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PubMed1991

Low serum levels of alpha-interferon, gamma-interferon, and interleukin-2 in alcoholic cirrhosis.

The existence of cellular immune deficit in alcoholic cirrhosis, together with the role of alpha- and gamma-interferon and interleukin-2 in the immune system, led us to compare serum levels of these immune system mediators in a group of 40 patients with alcoholic cirrhosis classified according to Child-Pugh's grade of severity of liver disease and 23 healthy volunteers. Serum levels of alpha-IFN, gamma-IFN, and IL-2 were significantly depressed in alcoholic cirrhotics, with no significant differences between the different degrees of hepatic damage. The results suggest a profound alteration in the immune system of alcoholic cirrhotics, which may contribute to the development of the disease and the accompanying immune system deficit.

Female↗
PubMed1994

Isolation and characterization of a novel mutant mouse cell line resistant to Newcastle disease virus: constitutive interferon production and enhanced interferon sensitivity.

In our attempt to isolate mutant cell lines resistant to Newcastle disease virus (NDV) we developed an improved procedure for enrichment of NDV-resistant cells from mouse FM3A cells and isolated a novel NDV-resistant mutant cell line, Had-2, with characteristics different from Had-1, a previously reported NDV-receptor-deficient mutant strain. Had-2 cells adsorbed NDV normally but the accumulation of viral mRNAs and proteins was inhibited. Had-2 cells had to be grown at higher cell densities in order to be NDV-resistant, and it was revealed that they did not exhibit NDV-resistance when grown at lower cell densities. A conditioned medium prepared from a culture of Had-2 cells grown at high cell density was able to make a low-density culture NDV-resistant. The activity of the conditioned medium to induce NDV-resistance was completely neutralized by addition of both anti interferon (IFN)-alpha and anti IFN-beta antibodies, indicating that Had-2 cells were constitutively releasing IFNs, though their levels were rather low. Had-2 cells were also characterized by an increased sensitivity to IFNs as compared with the parental FM3A cells, since the conditioned medium containing IFNs did not render FM3A cells resistant to NDV.

Animals↗
PubMedDate not supplied

Ribavirin enhances interferon-gamma levels in patients with chronic hepatitis C treated with interferon-alpha.

Some patients with chronic hepatitis C respond to interferon (IFN)-alpha treatment, and the efficiency can be improved by combining it with ribavirin. The mechanism of this improvement is unknown. To investigate the effects of these two regimens on the immune responses in 51 patients with chronic hepatitis C, we examined the hepatitis C core antigen-specific proliferative response and cytokine production profiles, natural killer (NK) cell cytotoxicity and cytotoxic T cell function during treatment. The results are as follows: (1) both viral clearance and biochemical normalization occurred more frequently in patients receiving combination therapy; (2) the function of NK cells increased after treatment in the responders of both groups (p < 0.05); (3) the level of IFN-gamma produced by hepatitis C core antigen-stimulated peripheral blood mononuclear cells was higher in patients receiving combination therapy, especially in responders; (4) the core antigen-specific proliferative response decreased after treatment, and (5) in addition, the core-specific cytotoxic T cell activities of five responder patients also increased significantly after therapy. In conclusion, enhancement of immune responses, especially those related to type-1 T helper cell activity, may contribute to better efficacy in combining ribavirin with IFN-alpha for treatment of chronic hepatitis C.

Adult↗
PubMed1996

Incidence and in-vivo relevance of anti-interferon antibodies during treatment of low-grade cutaneous T-cell lymphomas with interferon alpha-2a combined with acitretin or PUVA.

Interferon-alpha combined with retinoid or PUVA is used for the treatment of cutaneous T-cell lymphoma. Anti-IFN-alpha antibodies (IFN ab) occur regularly during IFN-alpha treatment. We investigated the incidence of neutralizing and binding IFN ab and analysed their relationship with clinical and immunological parameters. A group of 17 CTCL patients were treated with IFN alpha-2a three times weekly subcutaneously at a dose of 3 Mill. I.U. combined either with retinoid (acitretin, Neotigason; 0.5 mg/kg bodyweight) daily or with 5-methoxypsoralen (1.2 mg/kg bodyweight) plus UVA radiation three times weekly. Prior to and during treatment we monitored stage, skin involvement by a tumour burden index, serum levels of beta 2-microglobulin, neopterin, binding and neutralizing IFN ab, Interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2r) and the CD4/CD8 ratio of peripheral blood mononuclear cells. We observed two complete, two partial and six minor responses, four patients with stable disease and three patients with progressive disease. Of the 17 patients, 7 developed binding IFN ab, but only 2 had neutralizing IFN ab which were associated with high titres of binding IFN ab. IFN ab formation was more frequent in patients with normal CD4/CD8 ratios and a high tumour burden index and showed a trend to be more frequent in PUVA-cotreated patients than in retinoid-cotreated patients. Responses were more frequently seen in IFN ab-negative patients. IFN ab developed in patients treated with PUVA or retinoid combined with IFN. Binding as well as neutralizing IFN ab may have an impact on the treatment success in CTCL patients.

Acitretin↗
PubMed2005

Interferon-alpha/beta upregulate IL-15 expression in vitro and in vivo: analysis in human hepatocellular carcinoma cell lines and in chronic hepatitis C patients during interferon-alpha/beta treatment.

Type I interferon (IFN) possesses antiviral and antitumor activities and also having an immune regulatory effect, activating cellular immune response and upregulating several cytokines. Recent study has shown that type I IFN upregurates the dendritic cell production of IL-15 capable of activating natural killer cells and CD8+ memory T lymphocytes. However, it is still unknown if type I IFN induces IL-15 production in non-immune cells and if type I IFN affects IL-15 production in vivo. The present study investigated the effect of type I IFNs on IL-15 expression in hepatocellular carcinoma (HCC) cell lines in vitro and in patients with chronic hepatitis C in vivo. When three HCC cell lines, Huh7, HepG2, and JHH4 were cultured in vitro, IFN upregulation of IL-15 expression was observed at both the mRNA and protein levels. In experiments using Huh7 cells, upregulation of IL-15 expression occurred within 24 h of the start of IFN stimulation, and both IFN-alpha and -beta dose-dependently increased IL-15 production in the range from 100 U/ml to 10,000 U/ml of concentration. IFN-beta showed stronger activity in IL-15 production induction in vitro than IFN-alpha. For in vivo examination, sera were obtained from 21 chronic hepatitis C patients treated with IFN and 29 healthy individuals, and the serum IL-15 level was quantified by ELISA. The serum IL-15 level of chronic hepatitis C patients before IFN treatment was similar to that of the healthy controls and significantly increased only during the IFN administration period. These results confirm that IFN-alpha/beta induce IL-15 production and also suggest that IL-15 may be associated with type I IFN-induced immune response.

Adult↗
PubMed2001

Life-threatening complications of hepatitis B virus-related polyarteritis nodosa developing despite interferon-alpha2b therapy: successful treatment with a combination of interferon, lamivudine, plasma exchanges and steroids.

Polyarteritis nodosa (PAN) is a rare vasculitis associated with hepatitis B virus (HBV) infection in a significant proportion of cases. When used to treat HBV-related PAN, immunosuppressive agents may enhance viral replication and relaspes are frequent. In recent years the use of antiviral drugs has been proposed. We report the case of a patient with HBV-related PAN who, despite 6 weeks of interferon-alpha2b (IFN-alpha2b) monotherapy, developed life-threatening complications with bowel perforation. He was thereafter successfully treated with a combination of IFN-alpha2b, lamivudine, plasma exchanges and short-term steroids. In contrast to IFN-alpha2b, lamivudine is effective in rapidly suppressing viral replication. This may be valuable in the treatment of HBV-related PAN by contributing to a faster diminution of circulating immune complex levels. This case report highlights the importance of aggressive combined therapy in patients with HBV-related PAN.

Adult↗
PubMed2003

A prospective comparison of the effect of interferon-alpha and interferon-beta treatment in patients with chronic hepatitis C on the incidence of hepatocellular carcinoma development.

To investigate differences in the effect of interferon (IFN) -alpha and IFN-beta treatment for hepatitis C on hepatocellular carcinoma (HCC) development, we prospectively followed 351 consecutive patients (median age, 56.6 years; mean follow-up, 5.7 +/- 2.6 years) with chronic hepatitis C virus (HCV) viremia. Of 260 IFN-alpha and 91 IFN-beta treated patients, 17 (6.5%) and 4 (4.4%), respectively, developed HCC. Virological response (VR) was defined as persistent HCV RNA disappearance from serum, and biochemical response (BR) as persistent alanine aminotransferase (ALT) normalization after treatment. No significant between-group differences in HCC development were found between those with and without VR. Although the HCC development rate in patients without BR was significantly higher than that in patients with BR in the IFN-alpha group (11.4% and 0.8%; P << 0.05), no significant difference was found in the IFN-beta group (6.3% and 2.3%). Similar rates of HCC development were found in patients with chronic HCV viremia treated with either IFN-alpha or IFN-beta.

Adult↗
PubMed2005

Interferon alpha-2a plus ribavirin 1,000/1,200 mg versus interferon alpha-2a plus ribavirin 600 mg for chronic hepatitis C infection in patients on opiate maintenance treatment: an open-label randomized multicenter trial.

BACKGROUND: Many intravenous opiate users are infected with hepatitis C virus (HCV) but few are treated. Although this complies with various guidelines, virtually no published evidence supports such a recommendation. PATIENTS AND METHODS: In a multicenter study, HCV-infected patients in opiate maintenance treatment programs received interferon plus high- or low-dose ribavirin (1,000/1,200 mg or 600 mg). HIV-coinfected patients were not included. Endpoints were feasibility, efficacy, side effects, and reasons for dropout. RESULTS: Of the 420 patients who tested positive for HCV, 27 (6%) were enrolled; 393 (94%) either failed to meet the inclusion criteria or refused treatment. Virologic end-of-treatment response was achieved in 12/27 patients, and sustained response in 13/27 (48%). Response depended on viral genotype, not ribavirin dose. The two doses of ribavirin did not differ in their side effects. CONCLUSION: In a small fraction of HCV-infected intravenous drug users in an opiate maintenance treatment program, antiviral therapy was feasible, safe, and effective. The success rate was comparable to that achieved in controlled studies that excluded drug users.

Antiviral Agents↗
PubMed1984

Enhanced xanthine oxidase activity in mice treated with interferon and interferon inducers.

Administration to mice of either interferon (IFN) or IFN inducers resulted in a marked increase of xanthine oxidase (XO) activity in different organs. Dose response studies revealed that serum XO was increased by administration of polyinosylic-polycyticylic acid (poly I-C) at doses as low as 0.1 mg/kg. In view of the well known ability of XO to generate superoxide radicals it is suggested that its induction might play a role in several biological effects of IFN.

Animals↗
PubMed1983

Alternative induction of alpha/beta interferons and gamma interferon by listeria monocytogenes in mouse spleen cell cultures.

Production of interferon (IFN) by Listeria monocytogenes (LM) in nonimmunized mouse spleen cell cultures was studied. IFN-gamma defined by virtue of its acid stability and antigenicity was produced in spleen cell cultures obtained from ddY mice, C57BL/6 mice, and BALB/c mice in response to heat-killed (HK) LM within 24 hr. On the other hand, production of IFN-alpha/beta was demonstrated in spleen cell cultures obtained from one of four nude mice (BALB/c, nu/nu). Therefore, it is important to know the reason why the spleen cells of mice other than nude mice did produce only IFN-gamma, but did not produce IFN-alpha/beta in response to HK-LM. Spleen cells obtained from ddY mice were fractionated, and the cellular source for IFN production of either IFN-alpha/beta or IFN-gamma induced by HK-LM was investigated. IFN-gamma was produced only by a mixture of T lymphocytes (nylon wool-nonadherent, Thy-1-positive cells) and macrophages by HK-LM. Neither T lymphocytes nor macrophages alone produced IFN by HK-LM. Macrophage-depleted spleen cells produced neither IFN-gamma nor IFN-alpha/beta, but these cells acquired the ability to produce IFN-alpha/beta, not IFN-gamma, only when they had been treated with IFN-alpha/beta. A possible mechanism of both IFN-gamma and IFN-alpha/beta induction by Listeria in mouse spleen cell cultures is discussed.

Animals↗
PubMed1986

Modulation of lymphocyte proliferation and immunoglobulin synthesis by interferon-gamma and "type I" interferons.

Interferon (IFN)-alpha and IFN-beta ("type I" IFNs), but not IFN-gamma reduced phytohemagglutinin- or pokeweed mitogen (PWM)-induced proliferation in cultures of human mononuclear leukocytes. Proliferation induced by specific antigens (tuberculin PPD or tetanus toxoid) or by exogenous interleukin 2 (IL-2) was strongly inhibited by type I IFNs and, to a lesser extent, by IFN-gamma as well. Inhibition of proliferation in mitogen-stimulated cultures was not due to a reduced production of IL-2 or to an inhibition of IL-2 receptor expression. Type I IFNs inhibited immunoglobulin (Ig) production in PWM-stimulated unseparated mononuclear cells, whereas IFN-gamma enhanced Ig production in such cultures. In cultures of purified B cells type I IFNs caused a stimulation of Ig production and this B-cell differentiation factor (BCDF)-like activity of IFNs was synergistically enhanced in the presence of IL-2. IFN-gamma produced less BCDF-like activity than type I IFNs. These results show that in some instances type I IFNs can be more potent in affecting functions of cells of the immune system than IFN-gamma.

Antibody Formation↗
PubMed1987

A unifying model of the immunoregulatory role of the interferon system: can interferon produce disease in humans?

This hypothesis is a presentation of a unifying model of the interferon (IFN) system as a cascade of sequentially interacting responses of IFNs-alpha, -beta, and -gamma involved in modulation of the immune response. We propose that every antigen is an IFNogen. The first stage(s) of immune responsiveness is associated primarily with the production of the family of IFN-alpha. In certain immunologically mediated diseases, including the autoimmune diseases and AIDS, disturbances in the synthesis of IFN-alpha occur with a switch to the production of predominantly acid-labile types, which have a negative immunoregulatory effect. Moreover, disturbances of IFN synthesis in the embryo or fetus can lead to deformities. Some viruses and other biological and chemical substances manifest a pathological effect by the IFN they induce. This IFN may help sustain the viruses and other substances which induce this IFN. We think it is unsafe to give patients immunoregulators in incomplete form. Thus, there is a potential danger in giving patients recombinant forms of IFNs and interleukin 2 produced in bacteria. In certain immune disorders, we may be able to treat patients by the binding or removal of hyperproduced IFNs from the body. This may lead to the restoration of immunologic balance and clinical improvement.

Antibody Formation↗
PubMed1994

A novel member of the interferon receptor family complements functionality of the murine interferon gamma receptor in human cells.

Expression of the human interferon gamma receptor (IFN-gamma R) in mouse cells is not sufficient to confer biological responsiveness to human IFN-gamma and vice versa. An additional species-specific component is required for signal transduction. We identified this cofactor by expression cloning in simian COS cells stably transfected with the nonfunctional murine IFN-gamma R and a IFN-gamma-inducible reporter construct encoding the human Tac antigen (interleukin-2 receptor alpha chain, CD25). A cDNA clone was obtained that, upon stable transfection, rendered human HEp-2 cells expressing the murine IFN-gamma R fully responsive to murine IFN-gamma. This cDNA encodes a novel 332 amino acid type I transmembrane protein that belongs to the IFN receptor family and that we designate IFN-gamma R beta chain.

Amino Acid Sequence↗
PubMed1993

Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis.

Interferons (IFN) are biological molecules with anti-viral, anti-proliferative and immunomodulatory actions. There is evidence that IFN-gamma increases the frequency of exacerbations of multiple sclerosis (MS) whereas IFN-beta may reduce their frequency. Here we present evidence that IFN-beta significantly decreases concanavalin A (Con A)-induced proliferation of peripheral blood mononuclear cells (PBMC) of MS patients and healthy individuals. Similar results were obtained when PBMC were activated through the T cell receptor (TcR) by anti-CD3 monoclonal antibody or independently of it by phorbol ester and Ca2+ ionophore. These effects of IFN-beta were also noted when IFN-gamma and IFN-beta were added together. Furthermore, IFN-beta decreased proliferation when added to cells that were already pre-activated. Activated CD4+ and CD8+ T cells were downregulated to approximately the same extent. Analysis of cytokine production showed that IFN-gamma production by Con A activated PBMC was increased in MS when compared to controls. IFN-beta significantly decreased IFN-gamma production in MS patients and control individuals. Con A activated cultures treated with IFN-beta showed decreased IL2R expression and accumulation of IL2. These results show that IFN-beta decreases T cell activation and IFN-gamma production in vitro, effects that may be beneficial in MS.

Adult↗
PubMed1995

Interferon-beta downregulates interferon-gamma-induced class II MHC molecule expression and morphological changes in primary cultures of human brain microvessel endothelial cells.

Regulation of class II MHC (Ia) antigen expression by interferons beta and gamma was studied in an in vitro model of the blood-brain barrier. Primary cultures of human brain microvessel endothelial cells were incubated with IFN-beta, gamma or a combination of the two cytokines and surface expression of class II MHC molecules was investigated with the immunogold silver staining technique and enzyme-linked immunosorbent assay. Treatment of monolayers with IFN-beta (100-6000 U/ml) failed to induce Class II MHC molecules. Co-incubation with IFN-gamma (100 U/ml), with or without pretreatment with IFN-beta, significantly inhibited the IFN-gamma-induced de novo expression in a concentration-dependent manner. Downregulation was less significant when incubation with both cytokines was preceded by 2-day treatment with IFN-gamma and was not observed in cultures incubated for an additional 4 days with IFN-gamma. Endothelial cells treated with IFN-gamma exhibited prominent morphological changes and frequent overlapping. These changes were not observed in the presence of either IFN-beta or both cytokines in the media. IFN-beta alone, or in combination with IFN-gamma, significantly inhibited the growth of endothelial cells, while only slight inhibition was observed with IFN-gamma. The results of these studies suggest that IFN-beta may function in modulating IFN-gamma-mediated immune responses in the human central nervous system at the level of the blood-brain barrier and this negative regulatory mechanism may be, at least in part, responsible for the recently reported beneficial effect of IFN-beta in relapsing-remitting multiple sclerosis.

Cells, Cultured↗
PubMed1993

Synergistic anti-HSV effect of tumor necrosis factor alpha and interferon gamma in human corneal fibroblasts is associated with interferon beta induction.

HSV-1 (17) replicated to high titer in human corneal fibroblasts (> 10(8) PFU/10(5) cells) following infection at one PFU per 100 cells. Pretreatment of the cells for 24 h with 50 U/ml recombinant human tumor necrosis factor alpha (TNF-alpha) or 5 IU/ml of human interferon gamma (IFN-gamma) resulted in only modest reduction (2- to 19-fold) in virus yield. However, when the two cytokines were combined the antiviral effect was dramatically increased. There was > 1000-fold reduction in virus titer in 8 of 8 trials. In contrast, the combinations of 50 U/ml TNF-alpha with 5 IU/ml IFN-alpha or IFN-beta did not produce a synergistic effect. The pronounced synergistic antiviral activity of TNF-alpha+IFN-gamma could be demonstrated in fibroblast cultures from different donors, and HSV-2 as well as HSV-1 strains were inhibited. There was no evidence that dual cytokine treatment was toxic for uninfected or HSV-infected cells. Insight into the mechanism responsible for the synergistic effect was provided by the observation that TNF-alpha+IFN-gamma induced IFN-beta. In addition, anti-IFN-beta but not anti-IFN-alpha antibodies could reverse the antiviral effect, and reconstitution with IFN-beta could duplicate the phenomenon. We conclude that the combination of TNF-alpha and IFN-gamma at low concentrations can exert a powerful anti-herpes effect in human corneal fibroblasts which can be chiefly attributed to the induction of IFN-beta.

Antiviral Agents↗
PubMed1985

Differences in the expression and release of DR, BR, and DQ molecules in human cells treated with recombinant interferon gamma: comparison to other interferons.

This study presents a comparative analysis of the effects of different interferons (IFN) on the three recognizable subsets of human HLA class II molecules: DR, BR, and DQ. Both cellular expression and shedding of class II molecules have been determined on three different cell types. The results can be summarized as follows: class II molecules are markedly increased by IFN gamma; IFN beta has a lower enhancing effect, and IFN alpha has only a slight, if any, effect. Kinetically, the action of IFN gamma is prompter and longer lasting than that of IFN beta. DQ expression is much more enhanced by IFN gamma than either DR or BR; IFN beta has the same effect on all three subsets. Parallel changes of the cellular expression and of the shedding of these molecules are observed. A melanoma and a lymphoblastoid cell line and peripheral blood mononuclear cells show qualitatively similar modifications.

B-Lymphocytes↗
PubMed1995

Role of interferon-gamma in contact hypersensitivity assessed in interferon-gamma receptor-deficient mice.

The role of interferon-gamma (IFN gamma) in contact hypersensitivity induced by the haptens, oxazolone and 2,4,6-trinitrochlorobenzene (TNCB), was investigated in mice with a targeted disruption of the IFN gamma receptor (IFN gamma-R-/-). The 24-h ear-swelling response to oxazolone or TNCB in sensitized animals was not significantly reduced by the disruption of IFN gamma signalling. Dermal mononuclear infiltrates (MN) and epidermal microabscesses, however, were clearly diminished in the mutant mice. The hapten-induced upregulation of intercellular-adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) class I in IFN gamma-R-/- mice was smaller when compared to wild-type mice. It is concluded that oxazolone- and TNCB-induced contact hypersensitivity is partially dependent on a functional IFN gamma system. While the cutaneous oedema is IFN gamma-independent, the mononuclear cell infiltration and epidermal microabscess formation are at least partly IFN gamma-dependent. Therefore, reduced cellular infiltrates are likely due to a reduced upregulation of ICAM-1 and class I antigen expression in IFN gamma-R-/- mice.

Adjuvants, Immunologic↗