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At least 1,135 records · Page 63Linked to original sources
PubMed2005

Promoter polymorphisms of the interferon-alpha receptor gene and development of Interferon-induced depressive symptoms in patients with chronic hepatitis C: preliminary findings.

BACKGROUND: Interferon (IFN)-alpha treatment frequently induces depression, which can impair quality of life and reduce treatment adherence. Defining relevant risk factors for IFN-alpha-induced depression is essential for designing preventative treatment strategies. OBJECTIVE: The purpose of the present study was to determine whether promoter polymorphisms of -408C/T, -3C/T and GT repeat dinucleotide microsatellite in the IFN-alpha/beta receptor 1 (IFNAR1) gene are associated with the development of IFN-induced depression. METHOD: Fifty patients with chronic hepatitis C were treated with pegylated IFN alpha-2b plus a standard or weight-based dose of ribavirin. Severity of depression was assessed using the Zung Self-Rating Depression Scale (SDS) at baseline and at 4, 8, 12 and 24 weeks of treatment. RESULT: The baseline to maximum difference in the SDS index score of neurovegetative/somatic symptoms was higher in patients with the 5/14 genotype of the GT repeat dinucleotide microsatellite polymorphism than in those patients with other genotypes (p = 0.0084). CONCLUSION: This preliminary result suggests that the promoter GT repeat dinucleotide microsatellite polymorphism of the IFNAR1 gene may represent a risk factor for the development of depressive symptoms during IFN-alpha therapy for hepatitis C and other conditions.

Adult↗
PubMed1990

Low incidence of anti-interferon-alpha antibodies in patients treated with interferon-alpha-2a for AIDS-associated Kaposi's sarcoma.

Anti-interferon (IFN)-alpha antibodies were determined in the serum of 28 patients treated with high-dose human recombinant IFN-alpha-2a for AIDS-associated Kaposi's sarcoma. After a median treatment duration of 3 months, 3 patients developed anti-IFN-alpha antibodies, of whom 2 showed a long lasting tumour response despite the development of these antibodies. None of 3 patients with tumour progression after an initial treatment response had developed IFN-alpha neutralizing antibodies. In conclusion, a low incidence of anti-IFN-alpha antibodies during treatment with high dose IFN-alpha was found, but the appearance had no detrimental effect on the duration of tumour responses in a small number of patients.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Synergistic inhibition of human cytomegalovirus replication by interferon-alpha/beta and interferon-gamma.

BACKGROUND: Recent studies have shown that gamma interferon (IFN-gamma) synergizes with the innate IFNs (IFN-alpha and IFN-beta) to inhibit herpes simplex virus type 1 (HSV-1) replication in vitro. To determine whether this phenomenon is shared by other herpesviruses, we investigated the effects of IFNs on human cytomegalovirus (HCMV) replication. RESULTS: We have found that as with HSV-1, IFN-gamma synergizes with the innate IFNs (IFN-alpha/beta) to potently inhibit HCMV replication in vitro. While pre-treatment of human foreskin fibroblasts (HFFs) with IFN-alpha, IFN-beta or IFN-gamma alone inhibited HCMV plaque formation by approximately 30 to 40-fold, treatment with IFN-alpha and IFN-gamma or IFN-beta and IFN-gamma inhibited HCMV plaque formation by 163- and 662-fold, respectively. The generation of isobole plots verified that the observed inhibition of HCMV plaque formation and replication in HFFs by IFN-alpha/beta and IFN-gamma was a synergistic interaction. Additionally, real-time PCR analyses of the HCMV immediate early (IE) genes (IE1 and IE2) revealed that IE mRNA expression was profoundly decreased in cells stimulated with IFN-alpha/beta and IFN-gamma (approximately 5-11-fold) as compared to vehicle-treated cells. Furthermore, decreased IE mRNA expression was accompanied by a decrease in IE protein expression, as demonstrated by western blotting and immunofluorescence. CONCLUSION: These findings suggest that IFN-alpha/beta and IFN-gamma synergistically inhibit HCMV replication through a mechanism that may involve the regulation of IE gene expression. We hypothesize that IFN-gamma produced by activated cells of the adaptive immune response may potentially synergize with endogenous type I IFNs to inhibit HCMV dissemination in vivo.

Antiviral Agents↗
PubMed2002

Interferon-beta-1b and interferon-gamma have similar inhibitory effects on apolipoprotein-E production in the monocyte/macrophage.

Apolipoprotein-E (Apo-E) is the major lipid carrier in the brain, and is therefore important in the recyding of lipids and cholesterol to regenerating neurons during the remission phase of multiple sclerosis (MS). Interferon (IFN)-gamma has been shown to inhibit Apo-E production by a mainly post-transcriptional method in a macrophage cell line, and reduced Apo-E in cerebrospinal fluid is noted during the remission phase in patients. IFN-beta-1b is a recombinantly produced, anti-inflammatory cytokine, which has been shown to reduce the severity of MS relapses and reduce relapse rate. We have examined the effects of IFN-gamma and IFN-beta-1b on the production of Apo-E mRNA, cellular protein and secreted protein in primary monocytes derived from donor blood. IFN-beta-1b does not relieve the dose-dependent inhibition of Apo-E seen with IFN-gamma at up to 100 U/ml in these cells, and when used alone inhibits Apo-E production in a dose-dependent manner. This inhibition by IFN-beta-1b was seen to be at a transcriptional level, and dose dependent up to 100 U/ml. Apo-E genotype, which has also been linked to failure to recover from MS relapses, did not affect this inhibition. The mode of action of IFN-beta-1b in MS is therefore not thought to be through modification of Apo-E production.

Apolipoproteins E↗
PubMed2006

Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis (INCOMIN Trial) II: analysis of MRI responses to treatment and correlation with Nab.

BACKGROUND: In RRMS, clinical exacerbations are usually associated with different types of active lesions at MRI, including: hyperintense lesions on T1-weighted post-gadolinium sequences; new hyperintense lesions or enlarging old lesions on PD/T2-weighted scans; or new hypointense lesions on T1-weighted pre-Gd sequences. OBJECTIVE/METHODS: Primary outcome was the occurrence of patients with at least one active MRI lesion of the different types indicated above during treatment with 250 microg every other day (EOD) interferon beta (IFNbeta)-1b or 30 microg once weekly (OW) IFNbeta-1a in outpatients with RRMS (INCOMIN Trial). RESULTS: The number of patients with at least one 'active' lesion, evaluated over the two-year follow-up, was significantly (P = 0.014) lower in the EOD IFNbeta-1 b arm (1 3/76, 17%) then in the OW IFNbeta-1a arm (25/73, 34%). NAb frequency over two-year follow-up was 22/65 (33.8%) in the EOD IFNbeta-1b arm and 4/62 (6.5%) in the OW IFNbeta-1a arm, significantly greater in the EOD IFNbeta-1b arm. CONCLUSIONS: The development of MRI active lesions is strongly reduced by EOD-IFNbeta-1b compared with OW-IFNbeta-1a, indicating that EOD-IFNbeta-1b is more effective than OW-IFNbeta-1a in reducing ongoing inflammation and demyelination in MS. Logistic regression showed that NAb status did not affect the risk of MRI activity.

Adjuvants, Immunologic↗
PubMed1988

Recombinant interferon alfa-2a in metastatic renal cell carcinoma: assessment of antitumor activity and anti-interferon antibody formation.

Twenty-one patients with advanced, measurable, renal cell carcinoma (RCC) were administered recombinant interferon alfa-2a (rIFN-alpha 2a) (Roferon-A; Roche Laboratories, Nutley, NJ) intramuscularly beginning at 3 x 10(6) units and escalating to 36 x 10(6) units, 5 d/wk for a total induction period of 14 weeks. rIFN-alpha 2a antibody production was measured using an enzyme immunoassay (EIA). Those sera found to be positive for presence of antibody by the EIA were tested for the presence of neutralizing antibodies (NA) by an antiviral neutralization bioassay (ANB). All patients were evaluable for toxicity, and 19 were evaluable for response and for incidence of antibody formation. Five patients (26%; 95% confidence interval, 6% to 46%) had complete responses (CR) or partial responses (PR) with a median duration of 283 days. An additional ten patients (53%) had minor tumor regressions with a median duration of 86 days. Fifty-one percent of evaluable patients are alive at 18.6 months. Antibodies to rIFN-alpha 2a as measured by the EIA, were detected in 12 (63%) patients. NA were measured in the serum of six (50%) of those EIA-positive patients. Overall, six of 19 patients (32%) developed NA. Median time to the development of antibody as measured by EIA or NA was 8 and 14 weeks, respectively. Median NA titer was 1,200 IFN neutralizing U/mL. NA-positive and -negative patients had a median duration of response of 13.7 v 9.9 months, and survival of greater than 21.3 v 18.3 months, respectively. Clinical toxicity was mild and not therapeutically limiting. Autoantibody production (ANA, rheumatoid factor [RF], Coombs' direct/indirect) occurred in both NA-positive and -negative patients. The clinical significance of the antibodies to rIFN-alpha 2a and the associated autoantibody formation remain unclear; however, presence of antibody was not associated with adverse clinical sequelae.

Adult↗
PubMed2005

Phase I study of the sequential combination of interleukin-12 and interferon alfa-2b in advanced cancer: evidence for modulation of interferon signaling pathways by interleukin-12.

PURPOSE: To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN-gamma on Janus kinase-signal transducer and activator of transcription (Jak-STAT) signal transduction in patient peripheral-blood mononuclear cells (PBMCs). PATIENTS AND METHODS: Forty-nine patients with metastatic cancer received rhIL-12 on day 1 and IFN-alpha-2b on days 2 to 6 of either a 14-day (n = 43) or a 7-day treatment cycle (n = 6). rhIL-12 was initially administered subcutaneously at a dose of 100 ng/kg, whereas IFN-alpha-2b was escalated from 1 to 10 million units (MU) in cohorts of three patients (1, 3, 5, 7, or 10 MU). rhIL-12 was subsequently administered intravenously (IV) in escalating doses (100 to 500 ng/kg) to achieve greater IFN-gamma production. Peripheral blood was drawn for measurement of plasma IFN-gamma and the induction of Jak-STAT signal transduction in PBMCs. RESULTS: No IL-12-or IFN-alpha-related dose-limiting toxicities were observed. There were no responses in 41 assessable patients. Five patients exhibited stable disease lasting 6 months or longer while on therapy. Optimal induction of IFN-gamma by IL-12 occurred after an IV dose of 250 ng/kg. Patient PBMCs exhibited increased levels of STAT1 after IL-12 administration. The peak level of IFN-gamma achieved with IL-12 therapy correlated with the peak level of intracellular STAT1 in patient PBMCs (r = 0.38, P = .021). CONCLUSION: The combination of rhIL-12 and IFN-alpha-2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-alpha-induced Jak-STAT signal transduction in patient PBMCs.

Adult↗
PubMed2001

High levels of interferon gamma in the plasma of children with complete interferon gamma receptor deficiency.

We have found that children with complete interferon gamma (IFNgamma) receptor deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFNgamma in their plasma. This unexpected observation provides a simple and accurate diagnostic method for complete IFNgamma receptor deficiency in children with clinical disease caused by bacille Calmette-Guérin vaccines or environmental nontuberculous mycobacteria.

BCG Vaccine↗
PubMed1983

The physiological interferon response. I. Cells attached to intrauterine devices release interferon in vitro.

Cells attached to intrauterine devices (IUDs) release interferon (IFN) in the medium during incubation in vitro. Most of the IFN is released during the first hour suggesting that the cells had been previously induced and were probably already producing IFN in vivo. Characterization of the IFN indicates that most of it is of gamma-type with a trace of alpha. Production of IFN in the uterine fluid would represent a first example of the physiological IFN response and may serve to modulate some of the mechanisms preventing implantation of blastocyst. The actual presence of IFN in the uterine secretion remains to be demonstrated.

Culture Techniques↗
PubMed2001

[A trial of new interferon therapy for the patients with chronic hepatitis C resistant to interferon therapy].

HCV-RNA clearance rates are reported to be about 30-40% of the patients treated with IFN for less than 6 months. But IFN therapy is ineffective for chronic hepatitis C patients with HCV-genotype 1b and a high virus load. We evaluated the efficacy of different IFN therapy compared with standard IFN therapy for chronic hepatitis C patients resistant to interferon therapy. That is, we assessed the following therapy; 1) prolonged IFN therapy, 2) IFN-beta therapy of twice a day, 3) IFN-beta therapy daily for 24 weeks, 4) combination therapy of IFN-alpha and IFN-beta. In some cases, these IFN therapies were effective than a standard IFN therapy.

Adult↗
PubMed2002

Characterization of interferon gamma receptors on osteoclasts: effect of interferon gamma on osteoclastic superoxide generation.

Osteoclasts are the primary cells responsible for bone resorption. Osteoclast formation and bone resorption activities involve processes tightly controlled by a network of cytokines. The presence of interferon gamma (IFN-gamma) receptors on osteoclasts is a necessary prerequisite for IFN-gamma to directly affect osteoclastic activity. To date, the presence of the IFN-gamma receptor on osteoclasts has not been established. This study provides evidence that osteoclasts express the IFN-gamma receptor. Specific binding of IFN-gamma to the osteoclastic receptor stimulates osteoclastic superoxide generation. The p91 and p47 components of the NADPH oxidase increase after IFN-gamma stimulation and may account for the enhanced superoxide generation. Antisense experiments targeting p91 and p47 subunits abrogate the increased osteoclastic superoxide production stimulated by IFN-gamma. Thus, superoxide generation by osteoclasts is stimulated by activation of a functional IFN-gamma receptor on the osteoclast.

Cells, Cultured↗
PubMedDate not supplied

Changes of serum neopterin, beta 2-microglobulin and interferon-gamma in patients with chronic hepatitis C treated with interferon-alpha 2b.

OBJECTIVES: Treatment with interferon (IFN) reduces viral replication and normalizes aminotransferase levels in a significant percentage of patients with non-A, non-B hepatitis or hepatitis C. Soluble immune activation markers were evaluated in patients with hepatitis. PATIENTS AND METHODS: Serum concentrations of soluble immune activation markers neopterin and beta 2-microglobulin (B2M) were compared to endogenous IFN-gamma levels in 17 patients with chronic hepatitis C before, during and after 9-months of treatment with IFN-alpha 2b. RESULTS: Before therapy some patients had increased concentrations of the studied variables. During therapy neopterin and B2M concentrations further increased whereas IFN-gamma decreased. IFN-gamma and neopterin levels were correlated before but not during therapy. The correlations between neopterin and B2M were significant throughout the study. CONCLUSION: The data indicate that IFN-gamma decreases during treatment and IFN-alpha 2b appears to enhance formation of neopterin and B2M.

Adult↗
PubMed2006

Hepatic interferon receptor mRNA expression: clinical relevance and its relationship with effectiveness of interferon plus ribavirin therapy in patients with genotype 1b hepatitis C virus infection.

BACKGROUND/AIMS: Hepatic expression of interferon (IFN) receptor mRNA has been shown to correlate with the effectiveness of IFN monotherapy in patients with chronic hepatitis C virus (HCV) infection. We investigated the expression of hepatic IFN receptor alpha/beta (IFNAR2c) mRNA and its association with the effectiveness of IFN plus ribavirin (RBV) therapy and with the clinical features in patients with HCV genotype 1b (HCV-1b) infection. METHODS: A total of 42 naive patients who had chronic HCV-1b infection were treated with IFN alpha-2b 3 MU or 5 MU three times weekly plus RBV for 24 weeks. Hepatic IFNAR2c mRNA was quantified by real-time RT-PCR. RESULTS: There was no significant difference in the mean expression level of IFNAR2c mRNA between patients with sustained virological response (SVR) and non-SVR (0.069 +/-0.042 versus 0.053 +/-0.033, P=0.182). Multiple linear regression analysis showed that lower fibrosis scores (P=0.006) and younger age (P=0.03) were associated with hepatic IFNAR2c mRNA expression with r2=0.34. CONCLUSIONS: Hepatic IFNAR2c mRNA expression may not be useful for predicting the response to IFN plus RBV therapy in patients with HCV-1b infection, but appeared to correlate inversely with the fibrosis stage and age.

Adult↗
PubMed2006

Expression of type I interferon receptor as a predictor of clinical response to interferon-alpha therapy of gastrointestinal cancers.

Interferon (IFN) is used in the treatment of many malignancies and viral disorders. We recently reported a significant correlation between the efficacy of IFN-alpha combined with chemotherapy in the treatment of advanced hepatocellular carcinoma (HCC) and IFN-alpha/type I IFN receptor (IFNAR2) expression. It is possible that the expression of IFNAR2 in gastrointestinal cancerous tissue, apart from HCC, may predict the efficacy of IFN-alpha combination therapy. We investigated the expression of IFNAR2 in 100 gastrointestinal cancerous tissues. IFNAR2 expression was examined using immunohistochemistry, in surgically resected tissue samples (20 esophageal, 20 gastric, 20 colorectal, 20 cholangiocarcinoma, and 20 pancreatic samples). The expression rate of IFNAR2 was 35.0% (7/20), 25.0% (5/20), 20.0% (4/20), 45.0% (9/20), and 25.0% (5/20) in esophageal, gastric cancer, colorectal, cholangiocarcinoma and pancreatic cancer samples, respectively. In our previous report, the expression rate of IFNAR2 in HCC samples was 64.8% (59/91). Thus, the expression rates of IFNAR2 in the five types of gastrointestinal cancers tested here were low, compared with HCC. The clinical efficacy of IFN-alpha mono- or combination therapies in patients with gastrointestinal neoplasms is expected to be lower than in patients with HCC based on the expression level of IFNAR2.

Gastrointestinal Neoplasms↗
PubMed1991

Minimal residual disease in patients with chronic myelogenous leukemia undergoing long-term treatment with recombinant interferon alpha-2b alone or in combination with interferon gamma.

Interferon (IFN) therapy has become widely used for the treatment of chronic myelogenous leukemia. Hematologic remissions can be induced in about 60% of patients. Moreover, in a small number of patients loss of the Philadelphia (Ph) chromosome and of the BCR-ABL rearrangement is observed. We have used genomic Southern blotting as well as a two-step polymerase chain reaction (PCR) method to score for BCR-ABL messenger RNA (mRNA) in patients with hematologic remission induced by treatment with IFN alpha-2b alone or in combination with IFN gamma. Concomitantly, cytogenetic analysis was performed. In 11 of 115 patients reported here, a complete loss of rearranged BCR fragments was observed in Southern blots of peripheral blood (PB) and/or bone marrow (BM) cell samples. Malignant marker bands disappeared first in the PB. In six patients, this genotype remained stable, whereas in five patients, low-intensity, rearranged bands reappeared despite continuation of treatment. The reappearance of the malignant marker was not accompanied by a clinical relapse. Ph-negative metaphases were observed in PB cells of four patients and in the PB and BM cells of two of these patients. In the samples of the other patients, residual Ph-positive cells were detected. By two-step PCR, residual BCR-ABL rearranged transcripts were found in samples of 10 patients.

Adult↗
PubMed1989

Anti-interferon antibodies to interferon-alpha 2b: results of comparative assays and clinical perspective.

Previous studies have reported a low (less than 3%) incidence of anti-interferon (IFN) serum neutralizing antibodies following treatment with IFN-alpha 2b. Since this result contrasts with a higher incidence reported with IFN-alpha 2a, the question has been raised whether differences in assay techniques and patient comparability rather than inherent differences in the molecules might account for the reported differences in antibody incidence. In this report two patient groups, 151 hairy cell leukemia (HCL) patients and 101 patients with other malignancies, who have received long-term dosing with IFN-alpha 2b, are reported. The sera of both groups were studied before, during and after treatment by various assay methodologies. Utilizing three assay techniques, a less than 3% overall incidence of serum antibody formation was confirmed in these retested samples. With over 575 samples tested in multiple assays, the radioimmunoassay, as utilized in prior reports, demonstrated 99% agreement with a bioassay. Therefore, prior speculation that the assay technique for IFN-alpha 2b might produce a high false-negative rate was disproven. Additionally, the clinical outcome of these patients also failed to demonstrate a pattern of clinical relapse. In summary, these new analyses confirm the low (less than 3%) incidence of neutralizing antibody development following treatment with IFN-alpha 2b and confirm that no high rates of clinical relapse have developed in patients treated with chronic long-term dosing. Assay methodology does not appear to be a likely explanation for the low incidence of antibody formation reported with IFN-alpha 2. Rather, the unique molecular structure and pharmaceutical formulation of IFN-alpha 2b remains the most likely explanation of its minimal antigenicity.

Antibodies↗
PubMed1989

Alpha interferon treatment in HIV infected patients restores gamma interferon production in vitro.

We studied gamma interferon (IFN) production in vitro by lymphocytes from 5 patients with AIDS and 2 with advanced AIDS-related complex (ARC) before and during treatment with r-alpha 2a IFN at low doses, for up to 12 months. Patients were divided in responders (three) and non responders according to clinical data after six months of treatment. No immunological parameter was predictive of the clinical results. We found that subpopulations of T lymphocytes and lymphoproliferative response were not significantly modified in responders, while severely decreased in non responder patients. In 5/7 cases we observed a small but significant increase of gamma IFN production after six months of therapy, which rose to normal values after 12 months in responders.

AIDS-Related Complex↗
PubMed1989

Antibodies to interferon-alpha 2 in patients treated with interferon-alpha 2 for hairy cell leukemia.

Some patients treated with interferon (IFN) have developed antibodies (ABs) to that IFN. We examined the incidence of such ABs in hairy cell leukemia (HCL) patients treated with IFN-alpha 2a and IFN-alpha 2b. In the initial enzyme-linked immunosorbent assay (ELISA) assays, the serum samples were tested against their corresponding IFNs. Of 73 evaluable patients treated with IFN-alpha 2b, 6 patients, who tested negative prior to treatment, were positive by ELISA following treatment with IFN. Two of the samples tested positive in the neutralization assay. Regarding the samples from patients treated with IFN-alpha 2a, 2 of the 44 patients were ELISA positive following IFN treatment (while being negative prior to treatment) and 2 others became positive in the neutralization assay following IFN treatment. Five serum samples with neutralizing activity were tested for their ability to bind to each of eight natural IFN-alpha species derived from human lymphoblastoid cells induced with Sendai virus; a different cross-reactivity profile was seen for each sample. In conclusion, a low incidence of neutralizing and nonneutralizing ABs against IFN-alpha 2 was observed in patients with HCL treated with recombinant DNA-derived IFN-alpha 2a or IFN-alpha 2b. Finally, ABs against these IFNs cross-react by ELISA with several naturally occurring IFN-alpha s.

Antibodies↗