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PubMed1991

The induction of interferon-alpha and interferon-beta mRNA in human natural interferon-producing blood leukocytes requires de novo protein synthesis.

The induction of interferon-alpha (IFN-alpha) and IFN-beta mRNA in natural IFN producing (NIP) cells in cultures of human peripheral blood mononuclear cells (PBMCs), stimulated by glutaraldehyde-fixed Herpes simplex virus type 1 (HSV)-infected WISH cells, was studied. The protein synthesis inhibitor cycloheximide (CHX) totally prevented the appearance of both IFN-alpha and IFN-beta mRNA, also in cultures supplemented with a conditioned medium (CM) assumed to contain soluble factors necessary for the IFN induction. However, when PBMCs were preincubated for 4 h in medium supplemented with fetal bovine serum (FBS) with or without addition of CM, the subsequent induction of IFN-alpha/beta mRNA became partially resistant to CHX. In serum-free medium containing interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF), the early induction of IFN-alpha mRNA became resistant to CHX, and, in contrast to FBS and CM supplemented medium, this was observed also without a preincubation of the PBMCs. In contrast, IL-1, IL-2, IL-4, IL-6, tumor necrosis factor-alpha (TNF-alpha), IFN-alpha, or IFN-gamma had no such effects. Our results suggests that de novo synthesis of proteins normally is required for the induction of IFN-alpha/beta mRNA. Such proteins might be cytokines, possibly CSFs, which in turn also may require protein synthesis for their actions. In contrast, the actual triggering signal provided by the HSV-inducer is independent of protein synthesis.

Culture Media↗
PubMed1993

Interferon-resistant Daudi cells are deficient in interferon-alpha-induced ISGF3 alpha activation, but remain sensitive to the interferon-alpha-induced increase in ISGF3 gamma content.

Low levels of the transcription factor ISGF3 alpha were detected in the cytoplasm and nucleus of untreated Daudi cells, which increased markedly following interferon (IFN) treatment. In contrast no ISGF3 alpha was detected in an IFN-resistant clone of Daudi cells, DIF8, and only low levels were detected in these cells after IFN-alpha treatment. High levels of ISGF3 were produced in vitro, however, by the addition of ISGF3 alpha to extracts of IFN-treated DIF8 cells, indicating that IFN is unable to produce substantial amounts of functional ISGF3 alpha in DIF8 cells. A second clone of IFN-resistant Daudi cells, DIF3, also exhibited defective ISGF3 alpha production, which was restored to normal in the subclone DIF3REV5 that had reverted to high IFN sensitivity. Thus, the antiproliferative effect of IFN on Daudi cells and derived clones is closely related to the level of ISGF3 present in the nucleus of these cells. IFN-alpha, however, also enhances the content of ISGF3 gamma in IFN-resistant cells as well as certain proteins of unknown function, raising the possibility that a second pathway of IFN-alpha signal transduction, distinct from the ISGF3 pathway, remains functional in both DIF8 and DIF3 cells.

Base Sequence↗
PubMed1996

The human IgE germline promoter is regulated by interleukin-4, interleukin-13, interferon-alpha and interferon-gamma via an interferon-gamma-activated site and its flanking regions.

Class switching to IgE is preceded by the appearance of epsilon germline transcripts, which are induced by interleukin-4 (IL-4) and by IL-13. A 51-bp fragment of the human epsilon germline promoter conferred in reporter gene assays with the erythroleukemic cell line TF-1 upregulation of transcription by IL-4 or IL-13, and repression by interferon-alpha (IFN-alpha) and IFN-gamma. A central IFN-gamma activated sequence within the 51-bp fragment was sufficient for transcriptional regulation by the cytokines in the absence of its normal flanking regions. In contrast, deletion of either upstream or downstream sequences abolished repression by IFN-alpha or INF-gamma, but not upregulation by IL-4 or IL-13. IL-4 stimulated reporter gene transcription required more than ten times higher concentrations than cell proliferation or tyrosine phosphorylation of the IL-4 receptor.

Antibody Diversity↗
PubMed1986

Interferon structural genes do not participate in quantitative regulation of interferon production by If loci as shown in C57BL/6 mice that are congenic with BALB/c mice at the alpha interferon gene cluster.

Previous studies have shown that serum interferon (IFN) production in mice is quantitatively influenced by If loci, whose alleles determine high or low production. Although different loci influence IFN production in response to different inducers, such as Newcastle disease virus, Sendai virus, herpes simplex virus type 1, and polyriboinosinic-polyribocytidylic acid, BALB/c mice are in every instance low producers. It was therefore possible that, in addition to If loci, some feature of the BALB/c structural IFN genes contributed to low production. This was examined in the present work, in which IFN production was measured in two strains of C57BL/6 mice congenic with BALB/c at the murine alpha IFN (IFN-alpha) gene cluster on chromosome 4. One line, HW13 (B6.C-H-15c-H-16c-H-20c-H-21c/By) has a BALB/c fragment on chromosome 4 of at least 35 centimorgans which includes the BALB/c IFN-alpha gene cluster and four loci of the brown histocompatibility complex; the other line, HW13J (B6.C-H-15c/By), has a much shorter fragment (about 15 centimorgans), but it also comprises the BALB/c IFN-alpha gene cluster. We show that these mice, carrying the BALB/c IFN-alpha structural genes on a C57BL/6 background, are high IFN producers when stimulated by Newcastle disease virus, Sendai virus, herpes simplex virus type 1, or polyriboinosinic-polyribocytidylic acid. Thus, the low IFN production of BALB/c mice is not directly due to some feature of the IFN-alpha structural genes but is mainly the result of different alleles at If loci.

Alleles↗
PubMed1989

Bacterial lipopolysaccharide and gamma interferon induce transcription of beta interferon mRNA and interferon secretion in murine macrophages.

Bacterial lipopolysaccharide (LPS) induces interferon (IFN) secretion and an antiviral state in murine peritoneal macrophages (PM). These cells secrete predominantly IFN-beta, as shown by neutralization assays with monoclonal antibodies. Secretion of IFN-beta is also induced in PM by IFN-gamma. LPS and IFN-gamma synergistically stimulated PM to produce IFN in amounts almost comparable to those induced by infection with Newcastle disease virus. Low levels of IFN-beta mRNA can be detected in freshly harvested PM by hybridization assays. The accumulation of this mRNA is markedly increased in PM treated with LPS or IFN-gamma, and it is further enhanced in the presence of the inhibitor of protein synthesis, cycloheximide. Similar studies were carried out on the RAW 264.7 line of transformed macrophages. These cells are induced to secrete IFN-beta by LPS but not by IFN-gamma, suggesting that this cytokine may elicit such specific response only in PM. IFN-beta mRNA is undetectable in untreated RAW 264.7 cells, and accumulation of this mRNA is induced by LPS but not by IFN-gamma. The secretion of IFN induced by these agents in PM and by LPS in RAW 264.7 cells and the corresponding accumulation of IFN-beta mRNA are blocked by an inhibitor of protein kinase C, staurosporine. The activity of this kinase is apparently necessary to stimulate accumulation of IFN-beta mRNA. The induction of IFN-beta by IFN-gamma appears to be a characteristic response of PM and may be at least in part responsible for the resistance of these cells to viral infections.

Animals↗
PubMedDate not supplied

Transcriptional induction of H2 (class I) antigens and beta 2 microglobulin by interferon-gamma in interferon-sensitive and interferon-resistant Friend leukemia cells.

The effect of interferons (IFNs) type I (alpha/beta) and type II (gamma) on the stimulation of H2-Dd (class I) and beta 2 microglobulin genes transcription was analysed in IFN-sensitive (w.t.) and IFN-resistant Friend erythroleukemia cells (FLC). Type I IFN enhances the expression of H2-Dd and beta 2 microglobulin genes in w.t. FLC but does not modulate the expression of these genes in clones resistant to IFN-alpha/beta. IFN type II treatment of w.t. and IFN-alpha/beta resistant cell lines results in an increased expression of H2-Dd and beta 2 microglobulin genes, while being ineffective in the cell clone resistant to both types of IFNs. In this cell system the effect(s) of IFN type II is in part mediated by the induction of IFN-beta. The results reported in the present paper suggest that the IFN-gamma is able per se to increase the expression of H2-Dd and beta 2 microglobulin genes; since a reduced but clearly evident stimulation of the expression of these genes was observed in the FLC clone totally resistant to type I IFN.

Animals↗
PubMed1990

Regulation of indoleamine 2,3-dioxygenase gene expression in human fibroblasts by interferon-gamma. Upstream control region discriminates between interferon-gamma and interferon-alpha.

The interferon (IFN)-gamma-mediated induction of indoleamine 2,3-dioxygenase (IDO) enzyme, which converts tryptophan into N-formylkynurenine, has been implicated in the inhibition of intracellular pathogens, e.g. Toxoplasma gondii and Chlamydia psittaci, and in the antiproliferative effect of IFN-gamma on tumor cells. The IDO activity is induced strongly in many cell types by IFN-gamma but rather poorly by IFN-alpha or -beta. A genomic DNA clone containing part of the transcribed region of the IDO gene and approximately 13 kilobases (kb) of the 5'-upstream DNA sequence was isolated and analyzed. An approximately 1.4-kb fragment of this clone, containing 329 nucleotides of the transcribed sequence and approximately 1.1 kb of the 5'-upstream sequence, when ligated to chloramphenicol acetyltransferase (CAT) structural gene made its expression inducible by IFN-gamma, but this construct responded poorly, if at all, to IFN-alpha 2. Deletion constructs derived from this plasmid narrowed down the IFN-gamma-responsive region to a 151-nucleotide segment (-495/-344) which also contained a 14-nucleotide sequence (GGTTTCAGTTTTCC) highly homologous to the IFN(alpha)-stimulated response element (ISRE) that has been found so far in all cellular genes inducible with IFN-alpha or -beta. Expression of CAT activity was stimulated by IFN-gamma more effectively than by IFN-alpha 2 when a 155-nucleotide fragment (-495/-340) containing the 151-nucleotide segment required for IFN-gamma response was inserted before herpes simplex virus thymidine kinase promoter linked to CAT structural gene. The results indicate that despite the presence of an ISRE, the control region of the IDO gene can distinguish between IFN-gamma and IFN-alpha. This may account for the differential activation of IDO gene expression by IFN-gamma as against IFN-alpha or -beta in intact cells, and suggests that the response of ISRE to IFN-alpha or -beta may be governed by other features in the upstream control region of this gene.

Base Sequence↗
PubMed1987

Epitopes of human interferon-alpha defined by the reaction of monoclonal antibodies with alpha interferons and interferon analogues.

Five monoclonal antibodies reactive with human interferon (HuIFN)-alpha 2, but not with HuIFN-alpha 1, have been analyzed for their reaction with a series of IFN analogues and hybrid IFN molecules. Using analogues containing alpha 1 or gamma substitutions, it was shown that amino acids in the 107 to 113 region are implicated in the epitopes recognized by four of the five antibodies tested. Surprisingly, two of the antibodies that did not react with [alpha 1(113 to 114)112 to 113]alpha 2 also did not react with a truncated IFN-alpha 2(4 to 155). The presence of an epitope determined by amino acids at 112 and 113 and by the amino and carboxyl ends of the molecule supports a model for IFN where the carboxyl- and amino-terminals are adjacent to the proposed reverse turn around amino acid 110 to 115. The fifth alpha 2 specific antibody whose reaction with HuIFN-alpha 2 is not affected by the above substitutions and truncations recognizes IFN or IFN hybrids that, like alpha 2, have arginine at position 120, but does not react with IFN that, like alpha 1, have lysine at position 120. Amino acids 107 to 113 and 120 lie in regions of the molecule that have high hydrophilicity and are probably structurally involved in the epitopes recognized by the antibodies. Under conditions of antibody excess, the antibodies described here inhibit binding of HuIFN-alpha 2 to both human and bovine cells.

Animals↗
PubMed1995

[Interferon treatment for chronic hepatitis C--assessment of 3 regimens in patients received more than 500MU interferon treatment and their effect predictive factors for interferon treatment using multivariate analysis with the logistic regression model].

Chronic hepatitis C patients (n = 115) were treated with interferon (IFN). Total dose employed was more than 500 MU. The response rate was assessed among the three treatment groups: 2W continuous+TIW, 4W continuous+TIW, 8W continuous+TIW. The IFN treatment effect predictive factors were also assessed. Complete response (CR) rate, CR with serum HCV-RNA disappearance rate, responders' histology activity index score changes between before and after treatment, and responders' hepatocytes HCV-RNA disappearance rate did not differ among the three treatment regimens. CR to IFN treatment was dependent on serum HCV-RNA and HCV serotype. Patients of low serum HCV-RNA and serotype II were responsive to IFN treatment.

Chronic Disease↗
PubMed2002

Involvement of the interferon-gamma-induced T cell-attracting chemokines, interferon-gamma-inducible 10-kd protein (CXCL10) and monokine induced by interferon-gamma (CXCL9), in the salivary gland lesions of patients with Sjögren's syndrome.

OBJECTIVE: To elucidate the mechanism of the development of T cell infiltrates in the salivary glands of patients with Sjögren's syndrome (SS), we studied T cell-attracting chemokines and their receptors. METHODS: The expression of the T cell-attracting chemokines, interferon-gamma (IFNgamma)-inducible 10-kd protein (IP-10; also called CXCL10), monokine induced by IFNgamma (Mig; also called CXCL9), and stromal cell-derived factor 1 (SDF-1; also called CXCL12), in salivary glands from SS patients was investigated by polymerase chain reaction-enzyme-linked immunosorbent assay (ELISA). Cells that produce chemokines and lymphocytes that express chemokine receptors were identified by immunohistochemistry. The production of IP-10 and Mig proteins by salivary epithelial cells in response to IFNgamma was determined by ELISA. RESULTS: Expression of IP-10 and Mig messenger RNA (mRNA) was significantly up-regulated in SS salivary glands compared with normal salivary glands (both P < 0.01). There was no significant difference in SDF-1 mRNA expression between the SS and normal salivary glands. IP-10 and Mig proteins were predominantly expressed in the ductal epithelium adjacent to lymphoid infiltrates. Most of the CD3+ infiltrating lymphocytes in dense periductal foci expressed CXCR3, the receptor for IP-10 and Mig. IFNgamma induced the production of high levels of IP-10 and Mig proteins from cultured SS salivary epithelial cells. CONCLUSION: These findings suggest that IFNgamma stimulates the production of IP-10 and Mig in the SS ductal epithelium, and that IP-10 and Mig are involved in the accumulation of T cell infiltrates in the SS salivary gland. Chemokines or chemokine receptors could be a rational new therapeutic target in SS.

Adult↗
PubMed1982

Interferon and natural killer activity in multiple myeloma. Lack of correlation between interferon-induced enhancement of natural killer activity and clinical response to human interferon-alpha.

Natural killer (NK) activity of peripheral lymphocytes was measured in 39 patients with multiple myeloma prior to and during interferon (IFN) therapy. NK activity increased in a majority of patients following the first injection of IFN and remained at an increased level during 1 year of therapy. Lower doses of IFN seemed to induce a greater increase in NK activity than higher doses. No correlations could be observed between the response of the tumors to IFN therapy and pretreatment levels of NK activity, IFN-induced enhancement of NK activity in vitro or IFN-induced enhancement of NK activity in vivo.

Adult↗
PubMed1984

Decreased interferon synthesis and responsiveness to interferon by leukocytes from multiple sclerosis patients given natural alpha interferon.

Despite the use of interferon (IFN) in numerous clinical trials, relatively little is known about how IFN therapy influences leukocyte function. To evaluate some of its effects, leukocytes from multiple sclerosis (MS) patients given daily treatments of natural alpha IFN (IFN-alpha) were evaluated for IFN synthesis and two responses to IFN in vitro: enhancement (priming) of IFN synthesis and suppression of Concanavalin A (Con A)-induced T-cell mitogenesis. The IFN therapy had no effect on the sensitivity of Con A-stimulated leukocytes to the antiproliferative action of IFN-alpha. However, using Newcastle disease virus (NDV), measles virus, or poly I:C to stimulate IFN synthesis, cells from IFN-treated patients produced less IFN in response to all inducers, with titers ranging between 11% and 44% of pretherapy values. Also, unlike cells from these same patients before therapy or from the placebo recipients, cells from the IFN recipients were not primed by either IFN-alpha or -beta even though IFN-beta had not been used for therapy. The loss of these priming reactivities suggests that resistance to IFN had developed in IFN-treated patients.

Adult↗
PubMed1991

An interferon-induced 16-kD protein is present in the membranes of interferon-sensitive but not in interferon-resistant mouse cells.

Human interferon-alpha (IFN-alpha) or IFN-beta has been shown to induce a 17-kD membrane protein in human cells which when eluted from SDS gels inhibited the multiplication of cells of different human cell lines. We show herein that mouse IFN-alpha/beta induces a 16-kD membrane protein in L1210 and Friend erythroleukemia cells sensitive to IFN-alpha/beta, (but not in the derived IFN-alpha/beta-resistant cell lines) as well in primary and monolayer cultures of mouse embryonic fibroblasts and adult mouse hepatocytes, and in suspensions of spleen cells. In addition, IFN-alpha/beta enhanced the expression of an 11-kD membrane protein which could be shown by immunoprecipitation to be beta 2-microglobulin. Anticell proliferation activity was not recovered from the 16-kD fraction of the SDS gels.

Animals↗
PubMed1985

Interferon-induced 2'-5' oligoadenylate synthetase during interferon-alpha therapy in homosexual men with Kaposi's sarcoma: marked deficiency in biochemical response to interferon in patients with acquired immunodeficiency syndrome.

Titers of circulating interferon (IFN) and the activity of 2'-5' oligoadenylate (2-5A) synthetase, an enzyme specifically induced by IFN, were measured in 28 homosexual men with acquired immunodeficiency syndrome (AIDS) who received one- to six-month courses of antineoplastic therapy with IFN-alpha and in homosexual and heterosexual controls. Fifteen of the patients and two of seven healthy homosexual men had high endogenous levels of 2-5A synthetase. IFN therapy induced further increases in this enzyme in only 10 of the 28 patients with AIDS. Furthermore, peripheral blood cells from all but one of the patients with AIDS and homosexual controls tested were markedly deficient in their ability to respond to IFN in vitro, as measured by increased levels of 2-5A synthetase. We did not find a statistical correlation between cytomegalovirus viremia and pretherapy endogenous circulating IFN, nor any apparent correlation between disseminated infection with cytomegalovirus and either basal levels of 2-5A synthetase or changes in enzyme level during therapy. Pretherapy circulating IFN was significantly correlated with progressive Kaposi's sarcoma during therapy, but rises in levels of 2-5A synthetase were not sufficient to predict a good clinical response.

2',5'-Oligoadenylate Synthetase↗
PubMed1983

Cell surface receptor-mediated internalization of interferon: its relation to the antiviral activity of interferon.

The binding of [3H]leucine-labelled pure human interferon alpha from Namalwa cells to human FL and Daudi cells was studied, and evidence obtained to indicate receptor-mediated internalization of interferon. Cell surface-bound and internalized interferons were quantified separately as trypsin-released and unreleased radioactivities, respectively. At 37 degrees C, surface-bound interferon reached a maximum after 1 h and then decreased, while internalized interferon reached a maximum after 2 h. At 21 degrees C, in contrast, surface-bound interferon reached a maximum after 2 h and did not decrease thereafter; no internalization was observed. The same was true at 37 degrees C in the presence of NaF, indicating dependence of internalization on temperature and energy. In control cultures at 37 degrees C, internalized interferon, after reaching a maximum, decreased after prolonged incubation, and concomitantly acid-soluble radioactivity appeared in the culture medium. The decrease in internalized interferon and the emergence of degraded interferon were inhibited by the lysosomotropic agents, ammonium chloride and chloroquine. The fate of labelled interferon, bound to the cell surface of FL cells at 21 degrees C was studied at 37 degrees C, and the results indicated that trypsin-unreleased interferon was derived from the surface-bound interferon, and was secreted in part into the culture fluid in a degraded form upon prolonged incubation. The relation of internalization of interferon to its biological activity was studied in three ways. In FL cells, the antiviral activity was not induced when internalization of interferon was entirely blocked (at 21 degrees C or in the presence of NaF at 37 degrees C). In Daudi cells, both 2'-5'-oligoadenylate (2-5A) synthetase induction by interferon and internalization of interferon were inhibited completely by diethyldithiocarbamate (DDC), whereas in the case of FL cells, DDC inhibited neither 2-5A synthetase induction nor internalization of interferon. Raji cells, which have an interferon-specific binding site on the cell surface but are insensitive to interferon, were found not to internalize interferon, whereas other Burkitt's lymphoma cells, Daudi and Namalwa, which are sensitive to interferon, did internalize it. These findings suggest (but do not prove) that internalization is required for the establishment of interferon activity.

Biological Transport↗
PubMed1990

One interferon gamma receptor binds one interferon gamma dimer.

We investigated the stoichiometry of the interferon gamma and interferon gamma receptor interaction, using recombinant interferon gamma and recombinant soluble interferon gamma receptor, applying chemical cross-linking and chromatographic techniques, and analyzing the resulting products in denaturing polyacrylamide gels. Interferon gamma cross-linked to itself produced a major band of an apparent molecular mass of 34 kDa, which suggests that it exists as a dimer in physiological buffer and which agrees with published data. Soluble interferon gamma receptor cross-linked to itself produced mainly a 28-kDa band, suggesting that the interferon gamma receptor exists as a monomer. Interferon gamma cross-linked to the soluble interferon gamma receptor resulted in the formation of two main products of apparent molecular masses of 60 and 44 kDa. The predominant 60-kDa band resulted from the cross-linking of one interferon gamma dimer (34 kDa) to one interferon gamma receptor molecule (27 kDa). The 44-kDa band was formed by the cross-linking of one interferon gamma molecule to one interferon gamma receptor. Kinetic studies showed that the cross-linking of interferon gamma dimer to the soluble receptor proceeds through the intermediate formed by cross-linking one molecule of the interferon gamma dimer to the receptor. Reducing and dissociating agents inhibited complex formation. When chromatographed on Sephadex G-100, interferon gamma was eluted as a protein of 34-kDa molecular mass, the soluble interferon gamma receptor as a protein of 40 kDa, and their mixture was eluted in one peak corresponding to an apparent molecular mass of 73 kDa. Sodium dodecyl sulfate-polyacrylamide gel analysis of the eluted mixture showed the presence of both interferon gamma and interferon gamma receptor at a ratio of 2:1. The found results suggest that the interferon gamma receptor binds interferon gamma as a dimer.

Cell Line↗
PubMed1995

Combination antiviral therapy with ribavirin and interferon alfa in interferon alfa relapsers and non-responders: Italian experience.

BACKGROUND/AIMS: A sustained biochemical and virologic response to standard interferon therapy for chronic hepatitis C is seen in no more than 25% of patients, and the efficacy of re-treatment or of higher doses in non-responders and relapsers has not been established. A more effective therapy for interferon alfa-resistant hepatitis C is needed. METHODS: A study of ribavirin plus interferon alfa combination therapy was conducted in 30 patients with chronic hepatitis C resistant to a previous standard course of interferon alfa (14 interferon non-responders, 16 interferon relapsers). Patients were randomly assigned to receive either ribavirin, 800 mg daily, and interferon alfa, 3 MU thrice weekly (n = 15), or interferon alfa alone, 3 MU thrice weekly (n = 15), for 6 months. RESULTS: At the end of treatment, normal alanine aminotransferase levels were observed in eight patients in the combination therapy group: one (14%) interferon non-responder and seven (87%) interferon relapsers (p = 0.01). Six months post-therapy, sustained normalization of alanine aminotransferase was achieved in seven (87%) interferon alfa relapsers, but not in any of the interferon alfa non-responders (p = 0.001). In the group of patients treated with interferon alfa alone, sustained normalization of alanine aminotransferase was observed in one interferon relapser only. Serum HCV RNA became negative in eight patients receiving combination therapy--two (28%) interferon non-responders and six (75%) interferon relapsers. Six months later, circulating HCV RNA remained negative in seven patients: one (14%) interferon non-responder and six (75%) interferon relapsers (p = 0.04). Sustained clearance of HCV RNA was not observed in patients re-treated with interferon alone. The sustained response to combination therapy was accompanied by reduced hepatic necroinflammatory activity on liver biopsy. Hepatitis C virus genotype was not significantly associated with response to combination therapy. Side effects were mild and well tolerated. CONCLUSIONS: Our experience indicates that combination therapy of ribavirin plus interferon alfa induces sustained biochemical, virologic, and histologic responses in most patients who are interferon relapsers.

Antiviral Agents↗
PubMed1994

Immunolocalisation of interferon-alpha in hepatitis C patients and its correlation with response to interferon-alpha therapy.

Localised interferon-alpha production was investigated in hepatitis C patients entered into a trial of interferon-alpha-2a therapy. Antibodies capable of reacting specifically with interferon-alpha-2, interferon-alpha-4 or with all interferon-alpha subtypes were used as immunohistochemical and immunofluorescence probes to study interferon-alpha production in liver biopsy tissue, and peripheral blood mononuclear cells prior to and after stimulation with Sendai virus. Measurement of cytoplasmic interferon-alpha, specifically interferon-alpha-2 and interferon-alpha-4, in peripheral blood mononuclear cells isolated from the hepatitis C patients and of total interferon-alpha secreted into culture supernatants by these cells showed interferon-alpha production similar to that of peripheral blood mononuclear cells isolated from normal individuals. Interferon-alpha-positive cells were observed in the infiltrating mononuclear cells of the liver biopsy tissue obtained from 8 of the 14 patients. Lymphocytes, fibroblasts, Kupffer cells, polymorphonuclear cells and monocytes stained positive for interferon-alpha, and specifically interferon-alpha-4, in all of the eight patients. The cytoplasm of hepatocytes also stained weakly positive in three of these patients. Interferon-alpha positive cells showed a good correlation with the degree of histological damage observed in the liver biopsies but not with presence of antibodies towards hepatitis C virus or levels of serum alanine aminotransferase measured prior to interferon-alpha-2a therapy. Interestingly, response to therapy seemed linked to local interferon-alpha production status. Those patients who responded best to therapy displayed no or only low levels of interferon-alpha positive cells in liver biopsy tissue. Thus patients with a lower activation of their endogenous interferon-alpha system may benefit from administration of exogenous interferon-alpha.

Adolescent↗