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PubMed1986

Natural antibodies to interferon-alpha and interferon-beta are a common feature of inbred mouse strains.

Neutralizing antibodies to murine interferon-alpha (MuIFN-alpha) and MuIFN-beta of the immunoglobulin (Ig)G and IgM class were naturally present in sera of BALB/c and C57BL/6 mice of four different age groups, ranging from 1 to 15 mo. These antibodies not only neutralized IFN made by C-243 cells (Swiss genotype), but also isogenic IFN-alpha and IFN-beta, and can therefore be considered to be real autoantibodies. Natural anti-MuIFN antibodies were also found in the sera of mice from 12 other inbred strains, and seem to be a common feature of inbred mouse strains.

Animals↗
PubMed1981

Polyenzymatic activation of cellular hydrolases induced by interferon; its role in cell lysis and other interferon--related phenomena.

Treatment of human cultured T cells by interferon (IFN), which enhances cell-mediated cytotoxicity directed against human K562 cell targets (NK-like activity) induces an activation of cell hydrolases. Treatment of mouse cultured L929 cells by IFN and double strand RNA enhancing cell autolysis induces first an activation of tested hydrolases (hexosaminidase, beta-glucuronidase, acid and alkaline phosphatases). Polyenzymatic activation of hydrolases induced by IFN is similar to coordinate enzymatic induction described by Hosli which occurs by lack of specific enzyme when non-digestible substrates are absorbed by cells. It is hypothesized that the polyenzymatic activation which accounts for cell lysis is a general defense mechanism which might also explain other actions related to IFN such as antiviral effect, inhibition of cell division, diminution of protein synthesis and cell surface alteration.

Animals↗
PubMed1981

Natural cytotoxicity and interferon production in human cancer: deficient natural killer activity and normal interferon production in patients with advanced disease.

Natural cytotoxicity was measured in 51 adult patients with solid epithelial malignant tumors and in 27 normal subjects. Peripheral blood leukocytes (PBL) from 31% of the patients and 7% of the controls failed to kill target cells (K562) in a short-term chromium-release assay. When patients were classified according to clinical stage, PBL from 12% of patients with localized cancers, but 50% of patients with advanced disease, failed to exhibit cytotoxicity within the normal range. Pretreatment of PBL with interferon alpha (IFN alpha) or with Newcastle Disease Virus (NDV), a potent inducer of IFN alpha, enhanced cytotoxicity from all normal subjects. Of patients whose PBL lacked spontaneous cytotoxicity, half were able to kill normally after pretreatment of PBL with IFN alpha or NDV. Virtually all the patients whose PBL were unable to kill despite pretreatment with IFN alpha or virus had disseminated malignancies. IFN alpha production by PBL exposed to NDV and to K562 cells was normal in all the patients regardless of stage of disease or ability to kill K562 cells. The observed defect in natural cytotoxicity is thus unlikely to be due to a failure of PBL to produce IFN alpha.

Adult↗
PubMed1982

[Polyenzymatic activation of cellular hydrolases induced by interferon; its role in cytolysis and other cellular manifestations induced by interferon].

Interferon (IFN) treatment of human effector T cells activates CMC directed against K562 targets. An increase of the activity of the different hydrolytic enzymes tested (hexosaminidase and acid-phosphatase) measured in the effector cell population parallels cytolysis activation. IFN and IFN inducers (PIC) treatment of cultured murine L-929 cells generate molecular mediated cytolysis. An increase of hydrolytic enzyme activity (hexosaminidase; B-glucuronidase, acid and alkalin phosphatases) precedes cell lysis. Thus, in both cytolytic systems, IFN induced a polyenzymatic activation of hydrolases. This activation is similar to coordinate enzyme induction discovered by Hosli [16] in pathological and experimental instances, when absorbed substrates cannot be hydrolyzed by lack of specific enzymes. Activation of hydrolytic enzymes induced by IFN which determines its enhancing effect on CMC and on fibroblast autolysis [17] could speculatively explain other effects of IFN such as antiviral action, diminution of cell protein synthesis, inhibition of cell division or molecular alterations of cell surface.

Alkaline Phosphatase↗
PubMed1982

Deficiency of interferon-gamma but not interferon-beta in Arabian foals with severe combined immunodeficiency.

The results of a study on the induction of IFN-alpha, IFN-beta, and IFN-gamma in normal and SCID foals showed a deficiency of IFN-gamma but not IFN-beta in SCID foals. The ability of SCID mononuclear cells to produce IFN-alpha in response to poly I:C but not to NDV may indicate a partial deficiency of IFN-alpha in SCID foals. The deficiency of IFN-gamma and presence of IFN-beta in SCID foals supports the classification of IFN-gamma and IFN-beta as immune and nonimmune interferons, respectively. Furthermore, the deficiency of IFN-gamma in SCID foals may in part explain the high susceptibility to infections observed in SCID foals.

Animals↗
PubMedDate not supplied

Treatment of lymphoid neoplasias with interferon. II. Human leucocyte alpha-interferon in chronic lymphatic leukemia (CLL). PHase I-II trial.

Nine patients with chronic lymphoid leukemia (CLL) were treated with subcutaneous human (leukocyte) interferon a (IF a). In the first part of the study, 7 patients received intermittent 10 day courses, with free intervals of 10 to 15 days and with dose escalation in the same patient from cycle to cycle from 1.5 to 6 X 10(6) units daily, if tolerated. As we observed a decrease of peripheral lymphocytosis with low doses, and as high doses gave more side-effect in the second part of the study, 4 patients (including two who has previously received intermittent courses) were treated for three months or more at a dose of 1.5 X 10 units daily. Tumor mass reduction was seen in only three patients. However, a significant decrease in peripheral lymphocytosis was seen in 7 patients who were sustained in the continuous treatment group; with relapse at treatment discontinuation in one patient and despite continuation in another. Immune monitoring with currently available T, B, NK and macrophage tests, showed a good correlation between NK cell activity and clinical response, in this group of patients. Further studies are warranted to determine the best modalities of treatment, the population of patients likely to benefit from such treatment, the possible special respective indications of IF, and also the other treatments of CLL. One can already consider as a reasonable indication CLL presentations with myeloid insufficiency as IF is not myelotoxic, contrary to chemotherapy.

Aged↗
PubMed1982

Mechanism of interferon action. Kinetics of induction of the antiviral state and protein phosphorylation in mouse fibroblasts treated with natural and cloned interferons.

The induction of phosphorylation of both protein P1 and protein synthesis initiation factor eIF-2 alpha and the inhibition of virus replication were examined in mouse L929 fibroblasts treated with either natural mouse or individual cloned human interferons (IFN). Natural mouse IFN synthesized in Newcastle disease virus-induced L929 cells and two cloned human leukocyte IFN subspecies synthesized in Escherichia coli, IFN-alpha D and IFN-alpha A/D, possessed antiviral activity in L929 cells as measured by single cycle virus yield reduction with both vesicular stomatitis virus and reovirus. Natural L929 IFN and cloned IFNs, alpha D and alpha A/D, also induced the protein kinase that catalyzed the phosphorylation of endogenous ribosome-associated protein P1 and the alpha subunit of purified initiation factor eIF-2. Two other cloned human IFNs, alpha A and alpha D/A, were poor inducers of both the antiviral state and the phosphorylation of P1 and eIF-2 alpha in mouse L929 cells. The ability of individual human IFN-alpha subspecies to induce P1 and eIF-2 alpha phosphorylation in mouse L929 cells correlated with their ability to induce an antiviral state. Furthermore, the detailed kinetics of induction, in mouse L929 cells, of P1 and eIF-2 alpha phosphorylation and of the antiviral state by the heterologous cloned human IFN-alpha A/D were equivalent to the kinetics of induction by the homologous natural mouse L929 IFN. These results suggest that different subspecies of biologically active IFN induce equivalent antiviral activities and biochemical changes in mouse L929 cells, and that protein phosphorylation may play a major role in the antiviral mechanism of IFN action in mouse L929 fibroblasts.

Animals↗
PubMed1982

Mechanism of interferon action. Kinetics of decay of the antiviral state and protein phosphorylation in mouse fibroblasts treated with natural and cloned interferons.

The kinetics of decay of the antiviral state and protein phosphorylation induced with natural mouse interferon (IFN) and with cloned human IFN were examined in monolayer cultures of mouse Ll929 fibroblast cells. The antiviral state measured by single cycle virus yield reduction with either vesicular stomatitis virus or reovirus decayed significantly within 2 to 3 days following removal of IFN and by 5 to 8 days virus yields had returned to the level of untreated control cells. Trypsinization of IFN-treated cells did not detectably alter the rate of decay of the antiviral state; however, the decay occurred slightly more rapidly in actively growing as compared to stationary cell cultures. The decay of the IFN-induced protein kinase which catalyzes the phosphorylation of endogenous protein P1 and purified initiation factor eIF-2 alpha correlated with the decay of the antiviral state. The decay rates of the antiviral state and protein kinase observed in mouse L929 cells that had been treated with natural mouse IFN synthesized in Newcastle disease virus-induced L929 cells were comparable to the decay rates observed in L929 cells that had been treated with recombinant human IFN-alpha A/D synthesized in Escherichia coli. The induction and decay of the antiviral state and protein kinase following treatment with a single dose of IFN did not significantly affect the sensitivity of the cell population to a subsequent treatment with a single dose of IFN. However, continuous treatment of L929 cells with natural mouse IFN or recombinant human IFN prevented the decay of both the antiviral state and protein kinase but also ultimately lead to cell death. The results suggest that protein phosphorylation may play an important role in the mechanism of IFN action in mouse L929 fibroblasts.

Animals↗
PubMed1983

Mechanism of interferon action III--significance of pppA2'p5'A2'p5'A in the antiviral action of interferon.

This paper is to evidence that the antiviral effect of pppA2'P5'A2'P5'A(2'-5'P3A3) could cover a wide spectrum of viruses, the RNA viruses such as influenza H3N2/77, influenza H1N1/77, ECHO11, rhino, Sendai, Sindbis and VSV, and the DNA viruses such as herpes (type I). In addition, the antiviral effect of 2'-5'P3A3 on ECHO11 virus, as compared with other viruses, is more efficient than that of IFN. It seems likely that 2'-5'P3A3 plays an important role in the antiviral action of IFN. After comparing the action of 2'-5'P3A3 with interferon (IFN), it has appeared that the action of 2'-5'P3A3 is something parallel to that of IFN for most viruses. For a few viruses, however, considerable differences have been observed.

Adenine Nucleotides↗
PubMed1984

In vitro synergistic effects of interferon on human lymphotoxin activity: a new property of interferon in lymphocyte-mediated target cell killing.

Our recent studies have demonstrated a significant enhancement of human lymphotoxin (LT) induced in vitro target cell killing by human alpha and beta interferons (IFN), including highly purified recombinant DNA-produced IFN. This synergistic effect of IFN on LT activity was dose dependent, observed with as little as 10 U/ml IFN, was demonstrable on human normal and tumor cells, and was blocked by treatment with antiserum to IFN. When IFNs and target cells from other animal species were tested, a new finding was made showing protective effects of IFN on human LT activity. IFN-induced enhancement or protection depended on the particular IFN:target cell combination, with the highest degree of enhancement being observed in the homologous human combination. These results describe a new property of IFN in lymphocyte-mediated target cell killing and are discussed in relationship to previously observed enhancing and protective effects of IFN in natural killer (NK) cell systems, as well as to the role of IFN in viral infection.

Animals↗
PubMed1983

Interferon-induced enhancement of macrophage Fc receptor expression: beta-interferon treatment of C3H/HeJ macrophages results in increased numbers and density of Fc receptors.

Previous studies demonstrated that the augmentation of Fc receptor-(FcR) mediated phagocytosis and binding of opsonized sheep erythrocytes is cytokine mediated. Specifically, beta-interferon- (beta-IFN) and gamma-IFN-rich preparations were shown to increase binding and phagocytosis of opsonized erythrocytes by C3H/HeJ macrophages. In this report we extend these studies by examination of the mechanisms by which highly purified beta-IFN increases FcR capacity in C3H/HeJ macrophages. Our findings indicate that beta-IFN augments FcR function for both IgG2a and IgG2b receptor subclasses. Moreover, this increased ability to bind and phagocytose opsonized erythrocytes is associated with a concomitant increase in both the number and surface membrane density of FcR.

Animals↗
PubMed1983

Mechanism of interferon action: inhibition of vesicular stomatitis virus replication in human amnion U cells by cloned human leukocyte interferon. I. Effect on early and late stages of the viral multiplication cycle.

The kinetics of induction in human amnion U cells of the antiviral activity against vesicular stomatitis virus (VSV) produced by a single molecularly cloned subspecies of human leukocyte interferon (IFN-alpha A) were examined. IFN-alpha A-induced inhibition was found to be biphasic over a period of 24 h with the major extent of VSV inhibition occurring within the first 6 h of IFN treatment. The relationship of this major phase of inhibition to the early and late events of the VSV multiplication cycle was investigated. IFN-alpha A treatment had no detectable effect on the adsorption and penetration of VSV virions or on their uncoating to yield viral nucleocapsids. The polypeptides of adsorbed or uncoated VSV particles were neither preferentially degraded nor detectably altered in IFN-treated cells, as compared to untreated cells. Progeny virions released from IFN-treated cells, although greatly reduced in number, were found to be equally as infectious as those released from untreated cells. Progeny virions from IFN-treated cells also had a normal complement of VSV proteins in the same ratios as were seen in virions from untreated cells; specifically, IFN treatment produced no reduction in the incorporation of G or M protein into assembled virions. These results suggest that conditions of IFN treatment sufficient to reduce the yield of infectious VSV progeny greater than 99% do not detectably affect either the early or the late stages of the VSV multiplication cycle.

Amnion↗
PubMed1983

Mechanism of interferon action: inhibition of vesicular stomatitis virus replication in human amnion U cells by cloned human leukocyte interferon. II. Effect on viral macromolecular synthesis.

The effects of a single molecularly cloned subspecies of human leukocyte interferon (IFN-alpha A) on vesicular stomatitis virus (VSV) macromolecular synthesis in human amnion U cells were examined. IFN-alpha A was found to uniformly inhibit VSV protein synthesis to an extent sufficient to account for the overall inhibition of viral infectivity. IFN-alpha A treatment also prevented the shutoff of cellular protein synthesis observed in untreated, VSV-infected U cells. By use of the VSV mutant tsG41, which is competent in RNA transcription but defective in RNA replication at 40 degrees C, it was shown that IFN did not significantly inhibit the accumulation of VSV primary transcripts, although the in vivo translation of primary viral transcripts was greatly impaired as a function of IFN treatment. Thus, the major, and possibly only, effect of IFN-alpha A on VSV replication was translation inhibition. Analysis of RNA, separated by agarose gel electrophoresis after denaturation with glyoxal, with cDNA probes to individual VSV mRNAs, did not reveal any detectable difference in the structural integrity of VSV mRNA isolated from IFN-treated as compared to untreated cells. Likewise, in vitro protein synthesis did not reveal any major difference in the functional integrity of VSV mRNA isolated from IFN-treated as compared to untreated U cells. Viral mRNA isolated from either wild type or tsG41-infected U cells treated with IFN was translated only slightly less efficiently in vitro than viral mRNA from untreated cells. Thus, the principal cause of the IFN-induced inhibition of viral protein synthesis observed in vivo appears to be an alteration of a component of the translational machinery other than the mRNA template.

Amnion↗
PubMed1984

Role of interferon and 2',5'-oligoadenylate synthetase in erythroid differentiation of Friend leukemia cells. Studies with interferon-sensitive and -resistant variants.

It has been suggested that the interferon (IFN)-induced 2',5'-oligoadenylate (2-5A) synthetase, which polymerizes ATP into a series of 2',5'-linked oligomers with the general formula pppA(2'p5'A)n, plays a general role in cell growth and terminal differentiation. For instance, an increase in 2-5A synthetase activity has been described during dimethyl sulfoxide (Me2SO)-induced erythroid differentiation of Friend leukemia cells (FLC). 2-5A synthetase has been measured in two Friend leukemia cell sublines by various techniques including a radioimmunoassay of its products which would detect 10(-16) mol of 2-5A cores. Although cells of both sublines fully differentiate (as measured by benzidine staining), only in one subline was there an increase in 2-5A synthetase activity upon treatment with Me2SO. Hexamethylenebisacetamide, another potent agent of differentiation in this system, did not increase 2-5A synthetase activity in either of these two sublines. An IFN-resistant FLC variant differentiated normally upon treatment with Me2SO or hexamethylenebisacetamide while it was noninducible for 2-5A synthetase activity by exogenous IFN or by the inducers themselves. A similar situation has been observed with regard to the level of phosphorylation of the IFN-induced Mr = 67,000 protein band. In addition, treatment of IFN-sensitive and resistant FLC sublines with mouse alpha beta IFN antiserum did not affect differentiation. Even though we have duplicated previous findings on the increase of 2-5A synthetase activity in Me2SO-induced FLC, the lack of any such increase with other inducers or other sublines indicates that there is no causal relationship between the enzyme activation and FLC differentiation.

2',5'-Oligoadenylate Synthetase↗
PubMed1983

Parameters of interferon action: I. Immunological effects of whole cell leukocyte interferon (IFN-alpha) in phase I-II trials.

The antitumor mechanisms of the interferons (IFN) have yet to be fully elucidated. Augmentation of natural killer (NK) cell activity in vitro and in vivo by IFN has regularly been assessed in clinical trials. We have measured NK activity against K562 target cells at various effector-to-target ratios, in patients receiving leukocyte IFN-alpha (HuLeIFN) in various schedules, as well as T-cell subsets determined by indirect immunofluorescence using Leu series monoclonal antibodies (Becton-Dickinson). The effect of HuLeIFN on the endocrine system has also been examined in selected trials. The preliminary results of these studies reveal that NK activity rose during the first 8 days of HuLeIFN therapy in patients with initially low levels of target cell lysis (less than 50% NK activity at either 50:1 or 25:1 ratios). Tachyphylaxis, with a decremental effect of HuLeIFN on NK activity, ensued during treatment, whether at the same or escalated doses. NK activity rose repeatedly during intermittent schedules of i.m. HuLeIFN given daily x 5 every 21 days with escalation cycles. A decreasing trend in the ratio of Leu 3a to Leu 2a (helper phenotype/suppressor phenotype) was also seen overall. Of the endocrine parameters evaluated, the only remarkable finding was an increase in serum cortisol level following ACTH stimulation following HuLeIFN. Intramuscular HuLeIFN has been shown to augment NK activity, to perturb the T-cell-lymphocyte balance, and to affect the pituitary-adrenal axis in vivo.

Adenocarcinoma↗
PubMed1984

Mechanism of interferon action. Increased phosphorylation of protein synthesis initiation factor eIF-2 alpha in interferon-treated, reovirus-infected mouse L929 fibroblasts in vitro and in vivo.

The effect of interferon (IFN) treatment and virus infection on the phosphorylation both in vitro and in vivo of the alpha subunit of protein synthesis initiation factor eIF-2 (eIF-2 alpha) was examined in mouse fibroblast L929 cells. The [gamma-32P]ATP-mediated in vitro phosphorylation of eIF-2 alpha catalyzed by cell-free extracts prepared from IFN-treated, uninfected cells was dependent upon exogenously added double-stranded RNA (dsRNA). However, the dsRNA requirement for eIF-2 alpha phosphorylation in vitro was eliminated by prior infection of cells with reovirus Dearing strain virions but not with defective top component particles. The enhanced phosphorylation in vitro of eIF-2 alpha and ribosome-associated protein P1 depended in a similar manner upon the multiplicity of virus infection. The extent of phosphorylation in vivo of eIF-2 alpha prepared from L929 cells was also examined by utilizing two-dimensional isoelectric focusing/sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting techniques. About 5-10% of the eIF-2 alpha was typically phosphorylated in vivo in untreated, mock-infected cells, whereas 25-30% was phosphorylated in IFN-treated, reovirus-infected cells. An intermediate extent of eIF-2 alpha phosphorylation, routinely between 15 and 20%, was observed with either IFN treatment or reovirus infection alone. The integrity of eIF-4A and eIF-4B was also examined by two-dimensional electrophoresis and immunoblotting, and no significant alterations in molecular size or charge heterogeneity were detected when these factors were prepared from IFN-treated, reovirus-infected cells as compared to untreated, uninfected cells.

Animals↗
PubMed1984

Monoclonal antibodies that distinguish between subspecies of human interferon-alpha and that detect interferon oligomers.

Monoclonal antibodies to human interferons (HuIFN) of the alpha-class have been prepared by screening against 125I-labeled IFN in a rapid liquid-phase radioimmunoassay. All of the six antibodies produced react with HuIFN-alpha 2 and with some components of HuIFN-alpha N (Namalwa); three of the antibodies also bind HuIFN-alpha 1, and these either do not bind or bind very weakly the 25K component of Namalwa. Reaction of the antibodies with IFN components blotted onto nitrocellulose after separation on reducing gels suggests that two of the antibodies are against conformational determinants, whereas the epitopes recognized by the other antibodies are not destroyed by reduction or SDS treatment; these antibodies can be used to detect the presence of oligomers in IFN preparations. From the reaction of the antibodies with different alpha-IFN in immunoblots, in an antiviral assay, and in an ELISA, it was concluded that at least five different epitopes are recognized by the six antibodies, only one of which is non-neutralizing.

Animals↗
PubMed1983

Parameters of interferon action: II. Immunological effects of recombinant leukocyte interferon (IFN-alpha 2) in phase I-II trials.

Twenty-nine patients receiving recombinant interferon (IFN-alpha 2; Schering Plough Corp., Bloomfield, NJ) were studied for changes in natural killer (NK) activity measured by a 4-h 51Cr release assay against K562 cells, and T-cell subsets were determined by indirect immunofluorescence of Leu series monoclonal antibodies (Becton-Dickinson, Mountain View, CA). Seventeen cancer patients received daily i.m. injections of IFN-alpha 2 from 3 to 100 x 10(6) U/day for 28 consecutive days or to tolerance. Twelve of an anticipated 16 melanoma patients have been studied during a phase I trial using the i.v. route with the same recombinant IFN-alpha 2. NK activity rose during the first week of i.m. therapy from 49 +/- 6.5 to 67 +/- 6.2 (mean +/- SE, day 8) at both high (greater than or equal to 30 x 10(6) U/day) and low (less than or equal to 10 x 10(6) U/day) doses. This trend was not observed during therapy by the i.v. route at similar doses, in which NK activity tended to decrease in patients receiving 30 x 10(6) U/day or more. Changes in T-cell subsets were observed in both trials; Leu 3a/2a (helper phenotype/suppressor phenotype) ratio rose twofold in patients receiving i.m. IFN-alpha 2 at higher doses. A rise in Leu-3a+ and a fall in Leu 2a+ T cells account for the change. No change in T-cell subsets was seen in patients treated at low doses (less than or equal to 10(7) U/day) by the i.m. route. By contrast, the Leu 3a/2a ratio fell by 50% in patients who received 30 x 10(6) U/day or more of IFN-alpha 2 by the i.v. route, reflecting a fall in Leu 3a+ cells and a rise in Leu 2a+ cells. Thus, opposite changes in several parameters of immune competence occurred during treatment of patients with melanoma and other cancers, with a single recombinant IFN subspecies given by two different routes.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Evaluation↗