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PubMed2000

Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis.

UNLABELLED: Response to treatment with alpha interferon with or without concomitant ribavirin varies according to the viral genotype in patients with chronic hepatitis C. AIM: This study was undertaken in order to determine the response of genotype 4 chronic hepatitis C to interferon and ribavirin combination compared to interferon alone in patients without cirrhosis. METHODS: Fifty-two patients were given interferon alone at a dose of 5 million units, 3 times a week and another 60 patients were administered with interferon combined with ribavarin (1,000-1,200 mg/ day) for 24 weeks. Sustained biochemical response was defined as normal ALT, 6 months after end of therapy. Sustained virologic response was defined as negative HCV RNA, 6 months after the end of therapy. RESULTS: Only 10/52 (19%) patients showed sustained biochemical response after interferon alone, while 31/60 (52%) showed sustained biochemical response after interferon combined with ribavirin (p<0.01). Only 4/52 (8%) patients showed sustained virologic response after interferon alone, while 25/60 (42%) showed sustained virologic response after interferon combined with ribavirin (p<0.001). CONCLUSION: These results show that patients with chronic hepatitis due to hepatitis C virus type 4 show a poor response to interferon alone but a better response to interferon combined with ribavirin.

Adult↗
PubMedDate not supplied

Combination treatment of interferon alpha-2b and ribavirin in comparison to interferon monotherapy in treatment of chronic hepatitis C genotype 4 patients.

BACKGROUND AND AIM: Treatment of chronic hepatitis C patients, infected with genotype 4 with interferon-alpha yielded a limited response. Our aim was to compare the efficacy of interferon-alpha alone and in combination with ribavirin in chronic hepatitis C patients infected with genotype 4. PATIENTS: Fifty-two chronic hepatitis C patients (all males) infected with genotype 4, who had not received interferon, were randomized into 2 equal comparable groups. METHODS: Group I received interferon alpha-2b "Schering Plough" 3 MU, tiw combined with ribavirin (1000 mg/day). Group II received interferon alpha-2b alone in the same dose. Both groups were evaluated monthly, at the end of 24 weeks of treatment and 24 weeks later. Two patients were dropped from group I and one patient from group II. RESULTS: Biochemical response: at the end of treatment, a return to normal of ALT was obtained in 16/24 (66.7%) patients on combination therapy vs 8/25 (32%) patients on interferon alone (p = 0.0152). At the end of follow-up, a sustained response was achieved in 10/24 (41.7%) patients on combination therapy vs 4/25 (16%) patients on interferon (p = 0.0468). Virologic response: at the end of treatment, the rates of virological response were higher in the patients on combination therapy 9/24 (37.5%) than in those on interferon 4/25 (16%) (p = 0.0380). At the end of follow-up, loss of serum HCV RNA was reported in 5/24 (20.8%) patients on combination therapy vs 2/25 (8%) patients on interferon (p = 0.1916). Histologic response: mild histologic improvement was shown by a decrease in the inflammatory score, which was highest in patients in the combination group. CONCLUSIONS: In chronic hepatitis C patients infected with genotype 4, combination therapy with interferon-alpha and ribavirin was more effective than treatment with interferon monotherapy. At the end of the follow-up, about 50% of patients in both groups were still viraemic though their ALT remained normal.

Adult↗
PubMedDate not supplied

Efficacy of natural BALL-1 interferon-alpha treatment for patients with chronic hepatitis C and a possible enhancing effect of a twice-daily starting regimen with interferon-beta.

BACKGROUND/AIMS: Two distinct natural interferon-alpha (BALL-1 and Namalwa) are available for patients with chronic hepatitis C in Japan, but the efficacy has not been well documented. We investigated two studies using a natural BALL-1 interferon-alpha treatment for chronic hepatitis C and assessed its efficacy. METHODOLOGY: In interferon-alpha monotherapy (Study I), 42 patients with chronic hepatitis C received 10 mega units of BALL-1 interferon-alpha intramuscularly consecutively for an initial 2 weeks followed by three times a week for 6 months totally. In a combination therapy of natural interferon-alpha and interferon-beta (Study II), 24 patients received intravenous 3 mega units of interferon-beta twice daily for the initial 2 weeks followed by 10 mega units of natural BALL-1 interferon-alpha consecutively for 2 weeks and three times a week for 6 months totally. Efficacy and predictive factors for sustained viral response was investigated. RESULTS: Study II included significant younger patients than study I. Sustained virological response was obtained in 31.0% in Study I and 56.5% in Study II by intention-to-treat analysis. Sustained viral response in the group of genotype 1b and viral load more than 100 KIU/mL was 3/23 (13.0%) and 8/18 (44.4%) in Study I and II, respectively. The response rate in Study II was higher than that of Study I especially among the patients with high pretreatment viral load or genotype 1b (p<0.05). Multivariate analysis showed that pre-treatment HCV-RNA levels, HCV-genotype, and histological staging before the interferon treatment were significant predictive factors of sustained viral response. CONCLUSIONS: These studies suggest that natural BALL-1 interferon-alpha is useful for inducing sustained viral response in patients with chronic hepatitis C, even in those possessing genotype 1b and high viral load. In addition, the combination therapy with a starting regimen with twice-daily interferon-beta administration for 2 weeks may be more effective than monotherapy.

Adult↗
PubMed1993

[Interferon. An overview of the state of basic research with special regard to interferon-gamma].

Interferons / An overview on the state of basic research with special regard to interferon-gamma Interferons are multifunctional glycoproteins with a broad range of antiviral, antiproliferative and immunoregulatory effects on the target cell. This review deals with the basics as well as with more recent developments in interferon research. A historic overview of 35 years of interferon research since the discovery of interferons by Isaacs and Lindenmann in 1957 introduces the most important milestones in this field and appreciates the work of the participating researchers. A brief description of the classification of interferons based on different tissue sources, different antigenic properties and different induction behaviour is made. The main part of this review focuses on human interferon-gamma. We discuss recent work on the structure-function relationship of interferon-gamma. The interferon-gamma receptor and its role in signal transduction is another part of this paper. The structure and length of the C-terminal region of interferon-gamma seems to be important for receptor binding and expression of biological activities. A conservative estimate is that the family of IFN-activated genes numbers 15-20 in most cells.

Animals↗
PubMed2002

Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B.

BACKGROUND: Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon. OBJECTIVES: The objectives were to assess the effects of the sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone in hepatitis B 'e' antigen positive chronic hepatitis B on mortality, virological response, biochemical response, liver histology, quality of life, and adverse events. SEARCH STRATEGY: Electronic searches of the controlled trial registers of The Cochrane Hepato-Biliary Group and The Cochrane Library, MEDLINE, BIOSIS, and EMBASE were combined (May 2000). Reading the bibliography of retrieved articles identified further trials. Alfa interferon-manufacturing companies were approached in order to inquire about any published and unpublished randomised trials. SELECTION CRITERIA: The analyses included randomised trials comparing identical alfa interferon treatment regimens with and without glucocorticosteroid pretreatment for hepatitis B 'e' antigen positive chronic hepatitis. The trials could be open, single blinded, or double blinded. No patient exclusion criteria were applied. DATA COLLECTION AND ANALYSIS: Three reviewers independently selected the trials and one extracted the data, which were validated. Assessments of the outcome measures were performed at the end of treatment and at six months and at maximal follow up after the end of treatment with alfa interferon. MAIN RESULTS: A total of 13 randomised trials including 790 patients were included. Loss of hepatitis B 'e' antigen (OR 1.41, 95% confidence interval 1.03 to 1.92, P = 0.03) and hepatitis B virus DNA (OR = 1.51, 95% confidence interval 1.12 to 2.05, P = 0.008) were significantly more frequent among patients treated with the sequential combination of glucocorticosteroids and alfa interferon than among patients treated with alfa interferon alone. Glucocorticosteroid pretreatment did not significantly influence seroconversion from hepatitis B 'e' antigen to antibodies to hepatitis B 'e' antigen, loss of hepatitis B surface antigen, normalisation of alanine aminotransferase/aspartate aminotransferase activities, and severity of adverse events. Glucocorticosteroid pretreatment did not significantly affect mortality and adverse events. The effect of glucocorticosteroid pretreatment on liver histology and quality of life could not be assessed due to insufficient data. REVIEWER'S CONCLUSIONS: Pretreatment with glucocorticosteroids before treatment with alfa interferon in patients with hepatitis B 'e' antigen positive chronic hepatitis B may be more effective than treatment with alfa interferon alone with regard to loss of hepatitis B 'e' antigen and hepatitis B virus DNA, but evidence for effect on clinical outcomes is lacking.

Antiviral Agents↗
PubMed2002

Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C.

BACKGROUND: Interferon monotherapy leads to sustained virologic clearance in a minority of patients with chronic hepatitis C. Studies have yielded conflicting results regarding retreatment with interferon in nonresponders and relapsers. OBJECTIVES: To assess the beneficial and harmful effects of retreatment with interferon in chronic hepatitis C nonresponders and relapsers to previous interferon treatment. SEARCH STRATEGY: Trials were identified through electronic databases, manual searches, authors, and pharmaceutical companies (August 2001). SELECTION CRITERIA: Randomised trials comparing interferon versus control or different interferon regimens in chronic hepatitis C patients being nonresponders and relapsers to previous interferon were included. DATA COLLECTION AND ANALYSIS: The primary outcome was failure to achieve a sustained virologic response defined as positive serum hepatitis C virus RNA at least six months following treatment. Secondary outcomes included liver-related morbidity, mortality, biochemical responses, adverse events, and histology. MAIN RESULTS: Ten randomised trials involving 686 nonresponders and eight trials involving 484 relapsers were included; their methodological quality was poor. In nonresponders, interferon reduced the risk of not achieving an end of treatment biochemical response compared with no treatment (relative risk [RR] 0.77, 95% confidence interval [CI] 0.66 to 0.91); however, virologic responses were not reported. In a post hoc subgroup analysis, doses greater than 3 million units (MU) three times weekly offered no advantage compared with 3 MU three times weekly for biochemical sustained response. Failure to obtain a virologic sustained response was less likely with 48 than 24 weeks of therapy (RR 0.87, 95% CI 0.79 to 0.96). Adverse events did not differ significantly regardless of treatment dose or duration. In relapsers, none of the trials compared interferon with no treatment. In a post hoc analysis, doses greater than 3 MU three times weekly were no more effective in achieving a virologic sustained response than 3 MU three times weekly. Compared with 24 weeks, treatment durations of 48 weeks were less likely to fail to achieve a virologic sustained response (RR 0.69, 95% CI Random 0.51 to 0.95), but associated with more frequent dosage reduction (RR 9.07, 95% CI 1.20 to 68.63). No data regarding clinical outcomes or histology was available in either patient group. REVIEWER'S CONCLUSIONS: Retreatment with interferon leads to sustained virologic clearance in a minority of chronic hepatitis C patients with nonresponse or relapse following interferon monotherapy. Treatment durations of 48 weeks are superior to 24 weeks, but doses greater than 3 MU three times weekly are no more effective. No data exists regarding the effect on clinical outcomes.

Antiviral Agents↗
PubMed1987

Rat leukocyte interferons: production of an acid-labile interferon after induction with Newcastle disease virus.

Rat leukocytes produce three interferon species after infection with Newcastle disease virus. Two of the three interferon species (22-24,000 and 30,000 daltons) were acid and heat stable, protected rat and mouse cells from virus-mediated cytopathic effect (CPE), and were neutralized by antisera to mouse L-cell (alpha/beta) interferon. The third, 30,000-dalton interferon species was heat and acid labile; protected rat, mouse, human, and bovine cells from virus-mediated CPE; and was neutralized by antisera to mouse L-cell interferon and human leukocyte interferon. Thus, the rat leukocyte interferon system is similar to the human system in the kinetics of interferon production, the production of multiple interferons, heterologous antiviral activity, molecular weight, and in the production of an acid-labile species. The rat leukocyte interferon system therefore represents an important model for examining the normal production and action of acid-labile interferons and their possible role in the regulation of leukocyte function and cellular differentiation.

Animals↗
PubMed1980

Action of murine gamma (immune)interferon on beta (fibroblast)-interferon resistant L 1210 and embryonal carcinoma cells.

Treatment of leukaemic mouse L 1210 S cells with beta or gamma interferon results in the development of antiviral and anticellular effects, both of which are also induced by interferon in L 1210 R cells selected for their resistance to gamma-interferon. Here we show that treatment of L 1210 S cells with beta or gamma interferon results in the induction of two double-stranded (ds) RNA dependent enzymes which have been described previously in beta and gamma-interferon treated mouse L-929 cells: pppA (2'p5'A)n synthetase and protein kinase(s). Treatment of L 1210 R cells with beta-interferon does not result in the induction of any detectable enhanced pppA (2'p5'A)n synthetase and protein kinase activities whereas gamma-interferon is capable of inducing both of these enzymes. These results indicate that although beta and gamma-interferon induce similar intracellular events, they may have different mechanism of interaction with their target cells. In addition, here we show that similar to the action of beta-interferon, treatment of mouse embryonal carcinoma cells with gamma-interferon results in the induction of pppA (2'p5'A)n synthetase in the absence of any detectable protein kinase activity or any apparent development of antiviral and anti-cellular effects. The significance of this in relation to the mechanism of action of interferon is discussed.

2',5'-Oligoadenylate Synthetase↗
PubMed1980

Interferon and cytotoxic factor (cytotoxin) released in the blood of mice infected with Mycobacterium bovis BCG. III. Interferon and cytotoxin induced by the specific antigen as compared with those induced by bacterial lipopolysaccharide.

The time course of development and decline of the ability of BCG-infected mice to produce interferon in the serum in response to the intravenous infection of purified protein derivative of tuberculin (PPD) was very similar to that of their systemic hypersensitivity to PPD. A cytotoxic factor (cytotoxin) was produced in parallel with interferon in the serum of BCG-infected mice after stimulation with PPD. The duration of the period in which cytotoxin-production responsiveness to PPD was definitely detectable was much shorter than that for interferon-production responsiveness although the periods for the maximum production of interferon and cytotoxin coincided. The kinetics of release of interferon in the serum of BCG-infected mice after stimulation with PPD did not parallel that of release of cytotoxin. The four kinds of activities, interferons and cytotoxins induced by PPD and lipopolysaccharide (LPS) in the serum of BCG-infected mice, were compared for their stability to heating at 56 C and to treatment at pH 2. The kinetics of inactivation of these four activities differed significantly, when the serum was either heated at 56 C or treated at pH 2. Interferon produced in response to LPS could be neutralized by anti-L cell(NDV) interferon rabbit serum as easily as L cell (NDV) interferon, 16 times as much antiserum was required to neutralize the same amount of interferon in response to PPD, but cytotoxins induced by PPD and LPS were not neutralized at all by the antiserum. From these findings it is thought likely that interferons and cytotoxins induced by PPD and LPS in the serum of BCG-infected mice are different substances, although the antigenic relationship between cytotoxins induced by PPD and LPS remains unknown.

Animals↗
PubMed1978

Neutralizing antibodies against human leukocyte, lymphoblastoid and fibroblast interferons elicited by immunization with human leukocyte interferon.

Guinea pigs, rabbits, and sheep were immunized with partially purified human leukocyte interferon. The antisera were tested for their neutralizing activities against human leukocyte, lymphoblastoid (Namalva) and fibroblast interferons. Rabbits and sheep developed high levels of neutralizing antibodies against all three interferons. The ratios of the neutralizing activities of leukocyte/lymphoblastoid interferons varied from 1 to 25 and those of leukocyte/fibroblast interferons from 2 to 500. The ratios increased with prolonged immunization. The guinea pigs developed relatively low levels of anti-leukocyte and anti-lymphoblastoid antibodies and as a rule failed to produce detectable neutralizing activity against fibroblast interferon. One sheep was given a booster injection of fibroblast interferon after preimmunization with leukocyte interferon. The booster injection stimulated a rise in antibody levels, not only for fibroblast interferon, but also for leukocyte and lymphoblastoid interferons. The antigenic relationships between leukocyte, lymphoblastoid and fibroblast interferons are discussed.

Animals↗
PubMed1981

Mechanism of immune interferon production in vitro: interaction between immune interferon-producing cells and antigenic cells.

Various processes of in vitro immune interferon production by sensitized spleen cells stimulated with allogeneic cells were investigated. When L cells, an interferon-inducing antigen, were fixed with methyl alcohol or paraformaldehyde, the ability to induce immune interferon disappeared. In this immune interferon production system, the majority of sensitized spleen cells adhered to target cells within 1 h of cocultivation. Adherence of immune interferon-producing cells to target cells was observed only when L cell-sensitized spleen cells were cocultured with L cells or with mouse embryo cells derived from C3H mice. Fixation of antigenic cells with methyl alcohol or paraformaldehyde significantly reduced cell adherence. When L cells alone or sensitized spleen cells alone were pretreated separately with cytochalasin D, neither cell type could bind to partner cells. Specific adherence did not take place at 4 degrees C, nor in the presence of dinitrophenol or sodium azide. Continuous protein synthesis in both cells was not required for immune cell adherence. Divalent cations, Ca2+ or Mg2+, were required for this immune specific adherence to take place. However, once stable adherence was established, treatment with cytochalasin D, ethylenediaminetetraacetic acid, or sodium azide, or simple reduction of temperature, did not disrupt the binding. Interaction between immune interferon-producing cells and antigenic cells can be subdivided into two phases according to the requirement for divalent cations: (i) lymphocytes and antigenic cells interact transiently, and divalent cations are required to maintain the binding; (ii) lymphocytes and antigenic cells form a stable interaction, and deprivation of divalent cations does not disrupt the binding. Colchicine showed an inhibitory effect in the period after cell-to-cell adherence. Colchicine did not inhibit the release of interferon. On the other hand, vinblastine, another antimicrotubule agent inhibited the secretion of immune interferon. Since interferon synthesis was not stopped immediately after addition of cycloheximide, continued protein synthesis of sensitized spleen cells was not required for interferon secretion. The present study showed that adherence of immune interferon-producing cells to antigenic cells was a complex phenomenon involving a series of successive events.

Animals↗
PubMed1983

Interferon induction by viruses: one molecule of dsRNA as the threshold for interferon induction.

The studies chronicled in this chapter were chosen largely because they contained data amenable to the quantitative analysis of interferon induction dose-response curves and the IFP activity they represented. The interpretation of the data was predicated on the assumption that a single molecule of dsRNA, when properly introduced into a cell, either as a preformed entity or formed therein following some synthetic event, can induce a quantum yield of interferon. This novel view of interferon induction by viruses has provided an explanation for many seemingly discordant results and offers a unifying hypothesis regarding the nature of the interferon inducer moiety for viruses from widely different families. If we note the reluctance of some to accept dsRNA as a common interferon inducer molecule ( McKimm and Rapp , 1977; Kowal and Youngner , 1978; Joklik , 1980) but recognize that the threshold for activating the interferon induction system is one molecule per cell, many aspects of interferon induction heretofore enigmatic are rendered offerpretable . Furthermore, one molecule of dsRNA per cell suffices to induce a quantum yield of interferon, an apparent expression of the "one-shot affair" of interferon production recognized by Ho (1964). In some cases of induction (the r = 1 type dose-response curve) there is an exquisitely responsive modulation of production when a second molecule of dsRNA is simultaneously introduced into the cell. The experimental approach and concepts discussed herein offer a new perspective on the mechanism of interferon induction by viruses and its regulation, and point out the incredible biological potency of a dsRNA molecule--a molecule found to play a key role in viral infection and host defence (Carter and De Clercq , 1974), regulation of the immune system (Johnson, 1980), and perhaps some yet to be defined function in cell growth (Taylor- Papadimitriou , 1980) and differentiation ( Grossberg and Sabran , 1981-2) through its capacity to activate the interferon system.

Animals↗
PubMed1997

Pretreatment of astrocytes with interferon-alpha/beta impairs interferon-gamma induction of nitric oxide synthase.

Excessive nitric oxide/peroxynitrite generation has been implicated in the pathogenesis of multiple sclerosis, and the demonstration of increased astrocytic nitric oxide synthase activity in the postmortem brain of multiple sclerosis patients supports this hypothesis. Exposure of astrocytes, in primary culture, to interferon-gamma results in stimulation of nitric oxide synthase activity and increased nitric oxide release. In contrast to interferon-gamma, interferon-alpha/beta had a minimal effect on astrocytic nitric oxide formation. Furthermore, pretreatment of astrocytes with interferon-alpha/beta inhibited (approximately 65%) stimulation by interferon-gamma of nitric oxide synthase activity and nitric oxide release. Treatment with interferon-alpha/beta at a concentration as low as 10 U/ml caused inhibition of mitochondrial cytochrome c oxidase. Furthermore, the damage to cytochrome c oxidase was prevented by the putative interferon-alpha/beta receptor antagonist oxyphenylbutazone. In view of these observations, our current hypothesis is that the mitochondrial damage caused by exposure to interferon-alpha/beta may impair the ability of astrocytes to induce nitric oxide synthase activity on subsequent interferon-gamma exposure. These results may have implications for our understanding of the mechanisms responsible for the therapeutic effects of interferon-alpha/beta preparations in multiple sclerosis.

Animals↗
PubMed1984

Interferon receptor interaction. Internalization of interferon alpha 2 and modulation of its receptor on human cells.

Studies reported earlier [ Joshi et al. (1982) J. Biol. Chem. 257, 13884-13887] have indicated that human interferon-alpha 2 (HuIFN-alpha 2) binds to a specific macromolecular receptor on human cells as identified by cross-linking with bifunctional cross-linking reagents and analysis by polyacrylamide gel electrophoresis. We have carried out experiments to investigate the fate of the interferon-receptor complex on the cell surface under conditions which lead to cellular response. As analyzed by cross-linking and gel electrophoresis, the interferon-receptor complex, formed on incubation with 125I-IFN-alpha 2 at 4 degrees C, persisted at the cell surface for several hours at 4 degrees C; however, if the cells were switched to 37 degrees C, there was a rapid decline in the complex, apparently due to a loss of the interferon receptors from the cell surface. This was associated with an internalization of the 125I-interferon as indicated by the fact that, on incubation at 37 degrees C, an appreciable fraction of the cell-associated interferon (approximately equal to 50%) became resistant to trypsin digestion, or dissociation on incubation in growth medium or low-pH buffer. A large fraction of the trypsin-resistant (internalized) 125I-labeled material migrated as intact interferon in polyacrylamide gels, and it was immunoprecipitated by anti-(HuIFN-alpha)antibodies but not by anti-(HuIFN-beta)antibodies. The bulk of the internalized 125I-interferon was recovered in a particulate fraction and, on cross-linking with disuccinimidyl suberate, a 150000-Mr complex could be detected. The results suggest that interferon may be internalized as a complex with the receptor, which may account for the loss of the interferon-receptors on the cell surface. This modulation of the IFN-alpha/beta receptors was induced by HuIFN-alpha and HuIFN-beta but not by HuIFN-gamma. The recovery of the IFN-alpha/beta receptors, lost upon incubation with HuIFN-alpha, took several hours and required protein synthesis. The significance of the results is discussed.

Burkitt Lymphoma↗
PubMed1994

p135tyk2, an interferon-alpha-activated tyrosine kinase, is physically associated with an interferon-alpha receptor.

Recent genetic studies have linked the tyk2 gene, which encodes a novel type of non-receptor tyrosine kinase, to the interferon-alpha intracellular signaling pathway. In this report, biochemical evidence is presented which supports this proposed function for the tyk2 tyrosine kinase and further defines its role in the interferon-alpha signaling cascade. Specifically, the tyk2 gene is shown to encode a 135-kDa protein which is rapidly phosphorylated on tyrosine in response to interferon-alpha treatment. Indirect evidence suggests that the tyrosine phosphorylation of p135tyk2 is the result of autokinase activity, implying that the Tyk2 tyrosine kinase is activated by interferon-alpha treatment. Two complementary methods demonstrate a physical association between p135tyk2 and the alpha-subunit of the interferon-alpha receptor. First, immunoblots show that monoclonal antibodies against the alpha-subunit of the interferon-alpha receptor can co-immunoprecipitate p135tyk2. Second, interferon-alpha receptor proteins which have been labeled by affinity cross-linking with 125I-interferon-alpha 2 can be co-immunoprecipitated using anti-tyk2 antisera. Taken together, these data suggest that an interferon-alpha receptor-p135tyk2 complex functions, in a manner analogous to the CD4-lck tyrosine kinase complex, to initiate the interferon-alpha signaling cascade.

Animals↗
PubMed1993

Alpha-interferon enhances gamma-interferon production of peripheral blood mononuclear cells pre-activated with phytohemagglutinin.

The question of whether the state of T cell activation is responsible for gamma-interferon production in response to alpha-interferon was determined. When peripheral blood mononuclear cells were pre-incubated with phytohemagglutinin for 3 days, their gamma-interferon production was found to be augmented by alpha-interferon, accompanied by an increased proportion of DR-positive T cells. This did not occur with fresh cells. The effect was dose-dependent and inhibited by anti-alpha-interferon antibody. Therefore, alpha-interferon was considered to enhance the production of gamma-interferon of pre-activated peripheral blood mononuclear cells but not of resting ones. In conclusion, alpha-interferon augmented the production of gamma-interferon of peripheral blood mononuclear cells only when they had already been activated, suggesting a role of alpha-interferon as a modulator of the cellular immune response.

Flow Cytometry↗
PubMed1980

Interferon production in cocultures between mouse spleen cells and tumor cells: possible role of mycoplasmas in interferon induction.

Interferon production was measured in the murine mixed lymphocyte tumor cell interaction (MLTI) using spleen cells of three inbred mouse strains and a number of in vitro grown lymphoma cells. No difference in interferon production was observed when syngeneic or allogeneic combinations were compared. Interferon was not detectable during the first 6 h of culture and reached its maximum after 12--24 h. In contrast, natural killer cell activity of spleen cells against one of these lymphoma lines (YAC-1) was already high after 4h. A cell line that was not susceptible to natural killing (MDAY-D2) induced the same amount of interferon as YAC-1. These findings suggest that natural killer cell activity and interferon induction in the MLTI are not correlated. Several lymphoma cell lines induced interferon in the MLTI whereas some others did not. All lines that were inductive were found to contain mycoplasmas. Furthermore, even the cell-free supernatants of inducing lines contained mycoplasmas and induced interferon. Purified mycoplasmas and membranes thereof were able to induce interferon production in mouse spleen cells. Our data strongly suggest that interferon production in the MLTI is caused by mycoplasmas. This artifact is the relevance for three reasons. First, cocultures between lymphoma cells and lymphocytes are widely studied in immunology. Secondly, contamination with mycoplasmas is extremely common and often goes unnoticed in immunological laboratories. Thirdly, interferon is known to affect profoundly a number of in vitro functions of immunocompetent cells.

Animals↗
PubMed1998

Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT)

BACKGROUND: Only 15-20% of patients with chronic hepatitis C achieve a sustained virological response with interferon therapy. The aim of this study was to compare the efficacy and safety of interferon alpha2b in combination with oral ribavirin with interferon alone, for treatment of chronic infection with hepatitis C virus (HCV). METHODS: 832 patients aged 18 years or more with chronic HCV who had not been treated with interferon or ribavirin, were enrolled and randomly allocated one of three regimens: 3 mega units (MU) interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 48 weeks; 3 MU interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 24 weeks; or 3 MU interferon alpha2b three times a week and placebo for 48 weeks. All patients were assessed for safety, tolerance, and efficacy at the end of weeks 1, 2, 4, 6, and 8, and every 4 weeks during treatment. After treatment was completed patients were followed up on weeks 4, 8, 12, and 24. The primary endpoint was loss of detectable HCV-RNA (serum HCV-RNA <100 copies/mL) at week 24 after treatment. FINDINGS: Sustained virological response at 24 weeks after treatment, was found in 119 (43%) of the 277 patients treated for 48 weeks with the combination regimen, 97 (35%) of the 277 patients treated for 24 weeks with the combination regimen (p=O.055), and 53 (19%) of the 278 patients treated for 48 weeks with interferon alone (p<0.001 vs both combination regimens, intention-to-treat analysis). Logistic regression identified five independent factors significantly associated with response: genotype 2 or 3, viral load less than 2 million copies/mL, age 40 years or less, minimal fibrosis stage, and female sex. Among patients with fewer than three of these factors the odds ratio of sustained response was 2.6 (95% Cl 1.4-4.8; p=0.002) for the 48 week combination regimen compared with 24 weeks of the combination regimen. Discontinuation of therapy for adverse events was more frequent with combination (19%) and monotherapy (13%) given for 48 weeks than combination therapy given for 24 weeks (8%). INTERPRETATION: An interferon alpha2b plus ribavirin combination is more effective than 48 weeks of interferon alpha2b monotherapy and has an acceptable safety profile. Patients with few favourable factors benefit more from extending the duration of combination therapy to 48 weeks.

Administration, Oral↗