Search PubMed⌕ Search

Biomedical subjects

A Billiau

Publications and source records attributed to A Billiau.

At least 37 records · Page 2Linked to original sources
PubMed1999

Transcriptional control of the human MCP-2 gene promoter by IFN-gamma and IL-1beta in connective tissue cells.

Human monocyte chemotactic protein-2 (MCP-2) is a member of the CC chemokine family. It is produced by mononuclear leukocytes, diploid fibroblasts, and tumor cells after induction with IL-1beta or IFN-gamma. To understand the transcriptional regulation of the gene, we have analyzed the structure and function of the promoter region. The sequence of the 5'-flanking region was determined and the transcription start site was found to be located at 68 nucleotides upstream of the ATG translation start codon. 5'-Deletion mutants were generated and transfected into E6SM diploid fibroblasts and MG-63 osteosarcoma cells. Expression was measured by luciferase assay in transfected unstimulated cells and after stimulation with IL-1beta, IFN-gamma, or a combination. The region between nucleotides -143 and -73 (relative to the transcription initiation site), containing putative cis-elements for GATA-1, H-APF1, AP-1, and GAS, is important for basal transcription levels in both cell lines. Stimulation for 18 h with IL-1beta alone failed to affect expression of any of the constructs both in diploid fibroblasts and in osteosarcoma cells. In both cell lines IFN-gamma increased the activity of all mutants that possessed the region between -340 and -301. In MG-63 cells, stimulation with the combination of IL-1beta and IFN-gamma caused an additional increase in expression of the constructs from -340 onward. Finally, the presence of transcription factors in nuclear extracts of MG-63 cells and their specificity to bind to various oligonucleotide probes in this [-340; -301] region were evidenced by electromobility shift assays. These results show that IFN-gamma, produced by lymphocytes and NK cells, induces the transcription of the MCP-2 gene in fibroblasts and thereby can indirectly contribute to recruitment of various leukocyte cell types to inflammatory sites.

Base Sequence↗
PubMed1999

Analysis of an IFN-gamma gene (IFNG) polymorphism in multiple sclerosis in Europe: effect of population structure on association with disease.

An intronic dinucleotide polymorphism in the IFN-gamma gene (IFNG) was used as a marker for testing association with multiple sclerosis (MS). Disease association was analyzed in case-control sets sampled from four geographically separate European populations (Germany, Northern Italy, Sardinia, and Sweden). Only in the Swedish was a weak disease association of the IFNG allele pattern found, mainly due to a higher frequency of IFNG allele I1 in MS patients. No evidence for association was found in the German or Northern Italian populations. These results contrast with the situation in Sardinia. We have recently reported transmission disequilibrium of IFNG allele I2 in Sardinian MS siblings not carrying the predisposing DRB1 *03 or *04 alleles (Ann. Neurol. 44, 841-842, 1998). Further analysis now shows that I2 is significantly more often transmitted to DRB1 *03-/*04- males, than to DRB1 *03-/*04- females. The odds ratio (OR) for IFNG-associated susceptibility to MS in the total Sardinian DRB1*03-/*04- group was 1.88 for I2 heterozygotes but amounted to 8.235 for I2 homozygotes, suggestive of a recessive mode of inheritance. Score test-based statistics pointed to an I2 allele dosage effect acting in susceptibility. Comparison of the IFNG allele frequencies in seven European populations (Northern Finnish, Southern Finnish, Swedish, Danish, German, Italian, and Sardinian) revealed a highly different distribution pattern. We introduced latitude as a score variable in order to test for trend in binomial proportions. This test statistic showed that for both most common alleles, I1 and I2 (compiled allele frequency about 85%), a significant opposite north-to-south trend is seen throughout Europe. This effect is primarily due to the extreme values found in the outlier populations of Finland and Sardinia. Our findings are discussed with respect to recent literature pertinent to the role of the IFNG chromosome region in autoimmune diseases.

Alleles↗
PubMed1999

Role of endogenous interleukin-12 (IL-12) in induced and spontaneous relapses of experimental autoimmune encephalomyelitis in mice.

Actively induced, chronic relapsing experimental autoimmune encephalomyelitis (CREAE) was studied in SJL/J and in Biozzi ABH mice. In Biozzi ABH mice, relapses occurred spontaneously with high frequency. In SJL/J mice, spontaneous relapses occurred infrequently; however they could be induced reproducibly by reimmunization. In both models, moderately increased levels of serum IL-12(p40) were consistently found shortly before primary attacks, but irregularly at later times. Injections of anti-IL-12 antibody inhibited disease development in both SJL/J and in Biozzi ABH mice. The time window during which treatment needed to be initiated in order to be effective, ranged from before induction until shortly before the symptoms of primary attacks emerged. Such treatment inhibited not only the first attack but also the spontaneous or induced relapses. Most significantly, anti-IL-12 antibody given during remission of primary disease inhibited actively re-induced relapses in SJL/J, but not spontaneous relapses in Biozzi ABH mice. These results indicate that endogenous IL-12 favours EAE development by crucially affecting the active induction process, but that a second burst of IL-12 production may not be necessary for triggering spontaneous relapses.

Animals↗
PubMed1998

CD40 ligation prevents neonatal induction of transplantation tolerance.

To investigate the consequences of CD40 engagement on the neonatal induction of transplantation tolerance, BALB/c mice were injected at birth with (A/J x BALB/c) F1 spleen cells together with activating anti-CD40 mAb and grafted 4 wk later with A/J skin. Whereas A/J allografts were accepted in mice neonatally injected with F1 cells and control Ab, they were acutely rejected in mice injected with F1 cells and anti-CD40 mAb. Neonatal administration of anti-CD40 mAb resulted in enhanced anti-A/J CTL activity, increased IFN-gamma, and decreased IL-4 production by donor-specific T cells in vitro. Experiments using anti-cytokine mAb and IFN-gamma-deficient mice demonstrated that CD40 ligation prevents neonatal allotolerance through an IFN-gamma- and IL-12-dependent pathway. Finally, we found that newborn T cells express less CD40L than adult T cells upon TCR engagement. Taken together these data indicate that insufficiency of CD40/CD40L interactions contribute to neonatal transplantation tolerance.

Animals↗
PubMed1998

GroEL/ES chaperonins protect interferon-gamma against physicochemical stress--study of tertiary structure formation by alpha-casein quenching and ELISA.

Interferon-gamma (IFN-gamma) is a structurally labile cytokine that rapidly denatures upon exposure to acid or heat. Here we show that both acid-denatured (pH 2) and thermally inactivated (50 degrees C) porcine IFN-gamma can be rescued with the Escherichia coli GroEL/ES chaperonin system and ATP, and reassembled into bioactive dimers. At 35 degrees C, spontaneous refolding of acid-denatured IFN-gamma was found to be dependent on the presence of guanidinium hydrochloride (0.15-0.25 M) or NaCl (0.1-0.2 M). Under non-permissive reaction conditions for regain of native structure (low-ionic-strength buffer at 35 degrees C), the yield of IFN-gamma refolded with GroEL/ES/ATP increased about 30-fold above the level of spontaneous refolding. In the absence of GroES, GroEL captured IFN-gamma in a folding-competent complex. Under these conditions, both ATP and alpha-casein induced release of IFN-gamma from GroEL but with the released protein tending to partition into sedimentable aggregates. Only in the presence of GroES, did ATP induce complete discharge of IFN-gamma from GroEL, with the released protein refolded into a conformation that is (a) immunoreactive/bio-active, (b) resistant to precipitation and (c) in a dimeric configuration. Chicken egg albumin and 90-kDa heat-shock protein were inactive in the exertion of any protective effect against physicochemical stress. The precise amount of protein refolded to the native state at different times of the folding reaction was determined by alpha-casein quenching and ELISA. The former is based on the conversion by excess alpha-casein of any population of unfolded IFN-gamma into one that escapes antibody recognition by subsequent ELISA. Since the native dimers, however, are not affected by alpha-casein quenching, immunoreactivity is directly proportional to the yield of correctly refolded protein. The validity of this approach was confirmed by measurement of biological activity. GroEL/ES-meditated reactivation amounted to > 80% both by ELISA and antiviral assay.

Animals↗
PubMed1998

Anti-IL-12 antibody prevents the development and progression of collagen-induced arthritis in IFN-gamma receptor-deficient mice.

In several models of inflammation, including collagen-induced arthritis (CIA), the disease-promoting effect of IL-12 has been attributed to its well-known ability to produce IFN-gamma. However, IFN-gamma receptor knockout (IFN-gammaR KO) mice of the DBA/1 strain have been reported to be more susceptible to CIA than corresponding wild-type mice, indicating the existence of an IFN-gamma-mediated protective pathway in this model. In the present study the development of CIA was found to be completely prevented by pretreatment with a neutralizing anti-IL-12 antibody, not only in wild-type, but significantly also in IFN-gammaR KO mice. In both strains of mice, the protective effect of anti-IL-12 was associated with lower production of anti-collagen type II antibodies. In vivo stimulation with anti-CD3 antibody in arthritic IFN-gammaR KO mice resulted in production of higher levels of circulating IFN-gamma, TNF and IL-2 than in corresponding control mice that had not received the arthritis-inducing immunization. This was not the case in arthritis-developing wild-type mice. Furthermore, the protective effect of anti-IL-12 antibody in mutant, but not in wild-type mice, was associated with lower circulating IFN-gamma, TNF and IL-2 and higher IL-4 and IL-5 cytokine levels following an anti-CD3 challenge. The data indicate that IL-12 promotes the development of arthritis independently of its ability to induce or favor production of IFN-gamma. In fact, any IFN-gamma produced in the course of the disease process rather exerts a protective effect. Furthermore, our study suggests that, in the absence of a functional IFN-gamma system, endogenous IL-12 exerts its disease-promoting effect by favoring production of other Th1-associated cytokines (IL-2 and TNF), by inhibiting development of IL-4- and IL-5-producing T cells and by stimulating production of anti-collagen autoantibodies.

Animals↗
PubMed1998

Recombinant porcine IFN-gamma potentiates the secondary IgG and IgA responses to an inactivated suid herpesvirus-1 vaccine and reduces postchallenge weight loss and fever in pigs.

The effect of recombinant porcine interferon-gamma (IFN-gamma) on the immunogenicity in vivo of inactivated suid herpesvirus-1 (SHV-1, Phylaxia strain) was studied applying two successive i.m. immunizations. The animals were injected with inactivated virus alone or inactivated virus supplemented with 10(4) or 10(6) U IFN-gamma. After the first immunization, none of the animals responded with measurable virus-neutralizing antibody (VNAb), virus-specific IgG or IgA. Following a second immunization 4 weeks later, a significantly increased VNAb response was noted in animals that had received vaccine doses containing 10(4) U IFN-gamma (p < 0.05). These animals also had significantly augmented serum levels of IgG (p < 0.01) and IgA (p < 0.05). Inclusion of 10(6) U IFN-gamma in the vaccine preparation did not affect the antibody response. In one experiment, the pigs were challenged oronasally with 10(5) TCID50 of the 75V19 strain of SHV-1, 7 weeks after administration of the second vaccine dose. Those that had received 10(4) U IFN-gamma in the vaccination developed less fever during the postchallenge period (p < 0.004). In all challenged pigs, growth performance was compromised during the first week after challenge. However, the only animals retaining an average net increase in body mass were those covaccinated with 10(4) U IFN-gamma (p < 0.05). Nasal excretion of virus was not significantly different between groups that had been vaccinated with or without IFN-gamma. Multiple linear regression analysis of variables from individual vaccinated animals revealed the VNAb response to be correlated with serum IgG levels (p < 0.025) and with postchallenge growth performance (p < 0.0001) but not with serum IgA levels (p > 0.5). On the other hand, serum IgA appeared to be inversely correlated with early nasal virus excretion after challenge (p < 0.006). Taken together, our data suggest that addition of IFN-gamma to inactivated SHV-1 vaccine may be a useful tool for enhancement of both mucosal and systemic immune responses in pigs.

Animals↗
PubMed1998

[Interferon-gamma, the Th1/Th2 paradigm and autoimmune diseases].

Autoimmune diseases originate from a rupture in physiological immune tolerance towards self antigens. However, the formation of autoantibodies and autoreactive inflammatory cells is also regulated by the cytokine network, in which interferon-gamma (IFN-gamma), produced by NK and T lymphocytes, occupies a central position. IFN-gamma influences the function of all cell types involved in immune-mediated inflammatory reactions: antigen-presenting cells, cytotoxic and regulatory T lymphocytes, antibody-producing B lymphocytes, endothelial cells and mononuclear phagocytes. Experimental manipulations which affect the production or action of IFN-gamma invariably affect the course of experimentally induced autoimmune diseases in animals, but do so in divergent directions. A current explanatory framework for these actions of IFN-gamma invokes the T helper-1/T helper-2 (Th1/Th2) concept. According to this concept, autoimmune diseases, like other immune reactions, fall apart in two categories depending on whether the T helper lymphocytes assume a Th1 or Th2 profile. IFN-gamma is assumed to fulfill the function of a promotor and effector of the Th1 profile and is associated with inflammation and tissue damage typical for cell-mediated hypersensitivity reactions. Accordingly, IFN-gamma should boost autoimmune diseases of the Th1 type. However, experimental testing of this prediction contradicts this implication and necessitates revision of the function assigned to IFN-gamma in the Th1/Th2 concept.

Autoimmune Diseases↗
PubMed1997

Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice.

Collagen-induced arthritis (CIA) is a model for rheumatoid arthritis. Here, we describe experiments showing that IFN-gamma receptor knockout (IFN-gammaR alpha KO) mice of the DBA/1 strain develop CIA more readily than their wild-type counterparts. Symptoms of disease started 10 days earlier and the cumulative incidence of arthritis was significantly higher in the mutant mice than in wild-type mice. Similarly, accelerated onset of the disease was also found in wild-type DBA/1 mice treated with neutralizing mAbs against IFN-gamma. Histologic examination of the joints revealed a massive infiltration of the synovium with mononuclear cells and neutrophils, hyperplasia, and severe pannus formation in IFN-gammaR alpha KO mice when such inflammatory lesions were not yet detectable in wild-type mice. Serum levels of anti-collagen type II Abs, including total IgG and IgM, as well as IgG1, IgG2a, and IgG2b isotypes were found to be lower in the mutant mice. IL-2 and IL-4 remained undetectable in sera of both groups of mice, but did appear in the circulation after anti-CD3 Ab challenge. Significantly higher IL-2 and lower IL-4 serum levels were found in anti-CD3-challenged IFN-gammaR alpha KO mice than in wild-type counterparts, both at an early and at a later stage of the disease. These observations indicate that endogenous IFN-gamma counteracts development of collagen-induced arthritis and suggest that IFN-gamma does so by up-regulating IL-4 production and/or down-regulating IL-2 production. The data are in line with the concept of a pathogenic role of Th1-type cellular immunity in CIA in spite of a decreased Ab response to collagen type II.

Animals↗
PubMed1997

Production and characterization of recombinant active mouse gelatinase B from eukaryotic cells and in vivo effects after intravenous administration.

Gelatinase B is a matrix metalloproteinase involved in tissue remodelling. When mouse cells are triggered in vitro with interleukin-1, bacterial endotoxin, virus-mimicking double-stranded RNA or cytokine inducers, they produce gelatinase B. To test the effects of gelatinase B in vivo, the enzyme was expressed in Chinese hamster ovary (CHO) cells. Hybrid genomic DNA-cDNA constructs under the control of two constitutive viral promoters were generated by PCR-mediated exon amplification. In vitro transcription and translation of the mRNA in reticulocyte lysate yielded the correct 79-kDa protein, and expression in CHO cells resulted in an intact glycosylated 110-kDa gelatinase B which was enzymically active. However, the production yields of recombinant enzyme from 50 tested clones were low and cell-culture supernatants contained significant amounts of copurifiable endogenous CHO gelatinase B. Therefore, the enzyme was expressed in the yeast Pichia pastoris. Recombinant proenzyme was secreted and recovered from the yeast culture medium at 10 mg/l. Amino-terminal sequence analysis indicated that affinity purification of the recombinant protein on gelatin-Sepharose yielded the expected N-glycosylated proenzyme form (110 kDa) in addition to an amino-terminally truncated unglycosylated variant (69 kDa). Both forms had gelatinolytic activity on zymography. The recombinant mouse gelatinase B was used to determine its pharmacokinetics and its haematological effects in vivo. After intravenous injection in rabbits, gelatinase B disappeared from the circulation within 6 h. In addition to a transient leukopenia, we observed a rapid increase in leukocytosis, which indicates that gelatinase B might be a factor involved in the desorption of adherent leukocytes from the vascular bed and in the release of leukocytes from the bone marrow. Gelatinase B secretion and activation might well be one of the crucial molecular mechanisms explaining leukocytosis which is associated with infections and almost all types of inflammation.

Animals↗
PubMed1997

Cloning, bacterial expression and biological characterization of recombinant human granulocyte chemotactic protein-2 and differential expression of granulocyte chemotactic protein-2 and epithelial cell-derived neutrophil activating peptide-78 mRNAs.

Human osteosarcoma cells secrete a novel C-X-C chemokine called granulocyte chemotactic protein-2 (GCP-2), which was previously identified by amino acid sequencing of the purified natural protein. In order to understand the role of this new protein in inflammatory reactions, we cloned GCP-2 DNA sequences to generate recombinant protein and specific DNA probes and primers. By means of PCR on cloned cDNA of osteosarcoma cells induced by interleukin-1 beta and fibroblasts induced by lipopolysaccharide plus dsRNA, the complete coding domain of GCP-2 was isolated. This sequence was cloned into the bacterial expression vector pHEN1 and, after induction, GCP-2 was secreted into the periplasm of Escherichia coli. Recombinant GCP-2 (rGCP-2) was purified and characterized by SDS/PAGE as a monomeric 6.5-kDa protein and by amino-terminal sequencing. The chemoattractive potency of GCP-2 for neutrophilic granulocytes was about 10-times less than that of interleukin-8 and the minimal effective dose was 10 ng/ml. However, at optimal dose (100 ng/ml) the maximal chemotactic response was comparable with that of interleukin-8. Both characteristics correspond with those of natural GCP-2. In addition, intracellular calcium release in neutrophils by recombinant GCP-2 was achieved with as little as 10 ng/ml. Quantitation studies using reverse transcriptase and the polymerase chain reaction revealed higher GCP-2 mRNA production in normal fibroblasts than in tumor cells. When compared with epithelial-cell-derived neutrophil-activating peptide-78 (ENA-78) mRNA, the GCP-2 mRNA levels were higher in all cell lines tested. In addition, GCP-2 and ENA-78 expression seem to be differentially regulated in that phorbol ester and lipopolysaccharide have opposing effects on their mRNA induction in diploid fibroblasts and epithelial cells, respectively. Interleukin-1 was demonstrated to be a general inducer for both chemokines, while interferon-gamma down-regulates their mRNA expression. The availability of recombinant GCP-2 together with the quantitation studies on mRNA expression will help to further elucidate the biological role of GCP-2 during the inflammatory response.

Amino Acid Sequence↗
PubMed1997

Granulocyte chemotactic protein-2 and related CXC chemokines: from gene regulation to receptor usage.

Chemokines contribute to the inflammatory response by selective attraction of various leukocytic cell types. Human GCP-2 was originally identified by amino acid sequence analysis as a CXC chemokine co-produced with IL-8 by osteosarcoma cells. Furthermore, the complete coding domain of human GCP-2 was disclosed by means of RT-PCR. Similarly, mouse GCP-2 was isolated from fibroblastoid and epithelial cells and completely identified by sequence analysis. Human and mouse GCP-2 share 61% identical amino acids. Both chemokines occur as multiple NH2-terminally truncated forms. The shorter forms of mouse, but not those of human, GCP-2 showed a higher neutrophil chemotactic potency and gelatinase B releasing capacity. Mouse GCP-2 was a more potent neutrophil activator than human GCP-2, natural mouse KC, and MIP-2. Human GCP-2 was not chemotactic for monocytes, lymphocytes, or eosinophils. Quantitative studies of mRNA expression in diploid fibroblasts revealed GCP-2 induction by IL-1beta. Human GCP-2 induced [Ca2+]i increase in neutrophils, which was reciprocally desensitized by IL-8, GROalpha, and ENA-78. Human GCP-2 induced [Ca2+]i increases and chemotactic responses in both CXCR1- and CXCR2-transfected cells. Finally, GCP-2 provoked neutrophil accumulation and plasma extravasation in rabbit skin. In humans, GCP-2 complements the activity of IL-8 as neutrophil chemoattractant and activator but it constitutes a major neutrophil chemokine in the mouse. GCP-2 induces neutrophil chemotaxis and activation but it might also contribute to detrimental tissue damage in sepsis, acute respiratory distress syndrome, acute hypersensitivity reactions, and autoimmune diseases. It might also influence the invasive capacity of GCP-2-secreting tumor cells.

Amino Acid Sequence↗
PubMed1997

A competitive RT-PCR method for the quantitative analysis of cytokine mRNAs in mouse tissues.

The authors describe the design and validation of a competitive RT-PCR method for the efficient and reproducible quantitation of mRNA molecules of IFN-gamma, TNF-alpha, IL-4 and IL-10 in mouse spleen RNA extracts. Before being subjected to RT-PCR, the RNA extracts were supplemented with internal control RNAs (IC-RNAs), which were constructed by inserting DNA fragments in the cDNA of the respective cytokines. The efficiency of amplification of the target and the IC-RNA was shown to remain equal over a wide range of cycle numbers. Reproducibility was such that differences in mRNA contents that were greater than 17% could be detected between two RNA samples run in parallel. Normal mouse spleen tissue was found to contain 10(7)-10(8) molecules of TNF-alpha, IFN-gamma, IL-4 and IL-10 mRNA per micrograms total RNA extracted. Injection of animals with anti-CD3 antibody, a well-known cytokine inducer, resulted in a moderate increase in TNF-alpha and IL-10 mRNA levels (14- and 24-fold, respectively), and in a substantially greater increase in the levels of mRNA for IL-4 and IFN-gamma (199- and 851-fold, respectively). These results demonstrate an accurate and reliable quantitation of cytokine mRNA levels in animal tissues.

Animals↗
PubMed1997

Structural immuno-analysis of human and porcine interferon gamma: identification of shared antigenic domain.

We examined the antigenic resemblance between human (h) and porcine (p) interferon (IFN)-gamma by binding (ELISA) and neutralization assays. The murine polyclonal antisera and sets of murine monoclonal antibodies (mAbs) raised against either IFN were tested in confrontation with recombinant IFNs of either species, and with site-specific mutants of hIFN-gamma. Several of the mAbs raised against pIFN-gamma cross-reacted in ELISA with hIFN-gamma. In contrast, none of the anti-hIFN-gamma mAbs cross-reacted. By employing site-specific mutants of recombinant hIFN-gamma as antigens in ELISA we succeeded in identifying the C-terminal portion 97-111 as the antigenic site in hIFN-gamma recognized by the cross-reactive anti-pIFn-gamma mAbs. None of the mAbs recognizing the common antigenic structure had neutralizing potency, although His111 was determined by others as the residue important for bioactivity of hIFN-gamma. Mutations in the domain 97-111 had no or little influence on homospecific reactivity of anti-hIFN-gamma mAbs, indicating that this domain, while being mouse-immunodominant in the case of pIFn-gamma was poorly immunogenic in the case of hIFN-gamma. The epitopes of three out of five anti-hIFN-gamma mAbs mapped in the N-terminal region 1-23, indicating immunodominance of this region in hIFN-gamma. Another mAb (D9D10), also directed to the N-terminus of hIFN-gamma, apparently recognized a conformational epitope. This antibody lacked ELISA-reactivity with the wild-type hIFN-gamma but strongly bound mutant protein with an engineered disulfide bridge Cys7-Cys69. Surprisingly, D9D10 showed high reactivity also with the wild type hIFN-gamma produced by baculovirus construct coding for the mature protein with signal sequence or with wild type protein possessing residues Cys-Tyr-Cys from the signal sequence.

Animals↗
PubMed1997

Potential therapeutic use of antibodies directed towards HuIFN-gamma.

IFN-gamma is an important regulator of immune responses and inflammation. Studies in animal models of inflammation, autoimmunity, cancer, transplant rejection and delayed-type hypersensitivity have indicated that administration of antibodies against IFN-gamma can prevent the occurrence of diseases or alleviate disease manifestations. Therefore, it is speculated that such antibodies may have therapeutical efficacy in human diseases. Since animal-derived antibodies are immunogenic in patients several strategies are being developed in order to reduce or abolish this human anti-mouse antibody (HAMA) response. In our laboratory, we have constructed a single-chain variable fragment (scFv) derived from a mouse antibody with neutralizing potential for human IFN-gamma. A scFv consists of only variable domains tethered together by a flexible linker. The scFv was demonstrated to neutralize the antiviral activity of HuIFN-gamma in vitro and therefore might be considered as a candidate for human therapy.

Animals↗