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PubMed1994

Importance of the loop connecting A and B helices of human interferon-gamma in recognition by interferon-gamma receptor.

Characterization of murine-human hybrid interferon-gamma (IFN-gamma) molecules suggests that substitution of the peptide connecting the A and B helices in human IFN-gamma with the murine sequence significantly blocks the protein's binding to the human interferon-gamma receptor. Mutagenesis showed that this effect is localized to the central part of this A-B loop peptide, particularly Ser20, Asp21, Val22, and Ala23. One mutant, IFN-gamma/A23E,D24E,N25K, was examined by NMR. This "EEK" mutation does not significantly alter the conformation of interferon-gamma, suggesting that the effects of these mutations are not the result of global conformational changes. The A-B loop is near histidine 111, a residue previously shown to be important in receptor-ligand interaction (Lunn, C. A., Fossetta, J., Dalgarno, D., Murgolo, N., Windsor, W., Zavodny, P. J., Narula, S. K., and Lundell, D. (1992) Protein Eng. 5, 253-257). We show that copper forms a complex between histidine 19 in the A-B loop and histidine 111. This metal complex lacks the ability to interact with the interferon-gamma receptor. These results suggest that the A-B loop contains important structural information needed for receptor-ligand binding and hence biological activity of human interferon-gamma.

Amino Acid Sequence↗

PubMed2004

Cost-effectiveness of ribavirin plus interferon alpha-2b for either interferon relapsers or non-responders in chronic hepatitis C: a Japanese trial.

The aim of this study was to examine the cost-effectiveness of combination therapy with ribavirin plus interferon alpha-2b compared with interferon monotherapy for hepatitis C-infected Japanese patients who had either temporarily responded or not responded to initial interferon treatment. Data from a recent randomized clinical trial among relapsed or non-responding patients comparing combination therapy to interferon alone were applied to a computer cohort simulation Markov process model to project lifelong clinical and economic outcomes. Combination therapy for 24 weeks should increase life expectancy by 1.6 quality-adjusted life years and should reduce discounted (3% per year) lifetime costs by yen 121,000 when compared to retreatment with interferon alone. For the subgroup of patients with genotype 1b and high viral load, combination therapy should be cost-effective ( yen 187,000 per QALY gained with a 3% annual discount rate) by well-accepted international standards. These results were robust with combination therapy remaining cost-effective or cost saving in sensitivity analysis involving reasonable variation in all parameters. For patients similar to those enrolled in the interferon alpha-2b and ribavirin trials in Japan, combination therapy should be considered cost-effective with the higher drug treatment costs nearly completely offset by future savings through reductions in future liver complications from hepatitis C.

Journal Article↗

PubMed2002

A controlled randomised trial of t-UDCA as adjuvant to interferon for treatment of chronic hepatitis C: an interferon sparing effect of t-UDCA.

BACKGROUND: Combination of the cytoprotective effect of tauro-ursodeoxycholic acid (t-UDCA) with the antiviral effect of interferon may be more effective than interferon alone for treatment of chronic hepatitis C. METHODS: We randomised 106 patients with chronic hepatitis C to interferon 3 MU/m(2)/3 times per week given alone (regimen A, n=51) or in combination with t-UDCA 10 mg/kg/day (regimen B, n=55) for 6 months followed by IFN dose tapering for further 6 months. Control liver biopsies were obtained 6 months after stopping treatment. RESULTS: At the end of the trial a similar proportion of patients had normal serum alanine aminotransferase activity (ALT) levels (41 and 44%) and negative viremia (42 and 43%) with regimens A and B, respectively. The effect on liver histology was also similar, and the Knodell score decreased by 2.9+/-0.4 points with both regimens. During the dose tapering phase, the cumulative interferon dose to maintain ALT activity within the normal range was significantly lower for regimen B (142+/-4 million units, MU) than for regimen A (180+/-12 MU, P<0.005). CONCLUSIONS: Adjuvant t-UDCA exerts an 'interferon sparing effect' that may be of value for patients intolerant to high dose interferon.

Journal Article↗

PubMed1970

Effect of exogenous interferon on rubella virus production in carrier cultures of cells defective in interferon production.

An established cell line (Vero) defective in interferon production was used to evaluate the role of interferon in chronic rubella virus infections of cell cultures. Inoculation of Vero cells with a low multiplicity of virus resulted in the development of carrier cultures which had the characteristics of a regulated infection. Although added interferon did not alter rubella virus production in carrier cultures of cells capable of producing interferon, such added interferon caused a dramatic reduction of virus production in the carrier cultures of Vero cells. There was a reduction of the fraction of cells producing virus in Vero carrier cultures, but not in carrier cultures of other cells upon incubation in the continual presence of rubella virus antibodies. In addition, the fraction of infected cells fluctuated in carrier cultures in Vero cells. The data indicate that interferon is not necessary for maintaining a chronic rubella virus infection in vitro and suggest an instability of the virus genome in Vero cells.

Journal Article↗

PubMed1971

Inhibition by estrone of the antiviral protection and interferon elicited by interferon inducers in mice.

The susceptibility of mice to infection with MM virus is markedly increased after treatment with the sex hormone estrone. Studies were undertaken to determine if either suppression of production or interference with the action of interferon was involved in this phenomenon. The protection of mice against MM virus infection by several interferon-inducing agents was partially impeded by estrone treatment either 24 hr before or 24 hr after the administration of the inducing agent. The titers of circulating interferon induced by each of the agents were lower in estrone-pretreated animals than in untreated controls. The protection of mice by exogenous L cell interferon was blocked only when the hormone was given prior to the interferon. It is concluded that the adverse activity of estrone is related to its ability to interfere with the action of interferon.

Journal Article↗

PubMed1996

Purification and crystallization of a complex between human interferon gamma receptor (extracellular domain) and human interferon gamma.

X-ray diffraction quality crystals have been obtained from a complex between interferon gamma and the extracellular domain of its high-affinity cell surface receptor. The crystals were obtained from interferon gamma/interferon gamma receptor complexes purified by size exclusion chromatography. Diffraction quality crystals required analyzing these complex samples by isoelectric focusing gels to select purified complex fractions devoid of unbound interferon gamma. These studies used interferon gamma receptor engineered with an eight amino acid N-terminal deletion to eliminate heterogeneity generated due to proteolytic cleavage. In addition, the receptor was expressed in an E. coli secretion cell line which eliminated the need to refold the protein. Hexagonal crystals were grown from 1.6 M ammonium phosphate solutions and belong to a spacegroup of P6(5)22 with unit cell dimensions a = 145.9 A and c = 180.3 A. These crystals diffract to at least 2.9 A resolution when exposed to synchrotron radiation. SDS PAGE analysis of the crystals demonstrated that both interferon gamma and the receptor were present. Analysis of the x-ray diffraction data revealed that the crystals contain complexes with a stoichiometry of 2:1 receptor: ligand within the crystallographic asymmetric unit and consist of approximately 55% solvent.

Chromatography, Gel↗

PubMed1981

Variation of interferon induction at the bone marrow level. Studies on interferon induction in relation to natural cell-mediated cytotoxic mechanisms.

The effects of interferon inducers on different cytolytic mechanisms were studied in the high leukemia mouse strain AKR. A clear depression in baseline cytolytic potential and interferon-mediated stimulation of natural killer cell activities was demonstrated. This depression was most pronounced after 8 weeks of age. In contrast, antibody-dependent, cell-mediated cytotoxicity against IgG-coated chicken red blood cells was always normal. Bone marrow chimeras between CBA and AKR mice were produced to investigate the influence of bone marrow vs. host-mediated factors in these two strains with regard to interferon induction and cytolytic functions. Bone marrow genotype was found to be the dominating factor with regard to both parameters. Mice reconstituted with AKR bone marrow were deficient both in interferon production using tilorone and Newcastle disease virus as inducers, and at the level of natural killer cells responding to exogenously administered interferon. The possible relationship between these findings and the development of lymphomas in AKR mice is discussed.

Aging↗

PubMed1995

Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons.

Treatment of human amnion U cells with interferon increased the steady state level of mRNA encoding the double-stranded (ds) RNA-specific adenosine deaminase (AdD) as measured by Northern gel-blot analysis. A single major dsRNA-specific AdD transcript of approximately 6.7 kb was detected; the transcript was induced by both interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma). Likewise, Western immunoblot analysis revealed that a 150-kDa protein recognized by antiserum prepared against recombinant dsRNA-specific AdD was increased in the human amnion U and neuroblastoma SH-SY5Y cell lines treated with interferon. Both IFN-alpha and IFN-gamma induced the 150-kDa protein. These results, which establish that dsRNA-specific AdD is an IFN-inducible protein in human cells, have implications regarding the possible role of interferon in persistent viral infections.

Adenosine Deaminase↗

PubMed1987

Response to the combined administration of interferons alpha and gamma after failure of single interferon therapy in chronic myelogenous leukaemia.

A previously untreated patient with benign phase chronic myelogenous leukaemia (CML) was treated with recombinant Interferon alpha-2 b. Haematological remission was induced for a total of twelve months. Thereafter, the patient developed resistance to Interferon alpha manifested by an increase in leucocyte counts despite dose escalation (up to 7 x 10(6) IU/day s.c.). Subsequent treatment with recombinant Interferon gamma failed to control myeloid proliferation. However, combined administration of both Interferon alpha and Interferon gamma resulted in a renewed haematological remission which lasted six months.

Adult↗

PubMed1990

Recombinant interferon-alpha, but not interferon-gamma is effective therapy for essential thrombocythemia.

Recombinant interferon-gamma with a starting dose of 0.5 mg 3x/week subcutaneously, was administered to 6 patients with essential thrombocythemia (median platelet count 1172 X 10(9)/l, range 602-1564). Four of the patients had received alkylating agents previously. Hematological remission, defined as a decrease in platelet counts to less than or equal to 350 X 10(9)/l, was observed in none of these patients. Subsequently 4 of these 6 patients, supplemented by 2 others were treated with interferon-alpha 2c at a dose of 5 X 10(6) U daily subcutaneously. Five patients showed hematological remission. In case of hematological remission the interferon-alpha doses was reduced to 5 X an thereafter to 3 X weekly 5 X 10(6) U. During an observation period ranging from 12-41 weeks platelet counts remained normal in all patients. Side-effects were mild and consisted of fever, myalgias, malaise and itching occurring mainly during the first month of treatment. No dose adaptation was required. The patients treated previously with interferon-gamma experienced the side effects from this drug less tolerably than those from the alpha-compound. These observations suggest that recombinant interferon-alpha may be an effective drug in treating essential thrombocythemia resulting in a sustained response.

Adult↗

PubMed1988

Mechanism of interferon action. Expression of reovirus S3 gene in transfected COS cells and subsequent inhibition at the level of protein synthesis by type I but not by type II interferon.

The effect of interferon on the expression of the reovirus serotype 1 Lang strain S3 gene was examined in simian COS cells transfected with the expression vector pSVS3 containing the S3 gene under the control of the SV40 late promoter. When COS cells were treated with type I interferon-alpha 24 hr after transfection, the synthesis of the reovirus S3-encoded sigma NS polypeptide was inhibited about 10-fold as compared to that in untreated control cells. By contrast, under the same conditions, neither the plasmid DNA copy number nor the S3 gene mRNA levels were significantly affected by interferon treatment. Type II interferon-gamma, unlike the type I interferons-alpha, did not affect the rate of synthesis of polypeptide sigma NS in pSVS3-transfected cells.

Animals↗

PubMed1988

Down-regulation of interferon-gamma-induced class II expression on human glioma cells by recombinant interferon-beta: effects of dosage treatment schedule.

We have examined the influence of human recombinant interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma) on class II antigen expression on cultured glioblastoma multiforme cells by flow cytometry. Class II molecules were not constitutively expressed on these cells, nor induced by IFN-beta. IFN-gamma increased class II expression in a dose-dependent fashion. We demonstrate that IFN-beta is either antagonistic or synergistic with IFN-gamma in class II induction depending upon dose and schedule of administration. Both interferons at 100 IU/ml reduce class II expression by 18%, compared to IFN-gamma alone. Pretreatment with IFN-beta for 72 h, followed by both interferons yielded a 90% reduction. In contrast, lower concentrations (10 IU/ml) of both interferons were synergistic.

Drug Administration Schedule↗

PubMed1991

Increased intracellular killing of bacteria in vitro by monocytes of patients with metastatic melanoma before and during treatment with interferon-gamma and interferon-alpha.

The effect of recombinant human interferon-gamma (rHuIFN-gamma) and interferon-alpha (rHuIFN-alpha) as in vivo stimuli for the activation of human monocytes was investigated on the basis of the bactericidal activity of peripheral blood monocytes in 11 patients with metastatic melanoma before and during treatment with interferons. Patients received increasing doses of rHuIFN-gamma and a fixed dose of rHuIFN-alpha, both administered subcutaneously three times a week. The rates of intracellular killing of Listeria monocytogenes and Salmonella typhimurium after in vitro phagocytosis by monocytes collected from melanoma patients before interferon treatment were increased (P less than 0.01) by a factor of 1.7 and 1.4, respectively, relative to the rate constants in blood monocytes of healthy donors. During treatment with the interferons, the rates of intracellular killing of the bacteria by patients' monocytes did not further increase. The findings underscore the immunogenicity of malignant melanoma and put into question the macrophage activating activity of IFN-gamma with respect to the bactericidal activity of monocytes.

Adult↗

PubMed1994

A randomised trial of vindesine plus interferon-alpha 2b compared with interferon-alpha 2b or vindesine alone in the treatment of advanced malignant melanoma.

60 patients were entered into a randomised study comparing vindesine (3 mg/m2/week) plus interferon-alpha 2b (6 U/m2 3 times per week) to vindesine alone or to interferon alone for the treatment of metastatic malignant melanoma. Patients receiving the combination therapy arm (schedule A; vindesine plus interferon-alpha 2b) showed a complete and partial response rate of 8/20 (40%) which was significantly higher (P < 0.05) than that achieved with either single-agent treatment schedule. In addition, patients receiving the combined treatment schedule had a significantly prolonged survival (median 19 months) when compared to a median of 10 months for interferon alone and 5 months for vindesine alone. The combination was generally well tolerated with only additive toxicity. It is concluded that combination treatment regimens utilising interferons together with chemotherapeutic agents deserve further study in the treatment of metastatic malignant melanoma.

Combined Modality Therapy↗

PubMed2004

Evolution of the HALT-C Trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders.

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was designed to determine whether maintenance interferon therapy could slow disease progression in patients who had failed to eradicate hepatitis C virus (HCV) during prior interferon treatment (nonresponders). Ten clinical sites, a virological testing center, and a data coordinating center (DCC) were selected to collaborate in the design and implementation of the final protocol. Eligible patients had been treated previously with interferon for at least 12 weeks, with or without another antiviral, ribavirin, but still had persistent viremia. Because patients had received a variety of prior treatments, and as a perceived benefit of enrollment, we incorporated a Lead-in period of treatment with long-acting pegylated interferon alfa-2a plus ribavirin into the study design, a combination believed to be more effective but not approved by the Food and Drug Administration at the Trial's inception. If patients failed to achieve clearance of virus from the blood after 20 weeks of this Lead-in therapy, they were entered into the main trial at week 24 and randomized to receive either a lower dose of pegylated interferon weekly alone or no further therapy for an additional 3 1/2 years. The original protocol was amended later in three respects to improve enrollment and to adapt to Food and Drug Administration approval of the Lead-in therapy, including allowing patients to proceed directly to the randomized part of the study if treatment resembling the Lead-in had been completed. The protocol changes enhanced enrollment while upholding the original goals of the study and its integrity.

Antiviral Agents↗

PubMed2001

Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.

BACKGROUND: Surgery is the main treatment for localised renal cell carcinoma, but use of radical nephrectomy for metastatic disease is highly controversial. We aimed to establish whether radical nephrectomy done before interferon-alfa-based immunotherapy improved time to progression and overall survival (primary endpoints) compared with interferon alfa alone. METHODS: We included 85 patients from June, 1995, to July, 1998: two (one per group) were ineligible. 42 of the 83 participants were randomly assigned combined treatment (study group) and 43 immunotherapy alone (controls). All patients had metastatic renal-cell carcinoma that had been histologically confirmed and was progressive at entry. In study patients, surgery was done within 4 weeks of randomisation, and immunotherapy (5x10(6) IU/m(2) subcutaneously three times per week) started 2-4 weeks later. In controls, immunotherapy was started within 1 working day of randomisation. Follow-up visits were monthly. All analyses were by intention to treat. FINDINGS: 40 (53%) of 75 patients received at least 16 weeks of interferon-alfa treatment, which was also the median duration of treatment. Time to progression (5 vs 3 months, hazard ratio 0.60, 95% CI 0.36-0.97) and median duration of survival were significantly better in study patients than in controls (17 vs 7 months, 0.54, 0.31-0.94). Five patients responded completely to combined treatment, and one to interferon alfa alone. Dose modification was necessary in 32% of patients, most commonly because of non-haematological side-effects. INTERPRETATION: Radical nephrectomy before interferon-based immunotherapy might substantially delay time to progression and improve survival of patients with metastatic renal cell carcinoma who present with good performance status.

Adult↗

PubMed1988

Interferon alpha in hepatitis type B and non-A, non-B. Defective production by peripheral blood mononuclear cells in chronic infection and development of serum interferon in acute disease.

The production in vitro of interferon alpha and gamma by peripheral blood mononuclear cells of 25 patients with chronic hepatitis B and 13 patients with chronic hepatitis non-A, non-B was compared to that of healthy controls. Following induction by Molt 4 leukemia cells (P less than 0.001) and influenza A/X31 virus (P less than 0.01), there was a significantly lower interferon alpha response in patients with chronic hepatitis B and chronic hepatitis non-A, non-B. Yields of interferon gamma in patients with chronic hepatitis were comparable to those of normal individuals. The degree of interferon deficiency did not correlate with severity of liver disease. In patients with chronic hepatitis B, viral replication (presence or absence of HBeAg) was not related to the defect in interferon alpha production. Three of 10 patients with acute hepatitis B had measurable antiviral activity in the serum for 3-5 days after the onset of jaundice.

Acute Disease↗

PubMed2003

[Interferon, ribavirin and amantadine in prior nonresponders to interferon and ribavirin therapy with chronic hepatitis C (genotype 1)].

OBJECTIVE: Despite advances in the treatment of chronic hepatitis C virus (HCV), the disease persists after treatment with interferon and ribavirin in a large percentage of patients and other therapeutic options are lacking. We investigated the efficacy of retreatment with antiviral therapy including amantadine. EXPERIMENTAL DESIGN: prospective and open pilot study. PATIENTS: Thirty-nine patients with chronic HCV, genotype 1, who were nonresponders to interferon and ribavirin were included. The patients were given repeat treatment with interferon-alpha 2A (9 MU/week), ribavirin (1,000-1,200 mg/day) and amantadine (200 mg/day) for 48 weeks. RESULTS: HCV-RNA was undetectable in 5 patients in week 48 (12.8%) and in only 2 patients after 24 weeks of follow-up (5.1% of sustained responses). In patients with basal viremia of < 8 105 U/ml the probability of response at the end of treatment and of sustained response was 26.3 and 10.5%, respectively; in patients with elevated viremias response was 0%. CONCLUSIONS: In patients with chronic HCV genotype 1 without response to interferon and ribavirin, triple antiviral therapy with interferon, ribavirin and amantadine is not useful.

Adult↗