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PubMed2000

Randomized trial of interferon-alpha plus ursodeoxycholic acid versus interferon plus placebo in patients with chronic hepatitis C resistant to interferon.

BACKGROUND: Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. METHODS: Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. RESULTS: At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. CONCLUSIONS: An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids.

Adult↗
PubMedDate not supplied

Interferon efficiency in the treatment of herpetic dermatites. II. Comparison between human leukocyte interferon (Ginterferon) and a recombinant interferon (Roferon).

The comparative efficiency of a recombinant interferon-Roferon (R-IFN) and a human, naturally synthetized interferon-Ginterferon (G-IFN), applied as ointments in the treatment of herpetic dermatites, was studied in a blind trial. It was found that R-IFN in doses of 20,000 IU/g has practically similar results as G-IFN in doses of 10,000 IU/g therefore half the dose of the former product. Thus both preparations reduced significantly the mean duration of a herpetic dermatitis attack and both proved more efficient on smaller lesions (less than 2 sq.cm) than on larger ones (over 2 sq.cm). Likewise with both preparations the reduction of the healing period was more marked when administered in the first 2-3 days after onset. It was also found that the arrest of new vesicle appearance after two days of treatment is a reliable clinical criterion for the estimation of IFN capacity to block effectively viral multiplication in the host's epithelial cells. Finally the efficacy of both R-IFN and G-IFN proved similar whatever the localization of disease (oral or genital) or in their capacity to prevent relapses or the appearance of bacterial complications.

Clinical Trials as Topic↗
PubMed1999

Formation of a uniquely stable type I interferon receptor complex by interferon beta is dependent upon particular interactions between interferon beta and its receptor and independent of tyrosine phosphorylation.

Human type I interferons (IFN) require two receptor chains, IFNAR1 and IFNAR2c for high affinity (pM) binding and biological activity. Our previous studies have shown that the ligand dependent assembly of the type I IFN receptor chains is not identical for all type I IFNs. IFNbeta appears unique in its ability to assemble a stable complex of receptor chains, as demonstrated by the observation that IFNAR2c co-immunoprecipitates with IFNAR1 when cells are stimulated with IFNbeta but not with IFNalpha. The characteristics of such a receptor complex are not well defined nor is it understood if differential signaling events can be mediated by variations in receptor assembly. To further characterize the factors required for formation of such a stable receptor complex we demonstrate using IFN stimulated Daudi cells that (1) IFNAR2c co-immunoprecipitates with IFNAR1 even when tyrosine phosphorylation of receptor chains is blocked with staurosporine, and (2) IFNbeta1b but not IFNalpha2, is present in the immunoprecipitated receptor complex. These results demonstrate that the unique IFNbeta induced assembly of type I IFN receptor chains is independent of receptor tyrosine phosphorylation and the recruitment of additional proteins to the receptor by such events. Furthermore, the presence of IFNbeta1b in the immunoprecipitated IFN receptor complex suggests that IFNbeta interacts and binds differently to the receptor than IFNalpha2. These results suggest that the specific assembly of type I IFN receptor chains is ligand dependent and may represent an early event which leads to the differential biological responses observed among type I IFNs.

Humans↗
PubMed1996

Comparative effects of interferon-consensus 1, interferon-alpha 2a, and interferon-beta 1b on HLA expression and lymphoproliferation: a preclinical model for treatment of multiple sclerosis.

Interferon-consensus 1 (IFN-Con 1) is a novel synthetic protein generated from codons for the most frequent amino acids in different type 1 IFNs. Compared with natural IFNs, IFN-Con 1 has been shown to have higher specific activity and antiproliferative activity and a higher ability to induce natural killer cells. In this study, the effects of IFN-Con 1 were compared with those of IFN-beta 1b and IFN-alpha 2a on HLA expression and lymphoproliferation. Human umbilical vein endothelial cells (HUVEC) express HLA class I but not class II molecules; however, both class I and class II molecules can be upregulated by IFN-gamma. IFN-Con-1 shared with IFN-beta 1b and IFN-alpha 2a the capacity to enhance HLA class I expression on HUVEC, alone and in combination with IFN-gamma. Although IFN-Con 1 had no effect on the basal expression of HLA class II molecules, it inhibited the IFN-gamma-induced class II expression on the HUVEC in a dose-dependent fashion. When this effect was compared among the three IFNs on mass basis, IFN-Con 1 activity was intermediate between that of IFN-beta 1b and IFN-alpha 2a. IFN-Con 1 also demonstrated an inhibitory effect on mitogen-driven lymphoproliferation similar to that of IFN-alpha 2a and exceeded that of IFN-beta 1b. The results indicate that IFN-Con 1 has immunomodulatory effects similar to those of IFN-beta 1b and IFN-alpha 2a, which could be relevant to the treatment of autoimmune and virus-mediated diseases.

Adjuvants, Immunologic↗
PubMed1992

Interferon-gamma potentiates the antiviral activity and the expression of interferon-stimulated genes induced by interferon-alpha in U937 cells.

Binding of type I interferon (IFN-alpha/beta) to specific receptors results in the rapid transcriptional activation, independent of protein synthesis, of IFN-alpha-stimulated genes (ISGs) in human fibroblasts and HeLa and Daudi cell lines. The binding of ISGF3 (IFN-stimulated gene factor 3) to the conserved IFN-stimulated response element (ISRE) results in transcriptional activation. This factor is composed of a DNA-binding protein (ISGF3 gamma), which normally is present in the cytoplasm, and other IFN-alpha-activated proteins which preexist as latent cytoplasmic precursors (ISGF3 alpha). We have found that ISG expression in the monocytic U937 cell line differs from most cell lines previously examined. U937 cells express both type I and type II IFN receptors, but only IFN-alpha is capable of inducing antiviral protection in these cells. Pretreatment with IFN-gamma potentiates the IFN-alpha-induced protection, but IFN-gamma alone does not have any antiviral activity. ISG15 mRNA accumulation in U937 cells is not detectable before 6 h of IFN-alpha treatment, peaks at 24 h, and requires protein synthesis. Although IFN-gamma alone does not induce ISG expression, IFN-gamma pretreatment markedly increases and hastens ISG expression and transcriptional induction. Nuclear extracts assayed for the presence of ISRE binding factors by electrophoretic mobility shift assays show that ISGF3 is induced by IFN-alpha within 6 h from undetectable basal levels in untreated U937 cells. Activation of ISGF3 alpha, the latent component of ISGF3, occurs rapidly. However, the increase in ISGF3 activity ultimately correlates with the accumulation of ISGF3 gamma induced by IFN-alpha or IFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Line↗
PubMed1990

A direct comparison of biological response modulation and clinical side effects by interferon-beta ser, interferon-gamma, or the combination of interferons beta ser and gamma in humans.

To directly compare clinical side effects and biological response modification, IFN-beta ser, IFN-gamma, or the combination of IFN-beta ser plus IFN-gamma was administered to 21 cancer patients. Each IFN or the combination was given intravenously on days 1, 8, and 15 in varied order. Each IFN and the combination resulted in significant (P less than 0.05) modulation of IFN-induced proteins. IFN-beta ser was more effective than IFN-gamma in enhancing 2-5A synthetase activity (P = 0.001). IFN-gamma was more effective than IFN-beta ser in enhancing serum beta 2 microglobulin expression (P = 0.05) and indoleamine dioxygenase activity, as assessed by decreased serum tryptophan (P = 0.03). The combination enhanced tryptophan catabolism more effectively than IFN-beta ser in a dose-dependent manner (P less than 0.03). IFN-beta ser/IFN-gamma did not potentiate natural killer cells or antibody-dependent cellular toxicity (ADCC). IFN-beta ser/IFN-gamma enhanced monocyte guanylate cyclase activity, as assessed by serum neopterin, more effectively than IFN-gamma alone (P = 0.005). Both IFNs and the combination resulted in increases in HLA class II expression on monocytes. However, no significant difference in the level of induction of HLA DQ and HLA DR expression between IFN-beta ser/IFN-gamma and either IFN-beta ser or IFN-gamma was noted. Although frequency and servity of side effects of IFN-beta ser, IFN-gamma, or the combination were dose related, induction of induced proteins (with exception of influences on tryptophan catabolism) were not a function of dose administered over the 10-fold range. Continued treatment with the combination intravenously three times a week for 4 wk sustained but did not further potentiate, most of the changes in interferon-induced proteins. Thus, IFN-beta ser and IFN-gamma each resulted in effective and essentially equivalent patterns of induction of induced proteins. When combined, however, these IFNs did not result in potentiation of biological response modification in vivo.

2',5'-Oligoadenylate Synthetase↗
PubMed1996

Differences in interferon alpha and beta signaling. Interferon beta selectively induces the interaction of the alpha and betaL subunits of the type I interferon receptor.

All Type I interferons (IFNalpha, IFNbeta, IFNomega) bind to the Type I IFN receptor (IFNR) and elicit a common set of signaling events, including activation of the Jak/Stat and IRS pathways. However, IFNbeta selectively induces the association of the alpha subunit of the Type I IFNR with p100, a tyrosyl phosphoprotein, to transduce IFNbeta-specific signals. Using antibodies raised against the different components of the Type I IFNR, we identified p100 as the long form of the beta subunit (betaL subunit) of the Type I IFNR. This was also confirmed in experiments with mouse L-929 cells transfected with truncated forms of betaL. Thus, IFNbeta stimulation of human cells or mouse L-929 transfectants expressing the human alpha and betaL subunits, selectively induces the formation of a signaling complex containing the alpha and betaL subunits of the receptor. The IFNbeta-regulated interaction of the alpha and betaL chains is rapid and transient and follows a similar time course with the tyrosine phosphorylation of these receptor components. These data demonstrate that the signaling specificity for different Type I IFNs is established early in the signaling cascade, at the receptor level, and results from distinct interactions between components of the Type I IFNR.

Animals↗
PubMed1995

Comparison of the in vitro host range of recombinant met-interferon-con1, interferon-alpha 2b, and interferon-beta [corrected].

The antiviral activity of human r-metIFN-con1 was compared with that of IFN-alpha 2b and IFN-beta on a number of human, other primate, rodent, feline, and canine cell lines. Although the specific activities of r-metIFN-con1 and IFN-alpha 2b differed 10-fold, the host range was very similar. The host range of IFN-beta differed from that of r-metIFN-con1 and IFN-alpha 2b in that Vero cells were 100-fold better protected by IFN-beta and MDBK protected at a 100-fold less efficiency. In general, there were only minor differences between the host ranges of the three interferons, human and primate cells being better protected than those of other species. However, the tissue of origin of the cell appears to be more important than the species of origin in defining host range [corrected].

Animals↗
PubMed1994

Interferon-tau and interferon-alpha interact with the same receptors in bovine endometrium. Use of a readily iodinatable form of recombinant interferon-tau for binding studies.

Trophoblasts of ruminant species secrete multiple forms of a novel Type I interferon (IFN-tau) for a few days preceding implantation. These IFN-tau are structurally distinct from IFN-alpha, -beta, and -omega, but it remains unclear whether they have any distinguishing biological properties. It has been of interest, therefore, to study their interaction with Type I IFN receptors. However, a recombinant bovine IFN-tau (boIFN-tau 1) prepared for such use is rapidly inactivated during chemical iodination with 125I, presumably because a critical tyrosine becomes modified. Here we describe the synthesis of a novel IFN-tau 1 in which Leu169 and Leu171 in the carboxyl terminus have been replaced by 2 tyrosine residues. The recombinant product (rboIFN-tau 1Y2) can be readily iodinated without significant loss of antiviral and antiproliferative activities, provided that reaction time with 125I is minimized. Both rboIFN-tau 1Y2 and rboIFN-alpha 1 compete with each other for binding to bovine endometrial cell membranes and Madin-Darby bovine kidney cells. Dissociation constants of both IFN are quite similar (Kd = 3.7 x 10(-10) and 3.5 x 10(-10) M, respectively). Cross-linking studies reveal a single size class of receptor polypeptide on endometrium and Madin-Darby canine kidney cells whose molecular weight is reduced from approximately 130,000 to approximately 70,000 by treatment with N-glycosidase. These studies with a single recombinant form of boIFN-tau avoid the difficulties that arise from use of a mixture of naturally occurring isoforms. They provide further evidence for the presence of a receptor common to both IFN-tau and IFN-alpha in bovine tissues and no indication for a unique IFN-tau-binding polypeptide in endometrium.

Animals↗
PubMed1993

Porcine leukocyte interferon exhibits close antigenic relatedness to human interferon alpha 2, but not to human interferon alpha 1.

As reported by others using polyclonal antisera, natural human and porcine interferons (IFN)-alpha are antigenically related. Using monoclonal antibodies (mAb) in neutralization and ELISA experiments, we found differences in the subtype/antigenic composition between virus-induced porcine and human leukocyte preparations. Human leukocyte IFN-alpha contains two major antigenically distinct subtypes, IFN-alpha 1 and IFN-alpha 2. However, swine leukocytes produced only a single predominant species of IFN-alpha with high antigenic homology to human IFN-alpha 2. Moreover, we were unable to detect close antigenic relatedness between recombinant porcine and human IFN-alpha 1 subtypes.

Animals↗
PubMed1994

Delivery of interferon to intracellular pathways by encapsulation of interferon into multilamellar liposomes is independent of the status of interferon receptors.

The antiproliferative effect of interferon alpha (IFN-alpha) against cultured 253J human bladder tumour cells was enhanced when IFN-alpha was encapsulated into multilamellar phospholipid liposomes (MLV). Moreover, significant cytostasis of a variant 253J subline (253J alpha R, resistant to the antiproliferative effect of IFN-alpha), could be achieved by delivery of IFN-alpha contained in liposomes. Although the two cell lines have the same number and affinity of cell receptors for IFN-alpha, the 253J alpha R cells did not down-regulate receptors as observed for the IFN-sensitive 253J cells. The IFN-response genes, 2'-5' oligosynthetase and gene 6-16 were equally induced in both cell lines following incubation of the cells with either free IFN-alpha or liposome-encapsulated IFN-alpha. Incorporation of radiolabelled IFN-alpha into cells by liposomes was independent of the status of IFN-receptors (the receptors being either occupied or down-regulated). These observations are consistent with the hypothesis that the antiproliferative effects of IFN-alpha against 253J and 253J alpha R cells may be mediated by internalization of IFN-alpha.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes.

A family of interferon (IFN) regulatory factors (IRFs) have been shown to play a role in transcription of IFN genes as well as IFN-stimulated genes. We report the identification of a member of the IRF family which we have named IRF-3. The IRF-3 gene is present in a single copy in human genomic DNA. It is expressed constitutively in a variety of tissues and no increase in the relative steady-state levels of IRF-3 mRNA was observed in virus-infected or IFN-treated cells. The IRF-3 gene encodes a 50-kDa protein that binds specifically to the IFN-stimulated response element (ISRE) but not to the IRF-1 binding site PRD-I. Overexpression of IRF-3 stimulates expression of the IFN-stimulated gene 15 (ISG15) promoter, an ISRE-containing promoter. The murine IFNA4 promoter, which can be induced by IRF-1 or viral infection, is not induced by IRF-3. Expression of IRF-3 as a Gal4 fusion protein does not activate expression of a chloramphenicol acetyltransferase reporter gene containing repeats of the Gal4 binding sites, indicating that this protein does not contain the transcription transactivation domain. The high amino acid homology between IRF-3 and ISG factor 3 gamma polypeptide (ISGF3 gamma) and their similar binding properties indicate that, like ISGF3 gamma, IRF-3 may activate transcription by complex formation with other transcriptional factors, possibly members of the Stat family. Identification of this ISRE-binding protein may help us to understand the specificity in the various Stat pathways.

Amino Acid Sequence↗
PubMed1998

The heparan sulfate binding sequence of interferon-gamma increased the on rate of the interferon-gamma-interferon-gamma receptor complex formation.

Interferon-gamma (IFNgamma), in common with a number of growth factors, binds both to heparan sulfate or heparin-related molecules and to a specific high affinity receptor (IFNgammaR). Using surface plasmon resonance technology, kinetic analysis of the IFNgamma. IFNgammaR complex formation was performed with the extracellular part of IFNgammaR immobilized on a sensor chip. At the sensor chip surface, IFNgamma was bound by two IFNgammaR molecules with an affinity in the nanomolar range (0.68 nM). This binding was characterized by an important on rate, kon = 7.3 x 10(6) M-1.s-1, and an off rate, koff = 5 x 10(-3).s-1. This binding assay was used to investigate a possible role of heparin in the IFNgamma.IFNgammaR complex formation. In contrast to growth factors for which binding to heparin is usually required for high affinity receptor interaction, we found in this study that IFNgamma bound to heparin displayed a strongly reduced affinity for its receptor. This is consistent with the fact that a cluster of basic amino acids (KTGKRKR, called the C1 domain) in the carboxyl-terminal sequence of the cytokine was involved both in heparin and receptor recognition. To understand how a single domain of IFNgamma could be implicated in two discrete functions (i.e. binding to heparin and to IFNgammaR), we also analyzed in a detailed manner the role of the IFNgamma carboxyl-terminal sequence in receptor binding. Using forms of IFNgamma, with carboxyl terminus truncations of defined regions of the heparin binding sequence, we found that the C1 domain functioned by increasing the on rate of the IFNgamma.IFNgammaR binding reaction but was not otherwise required for the stability of the complex. Interactions between the IFNgamma carboxyl-terminal domain and IFNgammaR could increased the association rate of the reaction either by increasing the number of encounters between the two molecules or by favoring productive collisions. The mechanisms by which heparan sulfate regulates IFNgamma activity may thus include both control of selective protease cleavage events, which directly affect the cytokine activity, and also an ability to modulate the interaction of IFNgamma with the IFNgammaR via competitive binding to the C1 domain.

Amino Acid Sequence↗
PubMed1990

Isolation of cDNA clones for the interferon-induced 67,000-dalton protein: direct induction of a family of mRNAs by human interferon-alpha and interferon-gamma.

A partial cDNA clone for the interferon (IFN)-induced 67,000-dalton (67K) protein was isolated by immunological screening and used as a probe to study the expression of mRNAs encoding this protein. Northern blot analyses of RNA from IFN-treated GM2767 cells revealed the presence of two major 67K-specific RNA species, 2.7 and 4.3 kb in length, and two minor RNA species, 5.7 and 7.2 kb long. All of these 67K-specific RNAs were polyadenylated. Multiple 67K-specific mRNAs were observed to be induced in several cell lines. IFN-gamma was more effective at inducing these mRNAs than was IFN-alpha. In IFN-alpha-treated GM2767 cells, the 67K-specific mRNAs were detectable 6 h following IFN treatment, but not 12, 18, or 24 h following treatment. In IFN-gamma-treated cells, these mRNAs were detectable 6 h after treatment and continued to be present 24 h after treatment. The induction of the 67K-specific mRNAs in GM2767 cells did not require protein synthesis as the RNAs were induced by IFN-alpha or IFN-gamma in the presence of cycloheximide (CHX, 50 micrograms/ml). Treatment of cells with the combination of CHX and IFN-alpha mediated an enhanced accumulation of the 67K-specific mRNAs, suggesting that ongoing protein synthesis may downregulate the induction or accumulation of the IFN-alpha-induced 67K-specific mRNAs. Western blot analysis employing a monoclonal antibody to the 67K protein revealed that several distinctly sized but immunologically related proteins were induced in IFN-treated cells.

Cell Line↗
PubMed1993

Potentiation of interferon-alpha in vitro antiviral activity by interferon-gamma is not abrogated by antibody to interferon-gamma.

The addition of minute amounts of recombinant interferon-gamma (IFN-gamma) to recombinant IFN-alpha 2 significantly enhances its antiviral activity. Although this potentiating action of IFN-gamma is destroyed by treatment with acid, it is not significantly affected by treatment with antibodies to IFN-gamma, suggesting that IFN-gamma molecules can interact with cells to potentiate IFN-alpha activity, even in the presence of neutralizing antibodies. Implications of this phenomenon are multifaceted, including the possibility that other IFN activities can be altered synergistically by combinations of different IFN types, even in the presence of specific antibodies, which have been described to occur in vivo in several pathological conditions.

Antibodies↗
PubMed1987

Antigenic structure of human interferon omega 1 (interferon alpha II1): comparison with other human interferons.

Recombinant human interferon (IFN) omega 1 (IFN-alpha II1) was compared with other human IFNs with regard to antigenic structure, using polyclonal and monoclonal antibodies. Antisera to recombinant IFN-alpha 1 or IFN-alpha 2c cross-neutralized the antiviral activity of other species of IFN-alpha, but not that of IFN-omega 1. Antisera to IFN-beta or IFN-gamma likewise had no effect on IFN-omega 1. Conversely, antiserum to IFN-omega 1 did not neutralize any of the other IFNs examined (IFN-alpha 1, -alpha 2c, -alpha 10, -alpha B, -alpha F, -beta, -gamma). None of four monoclonal antibodies to IFN-alpha, including a broad-spectrum antibody that neutralized all five recombinant species of IFN-alpha tested, had any effect on the biological activity of IFN-omega 1. Various immunoassays for IFN-alpha did not recognize IFN-omega 1. In immunoprecipitation experiments, radiolabelled IFN-alpha 2c was not precipitated by antiserum to IFN-omega 1. In contrast, antisera to human leukocyte IFN or 'lymphoblastoid' IFN did neutralize IFN-omega 1, although with titres significantly lower than those towards the immunogen or recombinant species of IFN-alpha. In conclusion, human IFN-omega 1 is antigenically different from human IFN-alpha, IFN-beta or IFN-gamma, but is a component of 'natural' mixtures of IFN species produced by virus-induced leukocytes or Burkitt's lymphoma cells.

Amino Acid Sequence↗
PubMed1991

Protein binding to the interferon response enhancer correlates with interferon induction of 2'-5'-oligoadenylate synthetase in normal and interferon-resistant Friend cells.

The induction of transcription of the 2'-5'-oligoadenylate (2-5A) synthetase gene by type I (alpha/beta) and type II (gamma) interferons (IFNs) has been studied in wild-type (w.t.) and IFN-resistant Friend leukemia cells (FLC). Following IFN treatment, new complexes are formed in vitro between the IFN-responsive sequence (IRS) of the 2-5A synthetase gene and cellular proteins. Within minutes after IFN-alpha/beta addition to w.t. FLC, an IRS-protein complex, designated F1, is detected, as already observed in several human cell lines. In response to IFN-gamma, a novel complex, designated Fg, is observed in w.t. FLC. The Fg complex appears within 3 h, while an F1-like complex is faintly visible 10 to 24 h later. In the IFN-alpha/beta-resistant FLC, IFN-gamma induces only the Fg complex and fails to induce F1. Fg formation is correlated with the IFN-gamma-induced transcription of the 2-5A synthetase gene and the appearance of the corresponding enzymatic activity in both w.t. and IFN-alpha/beta-resistant FLC. These findings suggest that F1 and Fg represent two distinct effector complexes by which type I and type II IFNs, respectively, induce 2-5A synthetase.

2',5'-Oligoadenylate Synthetase↗
PubMed1987

Selective impairment of alpha-interferon-mediated natural killer augmentation in Sjögren's syndrome: differential effects of alpha-interferon, gamma-interferon, and interleukin 2 on cytolytic activity.

Natural killer (NK) function has been shown to be impaired in several autoimmune diseases including Sjögren's syndrome (SS). In the present study, in vitro effects of alpha-interferon (alpha-IFN), gamma-IFN and interleukin 2 (IL-2) on the NK cell activity were examined to analyse the regulatory system of NK-augmentation in patients with SS. The responsiveness of NK cell activity to alpha-IFN was markedly depressed in SS patients compared with normal controls, whereas the responsiveness to gamma-IFN was within normal limits. This is the first demonstration of the selective hyporesponsiveness of NK cell activity to one type of IFN in a certain disease. In addition, the kinetics study of NK-augmentation in normal donors revealed that alpha-IFN enhanced NK cell activity with a faster profile than gamma-IFN. These findings imply substantial differences between the two types of IFN in their mechanisms for enhancing NK cell activity, which deserve attention in evaluating the effects of IFNs. The present study also demonstrated that IL-2 could induce significantly higher levels of NK cell activity than alpha-IFN or gamma-IFN in SS and that this enhancing effect was almost comparable to that in normal controls. Thus, there seem to be multiple regulatory mechanisms for enhancement of NK cell activity, and a portion of the mechanisms may be selectively impaired in certain human diseases such as SS. The selective hyporesponsiveness to alpha-IFN could be relevant to the idea of viral participation in pathogenesis of SS.

Cytotoxicity, Immunologic↗