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PubMedDate not supplied

Resistance to recombinant alpha interferon therapy in idiopathic mixed cryoglobulinemia: reinduction of remission by natural alpha interferon both in antibody-positive and -negative patients.

A subset of patients treated with recombinant interferon alpha-2a (rIFN-alpha 2a) for idiopathic mixed cryoglobulinemia (IMC) developed clinical resistance to therapy after a sustained response. Neutralizing antibodies to rIFN-alpha 2a were found in the sera of three out of four such patients, and in none of the patients who remained responsive to treatment. rIFN-alpha 2a neutralizing antibodies appeared in serum samples of the former three patients 1, 5 and 6 months before evidence for clinical resistance, respectively. Antibody titres to rIFN-alpha 2a were consistently higher than those to natural interferon (nIFN). In the fourth patient with clinical resistance, neutralizing antibodies could not be detected by a very sensitive bioassay in any of several serum samples taken before and after relapse. All the four patients could be reinduced into remission by the administration of nIFN-alpha. These data indicate that mechanisms other than the production of neutralizing antibodies can mediate acquired resistance to IFN therapy. Furthermore, both antibody-related and -unrelated resistance can be overcome by switching to different species of IFN-alpha.

Antibodies↗
PubMed1993

Inhibition of interferon-gamma-induced major histocompatibility complex class II gene transcription by interferon-beta and type beta 1 transforming growth factor in human astrocytoma cells. Definition of cis-element.

To address mechanisms by which cytokines inhibit interferon-gamma (IFN gamma)-induced gene expression in astrocytic cells, we have been studying effects of type beta 1 transforming growth factor (TGF beta 1) and interferon-beta (IFN beta) on IFN gamma-induced expression of the well-characterized human major histocompatibility complex (MHC) class II gene DRA. This investigation was motivated by the observations that IFN gamma-induced expression of MHC class II antigen expression on astrocytic cells can be blocked in a tissue-specific fashion by several cytokines and neurotransmitters in tissue culture and that astrocyte expression of MHC class II is severely restricted in vivo. We previously showed that IFN beta inhibited IFN gamma-induced DRA expression at the transcriptional level. This inhibition was not global, since IFN gamma-induction of intercellular adhesion molecule-1 was not affected. Here, TGF beta 1-mediated inhibition of DRA is shown to exhibit similar characteristics. To address the mechanism of this inhibition, sequence requirements for IFN beta and TGF beta 1 to suppress IFN gamma-induced transcription of DRA were determined. A 135-base pair DRA sequence element containing the IFN gamma-responsive region and transcriptional start site was sufficient to direct IFN beta- or TGF beta 1-mediated suppression of a reporter gene. These experiments suggested that either IFN beta or TGF beta 1 could repress IFN gamma-induced DRA transcription directly, without requiring a cis-element extrinsic to the IFN gamma-inducible DRA sequences. Consistently similar effects of IFN beta and TGF beta 1 observed in these experiments prompted comparison of other gene regulatory effects of the two cytokines. TGF beta 1, unlike IFN beta, induced gene expression directed by upstream elements of the gene encoding plasminogen activator inhibitor type-1. IFN beta, unlike TGF beta 1, enhanced levels of 2'-5'-oligoadenylate synthetase activity. Additionally, direct assay of TGF beta 1 and monoclonal anti-TGF beta antibody blocking experiments were used to determine that cells treated with IFN beta did not produce increased amounts of active or latent TGF beta. These data argued that IFN beta and TGF beta 1 utilized distinct pathways to mediate the inhibition of IFN gamma-induced DRA transcription.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

[Histologic forms of chronic hepatitis and response to interferon treatment. Clinical effectiveness of interferon alpha and beta treatment compared with chronic active viral hepatitis of various histologic grades].

The authors evaluated the clinical response to treatment with interferons in relation to chronic virulent hepatitis, different on histological level. All the interferons until now commercially available have been employed following a casual standard of choice. The results underlined a certain therapeutic success in 70% with a clinical answer in course of therapeutic preservation; and a failure rate of 30%.

Adolescent↗
PubMed1994

Interferon and retinoic acid suppress the growth of human papillomavirus type 16 immortalized cervical epithelial cells, but only interferon suppresses the level of the human papillomavirus transforming oncogenes.

In the present study, we examine the effects of all-trans-retinoic acid (RA) and interferons-alpha and -gamma (IFN-alpha and IFN-gamma) on the growth of HPV16-immortalized cell lines, ECE16-1 and CaSki. Treating proliferating ECE16-1 cells with RA causes a concentration-dependent decrease in cell number. At 1 microM RA, cell growth is suppressed by 65% and the level of mRNA encoding cytokeratin K5, a biochemical marker of retinoid action, is also suppressed. In contrast, the level of transcript encoding the HPV16 oncogenes, E6 and E7, is reduced by only 5 to 10%. IFN-alpha at 1000 IU/ml or IFN-gamma at 200 IU/ml suppresses growth by 70%. This growth suppression by IFN-gamma is correlated with a > 90% reduction in E6/E7 mRNA levels. Additional growth suppression is observed upon simultaneous treatment with retinoid and interferon. Optimal suppression is observed in the presence of 200 IU/ml IFN-gamma and 1 microM RA. The rank order of effectiveness is IFN-gamma/RA > IFN-alpha/RA = IFN-gamma > RA > IFN-alpha. In contrast to the suppression of ECE16-1 cell growth, RA causes a concentration-dependent increase in CaSki cell number (50-60%) which is optimal at 1 microM RA. Cytokeratin K5 mRNA levels are markedly suppressed, and E6/E7 mRNA levels increased by 5% under these conditions. IFN-alpha at 1000 IU/ml or IFN-gamma at 200 IU/ml decreases CaSki cell growth by 20 and 45%, respectively, and 200 IU/ml of IFN-gamma reduce E6/E7 expression to undetectable levels. Addition of RA (1 microM) partially counters the IFN-dependent suppression of growth and E6/E7 mRNA levels. Our results suggest that retinoid-dependent changes in human papillomavirus-immortalized cervical cell proliferation are not always correlated with changes in E6/E7 transcript levels.

Animals↗
PubMed1993

[Interferons. Interferons alpha and gamma: indications in systemic diseases].

Interferon alpha (INF-alpha)--In systemic diseases, most indications for INF-alpha result from its effect on haematological or hepatological manifestations. The spectacular effect of INF-alpha in chronic myeloid leukemia has led to its use for the treatment of hypereosinophilia syndrome and systemic mastocytosis. Over the last 6 years, we have treated 7 patients with the hypereosinophilia syndrome who were resistant to corticotherapy and had markers of myeloproliferation. Although both hydroxyurea and INF-alpha can be effective alone, their combination led to a decrease in the eosinophilia count to 1,000/ml, a decrease which was long-lasting in most cases. INF-alpha is also used in histiocytosis X alone or in combination with retinoids or with etoposide and has been found effective in several observations. In carcinoid syndromes whether treated priorly or not with a 5-fluoro-uracil-streptozoticin combination, INF-alpha leads to an objective response in two-thirds of the patients. Several multicentric protocols are currently assessing the efficacity of INF-alpha in mixed cryoglobulinaemias. In most observations these cryoglobulinaemias are seen in patients with markers of hepatitis C (mainly HCV) and the early results are encouraging. Temporary improvement has been reported in discoid or subacute lupus in 8 out of 10 cases. Haemangiomas of the infant, when life-threatening and corticoresistant, may be a good indication for INF-alpha. Thus 20 newborns or infants (including 4 with Kasabach-Merrit syndrome) have been treated with good results in 18. Interferon gamma (INF-gamma).(ABSTRACT TRUNCATED AT 250 WORDS)

Hematologic Diseases↗
PubMed1993

Virus-mediated induction of interferon A gene requires cooperation between multiple binding factors in the interferon alpha promoter region.

Transcriptional activation of interferon A (IFNA) gene in virus-infected cells is controlled by a 35-nucleotide inducible element that is cell type specific. Within this region, two elements, alpha F1 and IRF-1 binding sites, were shown by mutation analysis to play a crucial role in the expression of inducible element. In this study, we have analyzed the binding of nuclear proteins to the alpha F1 sequence and have shown that the induction is associated with the formation of a novel complex alpha F1/B, which contains at least two DNA binding proteins of 68 and 96 kDa. In contrast, no binding of the purified interferon regulatory factor 1 (IRF-1) either to the alpha F1 or IRF-1 binding sites could be detected in vitro. However, the oligonucleotides corresponding to alpha F1 or IRF-1 binding sites competed efficiently for the induction of IFNA4 promoter region in a transient transfection assay. We suggest that the induction of IFNA promoter region requires cooperation between alpha F1 binding proteins and IRF-1. Interestingly, our data also show that the inability of IFNA6 promoter to be expressed in infected L-cells may be a result of a viral-induced repressor, which could act by binding and inactivating alpha F1 or by competing for the IRF-1 binding site. These results suggest that cell-specific expression of IFNA genes results from core-cruitment of trans-acting factors that bind to alpha F1 and the IRF-1 binding site with the cell-specific virus-induced activator or repressor.

Animals↗
PubMed1997

Differential effects of human interferon alpha and interferon gamma on xenografted human thyroid tissue in severe combined immunodeficient mice and nude mice.

We have studied the in vivo effects of human interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) administration on human thyroid tissue xenografted into two mouse strains: severe combined immunodeficient (SCID) mice and nude mice. Human lymphocytes survive in SCID mice but are lysed in nude mice. Thyroid tissues from Graves' disease or Hashimoto's thyroiditis, or paranodular [normal, (N)] tissue was xenografted into SCID mice (0.8 g/mouse) pretreated with anti-asialo GM-1 antiserum and radiation and also into nude mice. One week after xenografting, SCID and nude mice were divided into three groups. Group A was treated with IFN-alpha intraperitoneally (2,000 units/mouse) three times weekly; group B was treated with IFN-gamma similarly; group C was treated with phosphate buffered saline (PBS) only (control). Autologous human peripheral blood mononuclear cells (PBMCs) were added to mice receiving N xenografts. Blood was taken every 2 weeks for levels of IgG and thyroid antibodies (TAb). After 6 weeks of treatment, mice were sacrificed, and xenograft thyrocyte histocompatibility leukocyte antigen (HLA-DR) and intercellular adhesion molecule (ICAM-1) expression were measured. In addition, thyrocyte cultures were stimulated in vitro with 200 units/ml of either IFN-alpha or IFN-gamma or PBS (control). SCID mice xenografted with autoimmune thyroid disease (AITD) in group A showed a significantly higher TAb production than group C, whereas in group B, TAb production was not statistically increased compared to control (group C). SCID mice xenografted with N did not produce TAb in any group, nor did nude mice xenografted with AITD. Thyrocyte HLA-DR expression was markedly increased in group A and B in SCID mice xenografted with Graves' disease, Hashimoto's thyroiditis, and N tissue compared to group C. In contrast, only group B (IFN-gamma) showed an increase in thyrocyte HLA-DR in nude mice. In the in vitro studies, only IFN-gamma (not IFN-alpha) stimulated thyrocyte HLA-DR and ICAM-1 expression in Graves' disease, Hashimoto's thyroiditis, and N tissues. We concluded that in SCID mice, IFN-alpha causes TAB production in AITD xenografts but not in N xenografts, while increasing thyrocyte HLA-DR expression in both. Also, IFN-gamma does not cause a statistically increased TAb in AITD xenografts in SCID mice, despite a sharp rise in thyrocyte HLA-DR expression. In addition, because IFN-alpha has no effect in nude mice or in vitro on thyrocyte HLA-DR expression, its effects in SCID mice must be mediated via local infiltrating lymphocytes. Finally, IFN-gamma has a direct effect on thyrocytes to increase HLA-DR expression (and, in vitro, ICAM-1 expression) but may not stimulate TAb production.

Adolescent↗
PubMed1997

Interferon plus ursodeoxycholic acid versus interferon in the treatment of chronic C viral hepatitis.

BACKGROUND: The aim of as study was to ascertain whether the association of interferon alpha-2a and ursodeoxycholic acid (IFN+UDCA) was more efficacious in ameliorating liver parameters than interferon (IFN) alone in patients with chronic hepatitis C. METHODS: Forty-one chronic hepatitis C patients, who had at least twice the normal value of one transaminase, were randomly assigned to treatment with IFN + UDCA (n = 21) or IFN alone (n = 20). IFN was administered subcutaneously at a dose of 3 MU thrice weekly, UDCA orally at 10 mg/kg bw/day. IFN therapy was terminated 6 months later and the responders (normalized transaminases) of both groups were treated with UDCA alone for a further 12 months. RESULTS: In the IFN + UDCA group there were 2 drop-outs from therapy and 11 responders, while in the IFN group they were, respectively, 3 and 10. Transaminases normalized after the first month of treatment in 7/11 responders with IFN + UDCA compared with 3/10 in the IFN responders group. The trend to normalization was more rapid with IFN + UDCA than with IFN alone (chi 2t = 3.95; p < 0.05). Disease relapse (defined as at least one transaminase > x 1.5 the normal value) was 3/11 in the IFN + UDCA group and 4/10 in the IFN group. 2/11 responders in the IFN + UDCA and 1/10 in the IFN group were HCV RNA negative by PCR. The total Knodell histological score decreased more in the IFN+UDCA than in the IFN group (-2.67 +/- 3.44. vs -1.67 +/- 2.16, mean +/- SD). CONCLUSIONS: The administration of UDCA determine an earlier normalization-time of transaminases in the patients responders to IFN therapy and could be useful to reduce the relapse into disease after the IFN therapy.

Adolescent↗
PubMed1995

Antagonism of interferon beta on interferon gamma: inhibition of signal transduction in vitro and reduction of serum levels in multiple sclerosis patients.

Interferon gamma (IFN-gamma acts as a mediator of multiple sclerosis (MS) exacerbations through a number of biological effects, such as induction of major histocompatibility class II complexes (MHC-II), macrophage activation and potentiation of tumor necrosis factor (TNF-alpha). The clinical efficacy of interferon beta (IFN-beta) therapy in reducing exacerbations of relapsing-remitting MS has been related to antagonistic effects on various activities of IFN-gamma, including MHC-II gene induction. However, there is no model to explain such antagonistic effects of IFN-beta and IFN-gamma, and the two cytokines are also known to act synergistically against viruses and in the induction of MHC-I. We show that IFN-beta does inhibit an immediate molecular event of IFN-gamma, namely activation and DNA binding of the transcription factor Stat1. We propose a model of direct interference of the IFN-gamma and IFN-alpha,beta signal transduction pathways accounting for antagonistic effects on some genes, which in turn activate MHC-II transcription, as well as for synergistic effects on other genes. In addition, study of MS patients treated with natural IFN-beta shows that IFN-beta significantly reduces serum levels of IFN-gamma while increasing IL-4, strongly suggesting that IFN-beta also controls the relative activation of TH1- and TH2-type T lymphocytes.

Adjuvants, Immunologic↗
PubMed1998

Fas/APO-1 (CD95)-mediated apoptosis is activated by interferon-gamma and interferon- in interleukin-6 (IL-6)-dependent and IL-6-independent multiple myeloma cell lines.

A poor response to Fas-induced apoptosis is evident in some multiple myeloma (MM) cell lines and primary cells. In this study, we have examined the possibility to increase the sensitivity to Fas-induced apoptosis by pretreatment of MM cells with interferon-gamma (IFN-gamma) or interferon-alpha (IFN-alpha). Both IFN-gamma and IFN-alpha markedly increased the Fas-induced apoptosis in all cell lines tested (U-266-1970, U-266-1984, and U-1958). In the U-266-1970 and U-1958 cell lines, pretreatment with either IFN-gamma or IFN-alpha also inhibited proliferation in a dose-dependent manner. In contrast, IFN-gamma activation of the Fas death pathway in the U-266-1984 cells was not accompanied by growth inhibition. Incubation with the IFNs increased the Fas antigen expression in one of three cell lines but did not alter the expression of Bcl-2 or Bax. The IFNs are important regulators of growth and survival in MM cells. Our results suggest that activation of Fas-mediated apoptosis is a novel mechanism by which the IFNs exert inhibitory effects on MM cells.

Apoptosis↗
PubMed1998

Prospective randomized multicenter clinical trial on the use of interferon -2a plus acitretin versus interferon -2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II.

Cutaneous T-cell lymphoma (CTCL) constitutes a malignant proliferative disease involving mostly CD4(+) T cells arising in the skin. Because of the lack of curative treatment options, interferons (IFN) have been introduced into the therapy of CTCL. Although effective even in advanced disease, response rates were about 50% and the duration of response was short. To improve the results of interferon monotherapy, combinations of IFN with oral photochemotherapy (PUVA) or retinoids were investigated in nonrandomized trials showing higher response rates. We have therefore conducted this prospective randomized multicenter trial to compare these two combination therapies, ie, IFN plus PUVA and IFN plus acitretin. IFN -2a was administered at 9 MU three times weekly subcutaneously in both groups, with lower increasing doses during the first week. Photochemotherapy was applied after oral intake of 8-methoxypsoralen (0.6 mg/kg body weight) 5x weekly during the first 4 weeks, 3x weekly from weeks 5 through 23, and 2x weekly from weeks 24 through 48, with escalating doses beginning with 0.25 J/cm2. Twenty-five milligrams of acitretin was administered daily during the first week, and 50 mg was administered from weeks 2 through 48. Of 98 patients randomized in this study, 82 stage I and II patients were evaluable: 40 in the IFN+PUVA group and 42 in the IFN+acitretin group. With 70% complete remissions in the IFN+PUVA group, this treatment was significantly superior to the IFN+acitretin group with only 38.1% complete remissions. Time to response was significantly shorter in the IFN+PUVA group, with 18.6 weeks compared with 21.8 weeks in the IFN+acitretin group. Side effects were mostly mild to moderate and did not differ significantly in both treatment groups. However, there were more adverse events leading to study discontinuation in the IFN+acitretin group. Based on these findings, we conclude that IFN plus oral photochemotherapy is superior to IFN plus acitretin, inducing more complete remissions in patients with CTCL stages I and II.

Acitretin↗
PubMed1998

Regulation of the interferon system, immune response and oncogenesis by the transcription factor interferon regulatory factor-1.

Interferon regulatory factor-1 (IRF-1) is a transcriptional activator which was originally identified as the regulator of the type I interferon (IFN-alpha/beta) gene expression. Subsequent studies have revealed that IRF-1 is involved in a wide spectrum of the host defense mechanisms, including the antiviral response by IFNs. IRF-1 has also been shown to regulate a variety of cytokines and their target genes, thereby contributing to the development and function of the Th1-type immune response. Furthermore, IRF-1 is a critical regulator of cell growth and death, and its inactivation accelerates cell transformation. IRF-1 may be a prototypical example of a transcription factor which can selectively modulate distinct sets of genes depending on the cell type and/or nature of the cellular stimuli, so as to evoke appropriate response in each.

Animals↗
PubMed1999

Interferon-gamma secretion by peripheral blood T-cell subsets in multiple sclerosis: correlation with disease phase and interferon-beta therapy.

Interferon-gamma (IFN-gamma) is implicated as a participant in the immune effector and regulatory mechanisms considered to mediate the pathogenesis of multiple sclerosis (MS). We have used an intracellular cytokine staining technique to demonstrate that the proportion of ex vivo peripheral blood CD4 and CD8 T-cell subsets expressing IFN-gamma is increased in secondary progressing (SP) MS patients, whereas the values in untreated relapsing-remitting (RR) MS patients are reduced compared with those of controls. Patients treated with interferon-beta (IFN-beta) have an even more significant reduction in the percentage of IFN-gamma-secreting cells. The finding that the number of IFN-gamma-expressing CD8 cells is increased in SPMS patients, a group with reduced functional suppressor activity, and is most significantly reduced by IFN-beta therapy, which increases suppressor activity, indicates that IFN-gamma secretion by CD8 T cells and functional suppressor defects attributed to this cell subset in MS can be dissociated.

Adult↗
PubMed1997

The short form of the interferon alpha/beta receptor chain 2 acts as a dominant negative for type I interferon action.

We have characterized the functional properties of the short form of the human interferon alpha/beta receptor chain 2 (IFNAR2), denoted IFNAR2.1. IFNAR2.1 contains a shortened cytoplasmic domain when compared with the recently cloned full-length IFNAR2 chain (IFNAR2. 2). We show that IFNalpha8 and IFNbeta1b induce antiviral and antiproliferative activity in mouse cell transfectants expressing the human IFNAR1 chain of the receptor and induce the formation of STAT1/STAT2 dimers in IFN-stimulated response element (ISRE)-dependent gel shift assays. In contrast, coexpression of IFNAR2.1 with IFNAR1 reduces the IFN-induced antiviral, antiproliferative and ISRE-dependent gel shift binding activity conferred by IFNAR1 alone. No antiviral or antiproliferative response to IFN, nor IFN-induced ISRE-dependent gel shift binding activity, was observed when IFNAR2.1 was expressed alone in murine cells. Therefore, IFNAR2.1 acts as a dominant negative for these IFN-induced activities. Our results suggest that IFNAR2.1 represents a nonfunctional version of the full-length chain (IFNAR2.2).

Animals↗
PubMed1994

Molecular interactions between interferon consensus sequence binding protein and members of the interferon regulatory factor family.

Interferon (IFN) consensus sequence binding protein (ICSBP) is a transcription factor expressed mostly in the cells of the immune system. ICSBP belongs to the IFN regulatory factor (IRF) family, which also includes IRF-1, IRF-2, and the IFN-alpha-stimulated gene factor 3 gamma (ISGF3 gamma). We show here that ICSBP forms a complex with IRF-1 or IRF-2 both in vivo and in vitro and, in the presence or absence of the target DNA, with the IFN-stimulated response element (ISRE). Further, electrophoretic mobility shift assays show that this interaction greatly enhances the otherwise very low binding affinity of ICSBP to the ISRE. We show, on the other hand, that ICSBP inhibits binding of the IFN-alpha-stimulated gene factor 3 gamma to the ISRE. Through these interactions ICSBP is likely to exert complex modulatory functions in the regulation of IFN-stimulated genes.

Base Sequence↗
PubMed1986

Synergistic antiproliferative effects of human recombinant alpha 54- or beta ser-interferon with gamma-interferon on human cell lines of various histogenesis.

The antiproliferative effects of human interferon (IFN), IFN-gamma, IFN-alpha 54, and IFN-beta ser, alone and in combination, were assessed on 10 human cell lines. All IFNs were produced by recombinant technology and purified to homogeneity. In all cell lines except one, the addition of IFN-gamma to either IFN-alpha 54 or IFN-beta ser resulted in a synergistic antiproliferative effect, regardless of individual IFN sensitivities or tissue of origin. The only exception was a normal diploid fibroblast cell in which an additive antiproliferative effect occurred with combination IFN treatment. A malignant fibrosarcoma cell line of similar mesenchymal origin demonstrated a synergistic antiproliferative effect. One cell line was sensitive to both type I and type II IFN alone. Three cell lines were relatively resistant to IFN-gamma but not to IFN-beta ser, one was relatively resistant to IFN-beta ser but not to IFN-gamma, and the remainder were resistant to both IFN-gamma and IFN-beta ser or IFN-alpha 54. The addition of IFN-alpha 54 to IFN-beta ser in the SKCO 1 cell line resulted in an antagonistic interaction. Timing experiments with RT112 cells indicate that IFN-gamma and IFN-beta ser need not be in the media at the same time for the synergistic effect to occur. Combinations of type I and type II IFN thus resulted in synergistic antiproliferative effect for transformed human cells of various histogenesis, including some with a relative resistance to one or both IFN types.

Cell Cycle↗