Showing papers on "Interferon published in 1979"

The Interferon System

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Immune interferon in the circulation of patients with autoimmune disease.

Abstract: The observation that type II, or immune, interferon could be produced by peripheral-blood leukocytes in vitro on an immune-specific basis suggested that it also might be produced in vivo in various autoimmune disorders. We found immune interferon in the serums of patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma and Sjogren's syndrome. Among 28 patients with systemic lupus erythematosus, 71 per cent of those with active and 21 per cent of those with inactive disease showed interferon in their serums. Serial serum samples showed a good correlation between interferon titers and disease activity. Moreover, interferon titers correlated positively with antibodies to DNA and negatively with serum levels of the third component of complement. It is possible that the production of interferon may contribute to immunologic aberrations in auto-immune diseases and also protect the already compromised host from viral infections.

Augmentation of Mouse Natural Killer Cell Activity by Interferon and Interferon Inducers

Abstract: Interferon (IF), in addition to its anti-viral capacity, is increasingly being found to be a regulator of cell division, cell surface antigens, and cell function. To determine whether IF also plays a role in the regulation of natural killer (NK) cell activity in mice, the in vivo and in vitro effects of IF and IF inducers on NK activity were studied. We observed that pyran, lipopolysaccharide, and polyinosinicopolycytidylic acid (poly I:C) as well as crude and purified IF preparations significantly elevated splenic NK levels in normal mice within 3 to 24 hr of i.p. administration. Normal spleen cells treated with poly I:C or IF in vitro also had augmented NK activity. Poly I:C and IF were themselves not cytotoxic and their presence was not required during the lytic process, indicating that IF acts on lymphocytes to activate NK function. The addition of anti-IF in the incubation medium completely blocked the boosting of NK activity by poly I:C or IF. The characteristics of the effector cells activated by IF were consistent with those of NK cells rather than macrophages, since the boosted effector cells were not retained by a rayon column or removed by carbonyl iron. Moreover, they were resistant to treatment with anti-Thy 1.2 serum plus complement, which eliminated mature T cells.

Augmentation by interferon of human natural and antibody-dependent cell-mediated cytotoxicity.

Abstract: LYMPHOCYTES from normal individuals may have considerable levels of cytotoxic reactivity against tumour cells, mediated by NK (natural killer) cells1. There are many similarities between NK cells and the effector cells (K cells) mediating antibody-dependent cell-mediated cytotoxicity (ADCC) against tumour target cells2,3, and they may in fact be identical cells. In vivo inoculation of rodents with viruses4,5, immunostimulants4,6–8, tumour cells4 and other interferon inducers8 results in augmented NK activity. Interferon (IF) was shown to have a major role in rapidly boosting mouse NK activity, both in vivo9,10 and in vitro9. Trinchieri and Santoli11 have suggested that IF could also augment human NK activity. However, the preparations used might have contained a variety of other lymphokines. The present study shows that IF can indeed augment human NK activity and also ADCC.

Regulation of the interferon system: evidence that Vero cells have a genetic defect in interferon production.

Abstract: Summary A clone of Vero cells was isolated and shown to be totally unable to synthesize interferon and insensitive to the toxic effect of poly(rI).poly(rC) treatment. Cells of this clone and mouse L cells were fused by treatment with polyethylene glycol or Sendai virus. Hybrid cell clones were isolated following selection in medium containing hypoxanthine, thymidine and ouabain. The hybrids were sensitive to the antiviral effect of poly(rI).poly(rC) and synthesized mouse, but not primate, interferon. It is proposed that in Vero cells, the gene for interferon synthesis is defective or absent.

Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation. Effects on cytomegalovirus and herpes simplex virus infections.

Abstract: A double-blind, placebo-controlled trial of interferon prophylaxis against viral infections was conducted in renal-transplant recipients receiving standard immunosuppressive therapy with or without antithymocyte globulin. Interferon was administered for six weeks, beginning on the day of transplantation. Cytomegalovirus excretion began earlier and viremia was more frequent in placebo-treated than in interferon-treated patients. Cytomegalovirus viremia correlated with clinical syndromes and was more frequent in recipients of antithymocyte globulin. In contrast, neither interferon nor antithymocyte globulin altered excretion of herpes simplex virus. Reversible leukopenia and thrombocytopenia occurred in seven interferon recipients. Patient and graft survival were comparable in interferon and placebo groups. These preliminary results suggest that a six-week course of prophylactic interferon delays shedding of cytomegalovirus and decreases the incidence of viremia after transplantation. In contrast, ...

Accumulation of an mRNA and protein in interferon-treated Ehrlich ascites tumour cells.

Abstract: INTERFERONS are glycoproteins which are synthesised by various vertebrate cells in response to virus infection or some other stimuli. They are secreted and then interact with other cells and convert these into an antiviral state, in which the multiplication of viruses is impaired1. It is thought that transcription and translation are required for the establishment of the antiviral state as actinomycin D or inhibitors of protein synthesis, suitably administered, prevent or delay the effect2,3. Results with enucleated cells also support this idea4. We show here that treatment of Ehrlich ascites tumour (EAT) cells with highly purified interferon results in the accumulation of a particular mRNA and the corresponding protein within the cells. However, we have not yet identified the function of the induced protein.

Natural occurrence of 2-5A in interferon-treated EMC virus-infected L cells

Abstract: Until now the inierfer on-mediated 2′–5′ adenine oligonucleotide inhibitors (2–5A) of cell-free protein synthesis have not been detected in intact cells. Here we report their natural occurrence in interferon-treated, EMC virus-infected mouse L cells in amounts consistent with the idea that they play a part in the inhibition of virus growth.

The beige mutation in the mouse. I. A stem cell predetermined impairment in natural killer cell function.

Abstract: A point mutation, called beige, on linkage group 14 in C57BL/6 mice leads to a marked impairment in natural killing and antibody-dependent, cell-mediated cytolysis (ADCC) of tumor cells. The defect in NK cytolysis was predetermined at the level of progenitor cells in the bone marrow as revealed in radiation chimeras. This impairment in NK function could not be accounted for by an altered organ distrubution, target selectivity, or ontogenesis. Interferon did not fully restore the response, which suggests that the defect may not result solely from a lack of endogenous interferon stimulation in beige mice. The frequency of target-binding cells was normal in all lymphoid organs, which suggests that the defect is intrinsic to the NK cell and does not involve an altered population size or an inability to recognize and interact with the target. Rather, the defect may lie within the lytic pathway subsequent to target cell contact. These mice should provide a useful NK-deficient system for studies of T cell or macrophage immunity and in addition they provide a means for testing the in vivo significance of NK cells in resistance to tumors and virus-infected cells.

An interferon-induced phosphodiesterase degrading (2'-5') oligoisoadenylate and the C-C-A terminus of tRNA

Abstract: A phosphodiesterase characterized by a generally higher activity on 2'-5' than on 3'-5' phosphodiester bonds was isolated from mouse L cells treated with interferon. A similar enzyme was purified from mouse reticulocytes. The phosphodiesterase 2'-PDi splits the 2'-phosphate bond of pppA2'p5'A2'p5'A, the oligonucleotide activator of ribonuclease F. The level of phosphodiesterase 2'-PDi is increased by interferon treatment of L cells. The phosphodiesterase was also shown to degrade the C-C-A terminus of tRNA and to reduce the amino acid acceptance of tRNA in cell-free extracts, thereby causing a tRNA-reversible inhibition of mRNA translation.

Role of macrophages in the augementation of mouse natural killer cell activity by poly I:C and interferon.

Abstract: Mouse natural killer (NK) cell activity is readily augmented by interferon (IF) and IF inducers. To further our understanding of the regulation of NK activity by IF and poly I:C, we have investigated the cell types involved in in vivo and in vitro augmentation by these agents. Removal or inactivation of macrophages by silica, carrageenan, passage through rayon columns, or by the carbonyl iron-magnet technique before poly I:C treatment significantly depressed the augmentation of NK activity. In parallel, such treatments also decreased the level of IF induced by poly I:C. These observations were made in both conventional and nude mice. After induction of NK activity and IF by poly I:C, the removal of macrophages had no effect on the outcome of the activity. When a macrophage cell line, PU5 1.8, was treated with poly I:C, the culture fluid contained high concentrations of IF that were able to boost substantially NK activity in fresh spleen cells above the control level. Moreover, normal macrophages pretreated with poly I:C were able to produce IF by themselves and boost NK activity in fresh spleen cells. All these data taken together indicated that the requirement for macrophages in the boosting of NK activity by poly I:C was related to the need for these cells for the production of IF. In contrast, removal or inactivation of macrophages had no effect on the induction of NK activity by IF. Therefore, it appears that IF acts directly on NK cells to increase their function and that macrophages may play a secondary role, by production of IF, in response to inducers such as poly I:C.

Mechanism for discrimination between viral and host mRNA in interferon-treated cells

Abstract: In extracts of interferon-treated HeLa cells, RNA covalently linked to double-stranded RNA (dsRNA) is preferentially degraded compared with mRNA not linked in dsRNA. This was established by following the degradation of poly(A)-containing mRNA annealed with poly(U), of poly(C)-containing encephalomyocarditis virus RNA annealed with poly(I), and of the replicative intermediate of the virus isolated from infected cells. In extracts of interferon-treated cells, dsRNA promotes the synthesis of a series of oligonucleotides, designated (2'-5')oligo(A), which in turn activate an endonuclease. Several lines of evidence suggest that the (2'-5')oligo(A) polymerase/endonuclease system is involved in the preferential degradation of mRNA linked to dsRNA. Conditions that prevent synthesis of (2'-5')oligo(A) prevent this preferential degradation, whereas addition of (2'-5')oligo(A) or conditions that favor its synthesis result in degradation of mRNA both linked and not linked to dsRNA. These results are best explained by a localized activation of the endonuclease near the dsRNA region of our model substrates. We propose that in infected cells activation of the endonuclease takes place near the replicative intermediates of RNA viruses. The replicative intermediates of encephalomyocarditis virus promote synthesis of (2'-5')-oligo(A) in extracts of interferon-treated cells and are degraded to a 20S "core" resistant to digestion with RNase A. This mechanism may be responsible for discrimination between viral and cellular mRNA in interferon-treated cells.

Genetically determined, interferon-dependent resistance to influenza virus in mice.

Abstract: The genetically determined resistance towards orthomyxoviruses exhibited by mice homozygous (A2G) or heterozygous (A2G X A/J) for the gene Mx was abolished or greatly diminished by treatment with anti-interferon globulin (AIF). AIF induced increased susceptibility to challenge with hepatotropic, neurotropic, and pneumotropic strains of influenza A virus. Hepatotropic virus titers in blood and livers of AIF-treated, Mx-bearing mice were higher by a factor of 10(3)--10(6) than those in untreated mice of the same genotype, and were comparable to those in genetically susceptible (untreated or AIF-treated) mice. Peritoneal macrophages from Mx-bearing untreated mice were resistant to challenge with a macrophage-adapted strain of influenza A virus even in the presence of AIF. However, when macrophages were taken from resistant mice injected with AIF and also cultivated in the presence of AIF, they were as susceptible to the virus as macrophages taken from susceptible mice. We conclude that interferons is an important factor in resistance to orthomyxoviruses governed by the gene Mx.

Induction and kinetics of natural killer cells in humans following interferon therapy.

Abstract: Natural killer (NK) cells are non-B, non-T lymphocytes that effect spontaneous cytolysis of both virus-infected and neoplastically transformed target cells1,2. These NK lymphocytes have been detected in several species including man3–9. Interferon is a primary regulator of natural killer activity6,10,11. Because NK cells have been implicated in the regulation of tumour cell expression and can be induced by interferon in murine models, we have studied patients receiving large doses of interferon to determine (1) whether interf eron could induce NK lymphocytes in the peripheral blood of man, and (2) whether there are characteristic kinetics for the appearance, disappearance and reactivation of NK lymphocytes following interferon therapy. We report here the activation of human NK cells by the systemic inoculation of human subjects with interferon. Five patients received interferon as therapy for non-Hodgkin's lymphoma. All showed a marked increase in NK cell activity 12–24 h after inoculation. Peak NK activity occurred 18 h after introducing interferon, and thereafter declined rapidly but remained above pre-interferon levels. Induced NK activity occurred with reintroduction of interferon but at lower levels of activity and with different kinetics.

Enhanced expression of HLA antigens and beta 2-microglobulin on interferon-treated human lymphoid cells.

Abstract: Human leukocyte interferon increased the expression of HLA-A, B antigens and beta 2-microglobulin on two lines of human lymphoblastoid cells and on peripheral blood lymphocytes. No effect was observed on the expression of HLA-DR antigens.

Human natural killer cell activity is augmented by interferon via recruitment of 'pre-NK' cells.

Abstract: Contact with various cell-line targets increases the natural killer (NK) activity of human lymphocytes. Supernatants of such 20 h co-cultures augment the NK activity of virgin lymphocyte populations, and the augmenting factor penetrates 0.2 micrometer Millipore filters. The supernatants also contain interferon, and partially purified human leucocyte interferon increases NK activity when added to 20 h assays with 51Cr-labelled K-562 target cells. Potent anti-interferon antiserum added to the co-cultures inhibits the target-cell-induced augmentation phenomenon. Both the target-cell contact and interferon-induced augmentation affect a population of human lymphocytes, from which the 'mature' NK cells have been removed by adsorption-elution using fetal fibroblasts as adsorbents. The activity of 'mature' NK cells is not enhanced, and we conclude that the augmentation is mediated by recruitment of 'pre-NK' cells.

Potentiation of interferon activity by mixed preparations of fibroblast and immune interferon.

Abstract: Mixed preparations of fibroblast and immune interferons interacted with cells synergistically to cause the development of a much greater level of protection than expected on the basis of their separate activities. This increased level of protection was 5- to 20-fold greater than expected on the basis of a simple additive effect of the interferons. The potentiating factor copurified with both fibroblast interferon and immune interferon as they were partially purified. The potentiation was not an artifact of a more rapid development of immune interferon-induced antiviral resistance in the presence of fibroblast interferon. The results were consistent with the hypothesis that fibroblast and immune interferons mutually potentiate each other, thus supporting the supposition that they have different modes of action.

Properties of coxsackievirus B3 variants which are amyocarditic or myocarditic for mice.

Abstract: Inoculation of adolescent CD-1 mice with one variant of coxsackievirus B3 (CVB3m) results in induction of readily observable myocardial lesions, whereas inoculation of siblings with a second variant (CVB3o) results in little or no myocarditis. These variants could not be distinquished from each other on the basis of replication properties in HeLa cells or cardiac tissues in vivo, sensitivity to human interferon in HeLa cells, induction of interferon in the mouse, generation of detectable levels of defective-interfering particles in HeLa cells or in cardiac tissue in vivo, stimulation of serum-neutralizing antibody titers, nor in their rate of clearance by the spleen. Infectivity of CVB3o was slightly more heat labile at 34 degrees C than CVB3m. Little if any replication of either CVB3o or CVB3m occurred in either adherent or nonadherent populations of normal murine lymphoid cells. Cardiac tissues from mice inoculated with CVB3m but not CVBo contain new antigens that can inhibit migration of sensitized lymphocytes from CVB3m-immunized mice in an in vitro cell-migration-inhibition assay. However, the CVB3o variant was shown to have the genetic capability of inducing myocarditis if the mice were treated with cyclophosphamide prior to virus inoculation. These results suggest, in agreement with our previously published work, that induction of myocarditis by CVB3 requires destruction of myocytes by virus and subsequent stimulation of cell-mediated responses to new antigens produced in the myocardium during virus replication.

Regulation of lymphocyte mitogenesis by (2'--5') oligo-isoadenylate.

Abstract: Interferon has been reported to affect cell proliferation in various tumour and normal cell cultures1. In human cells, the anti-growth effect of Interferon is under the control of chromosome 21, like the antiviral effect2,3, and the two activities appear to reside in the same glycoprotein4. In synchronised fibroblast cultures Interferon inhibited DNA synthesis by blocking initiations of DNA replication5,6. Another system in which the inhibitory effect of interferon on DNA synthesis was particularly clear is lymphocyte mitogenesis. In lymphocytes stimulated by lectin mitogens or allogeneic cells, interferon inhibits DNA synthesis, and the RNA and protein synthesis observed before the S phase of the cell cycle7–9. In interferon-treated ceUs, several enzymes are induced, including the (2′–5′) oligo-isoadenylate [oligo(A)] synthetase E, which polymerises ATP into a series of oligonucleotides of general structure ppp(A2′p)n5′A (refs 10–12). The (2′–5′) oligonucleotides inhibit protein synthesis when added to cell-free systems10–12 or hypotonically permeabilised cells13, and the induction of (2′–5′) oligo(A) synthetase was correlated with the antiviral action of interferon14,15. In the present work, the involvement of this enzyme in the antigrowth effect of interferon was studied. We show that addition of the (2′–5′) oligo(A)nucleotides to the culture medium of intact lymphocytes mimics the antimitogenic effect of interferon. Experiments with lymphocyte extracts show that, while interferon increases the (2′–5′)oligo(A) synthetase E, the mitogenic stimulus of concanavalin A leads to a decrease in (2′–5′) oligo(A) accumulation.

Large-scale production and physicochemical characterization of human immune interferon.

Abstract: Large-scale production of crude high-titered (10(2.3) to 10(4) U/ml) human immune interferon (type II) was carried out in roller bottle cultures of human peripheral lymphocytes by using the T-cell mitogen staphylococcal enterotoxin A. Over 99% of human immune interferon was destroyed by pH 2 or heat at 56 degrees C for 1 h. The interferon was not neutralized by antibody to human leukocyte interferon. The kinetics of development of the antiviral state were slow for immune interferon relative to those for leukocyte interferon. Ultrogel AcA 54 chromatography of crude or the concentrated interferon resulted in two peaks of activity, a major one (87% of recovered activity) with a molecular weight of 40,000 to 46,000 and a minor peak of molecular weight 65,000 to 70,000. The column elution buffer consisting of 18% ethylene glycol and 1 M NaCl in phosphate-buffered saline resulted in at least 100% recovery of added interferon. The data suggest, then, that the interferon produced under large-scale conditions was immune (type II). The efficiency of the production was comparable to that described for large-scale production of human leukocyte interferon. Our large-scale production system for human immune interferon offers a feasible approach to preparation of large quantities of purified immune interferon for structure studies, antibody production, and clinical application.

Interferon enhances the excitability of cultured neurones.

Abstract: INTERFERON has varied biological effects on cells1,2 and induces modifications of the cell surface both in vitro3–6 and in vivo7. The particular capacity of the neuronal membrane to generate propagated action potentials (well retained in culture8) makes neurones excellent material for the study of substances that affect the cell surface. We have therefore determined the effect of interferon on the electrical activity of nerve cells. Most of the experiments reported here were carried out on the cat cerebral and cerebellar cortex, because the electrical patterns of these structures have been well defined in vitro8,9. Furthermore, as human leukocyte interferon exhibits a high degree of antiviral activity on cat cells10, we were able to study the effect of highly purified interferon preparations on the spontaneous and evoked electrical activity of these neurones. In other experiments, we studied the effect of rat interferon on rat neurones in culture. Our results, which show that human and rat interferon specifically enhance the excitability of cat and rat nerve cells, respectively, may have implications for the therapeutic use of interferon as well as for the understanding of some of the manifestations of viral diseases.

Natural Killer Cells in Mice Treated with 89Strontium: Normal Target-Binding Cell Numbers but Inability to Kill Even after Interferon Administration

Abstract: Natural Killer (NK) cell activity against YAC-1 lymphoma cells is greatly reduced in spleens of mice injected previously with the bone-seeking isotope, 89 Sr Spleen cells from 89 Sr-treated mice filtered over nylon wool and Sephadex G-10 columns failed to increase the low NK cell activity Cell mixture experiments failed to show inhibition of NK activity of normal spleen cells by spleen cells from 89 Sr-treated mice 89 Sr produced lowering of NK activity in athymic nude mice similar to that seen in control mice These experiments suggest that the low NK activity in 89 Sr-treated mice is not due to the presence of thymus-dependent or independent suppressor cells active at the effector phase of NK cell-mediated killing The low NK activity of 89 Sr-treated mice could not be stimulated by administration of interferon inducers, polyinosinic:polycytidylic acid and Corynebacterium parvum , or by preparations containing type I or II interferons The frequency of cells capable of binding to YAC-1 target cells in normal in spleens of 89 Sr-treated mice These data suggest that in 89 Sr-treated mice, NK cells exist in a state in which they can bind the target cells but cannot lyse them and are unresponsive to the activating effect of interferons Transformation of these cells into fully lytic and interferon-responsive cells appears to require an intact bone marrow Bone marrow cell infusions failed to restore NK activity in irradiated or unirradiated 89 Sr-treated mice, but were able to do so in normal lethally irradiated mice Thus functional NK cells reactive against YAC-1 lymphoma cells are not only marrow derived but also marrow dependent

Promonocytes have the functional characteristics of natural killer cells.

Abstract: Promonocytes isolated from a 5-day-old L-fibroblast-conditioned liquid bone marrow culture show strong NK cell cytotoxicity They kill YAC target cells in a short-term 125IUDR-release assay whereas P815 targets are unaffected This NK-like cytotoxicity is enhanced in the presence of interferon preparations Morphologically, these promonocytes resemble a medium size lymphocyte with a high nucleus to cytoplasma ratio, they are non-adherent, nonphagocytic, and negative in nonspecific esterase staining Promonocytes are precursor cells from macrophages, which have not yet developed the typical macrophage criteria Within 24 to 48 hr they mature to adherent macrophages We have shown previously, that the same promonocytes have the capacity to perform K cell killing of antibody-coated tumor target cells The cytotoxic effector functions of promonocytes are abolished when the cells are treated with the alloantimacrophage serum Mo 12 plus rabbit C The relationship or similarity between K cells, NK cells and promonocytes is discussed