhibition of EMCV in these lines occurs through a mechanism independent of the 2-5A system.

2',5'-Oligoadenylate Synthetase↗

PubMed1989

Interferon induction by viruses. XVII. Non-temperature-sensitive mutations regulate interferon induction by vesicular stomatitis virus.

Wild-type (wt) strains of vesicular stomatitis virus (VSV) strain Indiana are poor to non-inducers of interferon (IFN) which express IFN induction-suppressing activity. At non-permissive temperatures, temperature-sensitive (ts) mutants of this virus are either like their wt parents, or they are good to excellent inducers of IFN. IFN inducibility and IFN induction-suppressing activity are mutually exclusive phenotypes in VSV-Indiana. With one exception, all Orsay ts mutants derived by A. Flamand (CNRS, Gif-sur-Yvette, France), representing the five complementation groups, were poor to non-inducers of IFN and were also capable of suppressing IFN induction by other viruses. In contrast, all Glasgow ts mutants derived by C. R. Pringle (University of Warwick, Coventry, U.K.) were excellent inducers of IFN. We demonstrate that this difference in acquisition of IFN inducibility relates primarily to the origin of the mutations; spontaneous for Orsay, and mutagen-derived for Glasgow. Tests with newly generated spontaneous and mutagen-derived mutants, and temperature-stable revertants of IFN-inducing ts mutants indicate that IFN inducibility results from non-ts, multiple mutations rarely acquired spontaneously, but generated frequently upon mutagenesis with 5-fluorouracil. The capacity of VSV-Indiana to induce IFN is considered intrinsic to the virus, but is only manifested when the dominant IFN induction-suppressing phenotype is lost through mutagenesis. Thus, non-ts mutations appear to regulate the expression of the IFN induction-suppressing phenotype, and hence the IFN inducibility of VSV-Indiana.

Animals↗