Showing papers on "Interferon published in 1982"

Regulation of murine macrophage Ia antigen expression by a lymphokine with immune interferon activity.

Abstract: A culture supernatant of concanavalin A-activated spleen cells (Con A supernatant) induced murine macrophages to express Ia antigens in vitro. Biochemical characterization of the Con A supernatant indicated that the macrophage Ia antigen regulatory activity shares molecular weight, pI, and hydrophobic and affinity characteristics with immune interferon (IFN-gamma). Antiserum to mouse IFN-gamma neutralized both the macrophage Ia antigen regulatory and IFN-gamma bioactivities of the Con A supernatant. Furthermore, both partially purified murine IFN-gamma (10(7) U/mg protein sp act) and IFN-containing culture supernatants of the murine BFS T cell line-induced macrophage Ia antigen expression in vitro. Culture supernatants containing colony-stimulating factor, interleukin 1, interleukin 2, macrophage migration inhibitory factor, and a macrophage-activating activity that were distinct from IFN-gamma did not induce macrophage Ia antigen expression. Taken together, the data indicate that the in vitro expression of Ia antigens on macrophages is regulated by an activity that has the characteristics of interferon.

Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon

Abstract: A previously undescribed species of human leukocyte, or alpha, interferon is present in the serum of many patients with systemic lupus erythematosus. It was shown to be alpha-interferon by neutralization with specific antiserums, affinity column chromatography, and antiviral activity on bovine cells. However, 23 of 30 interferon samples tested were inactivated by incubation at pH 2, a characteristic of human "immune," or gamma, interferon. Multiple samples of interferon from the same patient had similar biological properties, but samples from different patients were not all identical, suggesting that several variants of this species of human alpha-interferon may exist.

Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients.

Abstract: Sixteen patients with advanced cancer were treated with recombinant-DNA-produced pure leukocyte A interferon (IFLrA) intramuscularly in doses ranging from 3 to 198 X 106units, with interva...

Preferential effect of gamma interferon on the synthesis of HLA antigens and their mRNAs in human cells.

Abstract: Interferons produce a variety of biological effects on cells. They induce resistance to virus proliferation, inhibit cell growth, modify cell structure and differentiation, stimulate some immune functions and inhibit others. However, the different interferon (IFN) species may vary in their mechanism of action and, hence, in their relative efficiency for inducing each of the effect. IFN-gamma (type II) appears to show stronger immunoregulatory and growth inhibitory effects than antiviral effects, but this conclusion has been challenged in other reports. The aim of the present work is to compare the action of IFN-gamma and other (type I) interferons on the induction of (2'-5') oligo(A) synthetase which is probably part of the antiviral response and the induction of the histocompatibility HLA-A,-B,-C antigens. We have shown previously that the induction of both proteins is regulated by interferons at the mRNA level, but show here that IFN-gamma from stimulated human lymphocytes and from monkey cells transfected by cloned human IFN-gamma cDNA induced the HLA-A,-B,-C and beta 2-microglobulin mRNAs or proteins at concentrations over 100 times lower than those needed to induce the (2'-5')oligo(A) synthetase and the antiviral state. This difference was not found with IFN-alpha and -beta (type I).

Virus-Induced Corticosterone in Hypophysectomized Mice: A Possible Lymphoid Adrenal Axis

Abstract: Infection of hypophysectomized mice with Newcastle disease virus caused a time-dependent increase in corticosterone and interferon production. Prior treatment with dexamethasone completely inhibited the virus-induced elevation in corticosterone concentration, but did not significantly alter the interferon response. Lymphocytes appear to be the most likely source of an adrenocorticotropin-like substance that is responsible for the increased corticosterone, since spleen cells from the virus-infected, but not from control or dexamethasone-treated, hypophysectomized mice showed positive immunofluorescence with antibody to adrenocorticotropin-(1-13 amide). Thus the adrenocorticotropin-like material and interferon appear to be coordinately induced the differentially controlled products of different genes. These findings strongly suggest the existence of a lymphoid-adrenal axis.

Interferon-dependent induction of mRNA for the major histocompatibility antigens in human fibroblasts and lymphoblastoid cells

Abstract: In human cells treated with interferons, there is an increase in the amount of HLA-A,B,C and beta 2-microglobulin exposed on the cell surface. We have used a cloned HLA-A,B,C cDNA probe to demonstrate by molecular hybridization that this effect of interferon is preceded by a large increase in the amount of HLA mRNA in the cell. This effect was found in five different human cell lines, with purified leukocyte and fibroblast interferons. The increase in HLA mRNA is comparable in its kinetics and dose-response to the induction of (2'-5') oligo(A) synthetase mRNA by interferons. Therefore, interferons seem to activate at least two cellular genes which have different biochemical functions.

Immune interferon release when a cloned cytotoxic T-cell line meets its correct influenza-infected target cell

Abstract: T cells stimulated by mitogens1, specific antigens2, including viral antigens3, and alloantigens4 have been shown to produce immune Interferon (IFN-γ). However, the exact circumstances of induction of IFN-γ in T cells have not yet been established, particularly the precise nature of the cell type producing the Interferon. We have recently described5 the selection and cloning of a BALB/c cytotoxic T(Tc)-cell line (L4) which grows in the presence of T-cell growth factor (TCGF), is Lyt-2 positive and kills H-2d target cells infected with any type A influenza vims. The aim of the present study was to examine whether this cloned cytotoxic T-cell line produced IFN-γ on contact with the appropriate target cell. It was found that small amounts of IFN-γ were produced on co-culture of L4 with target cells, whereas L4 cells on their own released no detectable Interferon. The pattern of antigenic specificity by L4 cells for interferon production resembled the requirements for killing in that Tc cell mediated lysis was restricted to H–2d targets infected with influenza A, but not influenza virus B strains, and interferon production was not prevented by a monoclonal antibody to the virus' haemagglutinin, which does not inhibit cytotoxicity while neutralizing the virus.

Interferon Induction by Glycyrrhizin and Glycyrrhetinic Acid in Mice

Abstract: Licorice extract is an herbal drug which has long been used as a demulcent and elixir in Chinese medicine. One of the main active components of licorice extract is glycyrrhizin (GL), a kind of saponin. The biological effects of GL and its aglycone, glycyrrhetinic acid (GA), have been extensively studied. Their anti-inflammatory (5), anti-ulcerous (3), and antiviral (14) effects have been reported from 1948 (15) to 1979 (14). Moreover, a preparation of GL combined with glycine and cysteine (SNMC), has been widely and successfully used in Japan as an antihepatitis drug (6, II, 19), although its mechanism of pharmacological action remains unclear. Recently, interferon (IFN) with or without adenine arabinoside (Ara-A) has been used to treat hepatitis B patients (4, 7). Studies show that IFN consistently decreases the level of either DNA polymerase or hepatitis B surface antigen in hepatitis patients. There are also many reports which suggest that some irnmunopotentiators induce IFN (13) and explain their antiviral activity in vivo as interferon mediated (8, 16, 18). Therefore, in the light of GL's clinical effect on hepatitis patients and of the fact that its structure resembles that of hydrocortisone, the possibility that GL induces IFN was proposed. In this study we investigated the ability of both GL and GA to induce IFN in mice. Sixto 8-week-old male DDI mice obtained from the Institute for Experimental Animals, Tohoku University School of Medicine, were used in this experiment. Six-week-old male C3H, ddY, CDF-l, C57BL, BALB/c, and athymic nude mice (nujnu) of BALB/c background were obtained from the Funabashi Farm Co., Ltd., and were used to study the effect of the different mouse strains on interferon induction. GL and GA were supplied by Minophagen Pharmaceutical Co. Drugs were dissolved in 0.01 M phosphate buffered saline (PBS) and adjusted to pH 7.2 with I N sodium hydroxide. Pooled sera obtained from three mice were tested for anti-viral activity, which was determined by the 50% plaque reduction method on L-929 monolayer cell cultures with vesicular stomatitis virus (VSV) and was expressed in international reference units based on NIH reference mouse IFN (Catalog No. 002-904-511) (12).

Comparative Antiproliferative Activity in Vitro of Natural Interferons α and β for Diploid and Transformed Human Cells

Abstract: The relative antiproliferative activity of natural interferons α and β was compared in 43 in vitro assays of 25 human cell lines or strains. After 120 hr of continuous exposure to 100 units/ml, interferon β produced >20% growth inhibition in 22 cells (88%), and interferon α produced 20% growth inhibition in 9 cells (36%). Only Daudi (Burkitt9s lymphoma) cells were consistently more inhibited by interferon α. In the other 24 human cells, the effect of interferon β was greater or equal to interferon α. Although no tissue specificity for interferon β was evident, interferon α generally had greater antiproliferative effects in cells of hematopoietic origin. The effect of interferon α was usually established by 72 hr with little further growth inhibition at 120 hr. Conversely, interferon β often had a greater antiproliferative effect at 120 than at 72 hr. These findings support the hypothesis that various interferons may differ in their biological, cell-regulatory, and clinical effects.

Human immune interferon

Abstract: Disclosed is a complete description of the preparation of novel, recombinant human immune interferon and des-CYS-TYR-CYS recombinant human immune interferon via recombinant DNA techniques utilizing any of an assortment of expression vectors and host cultures. The human immune (gamma) interferon (IFN-γ), is isolated and characterized in terms of DNA and amino acid sequences, physical attributes and biological activity.

Positive self regulation of cytotoxicity in human natural killer cells by production of interferon upon exposure to influenza and herpes viruses.

Abstract: Augmentation of natural killer (NK) activity by influenza A/PC and HSV-1 viruses appears to be caused by the induction of interferon (IFN) within the NK cell population itself. These viruses induced high levels of IFN production by human large granular lymphocytes (LGL) that could be readily isolated from peripheral blood by Percoll density gradients. These LGL, which have been previously shown to account for and to be highly associated with endogenous NK activity, became augmented in their lytic function during the 18-h period that IFN was induced. Non-LGL helper cells did not appear to be required in the NK-IFN system (either T cells, B cells, or monocytes). Removal of these latter cell types by treatment with OKT3 plus complement, anti-IgM plus complement, or preincubation with silica or carrageenan had no effect on the ability of LGL to respond to the viruses. Production of IFN was also detected, albeit at lower levels, from monocytes cultured for 18 h with viruses, but no cytotoxic activity was induced. On the other hand, T cells, even in the presence of monocytes, showed neither property, and longer cultures, with virus up to 4 d, still did not alter the pattern. The IFN produced by both LGL and monocytes were predominantly IFN-alpha, as assessed by neutralization assays with antisera to IFN-alpha, -beta, and -gamma. In an individual with detectable serum antibodies to influenza A/PC, however, the IFN induced in LGL appeared to be gamma, presumably because of specific recognition of the virus. These data suggest an efficient positive self-regulatory mechanism in NK cells that may be readily switched on by viruses.

Interferon: Immunobiology and Clinical Significance

Abstract: Interferons are proteins elaborated by infected cells that protect noninfected cells from viral infection. These proteins produce a temporary "antiviral state" by altering nucleotide metabolism and cytoplasmic enzyme induction. Interferons appear early after viral infection locally and systematically to limit spread of viral infection; they also affect cell differentiation, growth, surface, antigen expression, morphologic findings, and immunoregulation. Several human disorders have diminished interferon production. Newborns have normal interferon alpha but deficient interferon gamma production. Infants with congenital infections may also have defects in interferon production. Immunosuppressed patients receiving transplants (marrow, heart, of kidney) have diminished interferon production, particularly immediately after transplant. Deficiencies of interferon have also been noted in Down's syndrome, cellular immunodeficiencies, uremia, malnutrition, and hematopoietic malignancy. Leukocyte interferon has been of therapeutic value in herpes zoster infections, in patients with cancer, and in patients with hepatitis B infection. Interferon has not been proved to help children with congenital cytomegalovirus or rubella. Interferon can shrink lymphoid tumors, particularly non-Hodgkin's lymphoma.

Multiple interferons in the circulation of patients with systemic lupus erythematosus and vasculitis.

Abstract: Recently, we found interferon in the sera of patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and Sjogren's syndrome. In this study, we surveyed a variety of other immunologically mediated diseases. We did not find interferon in the sera of patients with Wegener's granulomatosis, sarcoidosis, infectious mononucleosis, minimal change nephritis, kidney transplants, myasthenia gravis, or uveitis, but we did find this protein in the sera of patients with active systemic and cutaneous vasculitis. Attempts to characterize the interferon in the sera of patients with systemic lupus erythematosus and vasculitis revealed that antibody to alpha (leukocyte) interferon, but not to beta (fibroblast) interferon, partially or completely neutralized the antiviral activity. The failure of antibody to alpha interferon to completely neutralize the antiviral activity in certain specimens and the lability of the antiviral activity in some specimens to pH 2.0 treatment both suggest that more than one type of interferon was present.

Alloreactive cloned T cell lines. VI. Multiple lymphokine activities secreted by helper and cytolytic cloned T lymphocytes.

Abstract: Culture supernatants generated by alloantigenic or lectin stimulation of a cloned helper T lymphocyte, designated L2, contain interleukin 2 (IL 2), granulocyte/macrophage colony-stimulating factor (CSF), B cell stimulating factor (BCSF), macrophage (Ia+)-recruiting factor (MIRF), (Ia+)-inducing activity, gamma-interferon, Fc receptor-enhancing activity, macrophage migration inhibitory factor (MIF), macrophage activation factor (MAF), interleukin 3 (IL 3), and a factor responsible for prolonging the synthesis and secretion of the fourth and second components of complement by guinea pig peritoneal macrophages. Erythropoietin was not detected. A spontaneously arising variant of L2, designated L2V, produces much lower quantities of macrophage-stimulating activities, IL 2, and interferon. However, when compared to L2, L2V produces much higher levels of BCSF, equivalent amounts of IL 3, and slightly smaller amounts of CSF. Unlike L2V, a cytolytic clone, designated L3, secretes lymphokines that primarily affect macrophage function. The time course of lymphokine production by L2 cells indicates that for the six lymphokine activities studied there are three different times at which maximal or near maximal levels are reached, as follows: 1) IL 2, 12 to 24 hr; 2) IL 3 and CSF, 24 to 48 hr; and 3) (Ia+)-inducing activity, MAF, and interferon, 48 hr or later. Only IL 2 activity disappears during the 8-day culture cycle. The time course data and the differential production of activities by the three types of lymphocyte clones suggest that at least four terminal effector lymphokine molecules account for the ten biologic activities tested.

Production of macrophage-activating factor by T lymphocyte clones and correlation with other lymphokine activities.

Abstract: The production of macrophage-activating factor (MAF) by antigen-stimulated murine T lymphocyte clones has been compared with their cytolytic function and release of other lymphokines. MAF activity was measured by the capacity of peptone-induced peritoneal exudate cells or bone marrow-derived macrophages to lyse 51Cr-labeled tumor cells after incubation with supernatant from the stimulated T cells and a nonactivating, amplifying dose of lipopolysaccharide. Of 72 clones generated against H-2, MIs, H-Y, or Moloney leukemia virus-associated antigens, 68 were found to produce detectable quantities of MAF. Release of MAF by clones 1) occurred within 1 to 12 hr of exposure to antigen, 2) required stimulation with cells of the relevant antigenic specificity, and 3) could also be induced by concanavalin A, indicating that the cloned cells were the source of the activity. The capacity of a clone to produce MAF was independent of its antigenic specificity, cytolytic activity, or ability to produce interleukin 2 or granulocyte-macrophage colony-stimulating activity. In contrast, production of interferon and MAF was not dissociated for any of the clones tested.

Interferon induces morphologic reversion with elimination of extrachromosomal viral genomes in bovine papillomavirus-transformed mouse cells

Abstract: The effect of mouse L-cell interferon on bovine papillomavirus type 1 (BPV-1) transformation of murine cells was examined. Mouse interferon reduced the level of BPV-1-induced transformation of mouse C127 cells by 95%. Long-term treatment of established BPV-1-transformed mouse cell clones with mouse L-cell interferon led to a decrease in the average number of the plasmid viral genomes present in these cells to 1/3 to 1/8. Although revertant lines could not be isolated from these lines in the absence of treatment with interferon, flat revertants were easily selected from two independent clonal transformed lines carried for 60 generations in the continued presence of 200 units of interferon per ml. These flat revertants had the biological characteristics of nontransformed C127 cells and could be retransformed by BPV-1. Southern blot hybridization failed to detect BPV-1 DNA in any of eight independent revertant lines examined under conditions that could detect 0.2 copies per cell. We conclude that interferon treatment has resulted in a selective reduction of the amount of extrachromosomal BPV-1 DNA in transformed cells and has cured some treated cells completely of their viral DNA.

Synthesis of (2'-5')oligoadenylate and activation of an endoribonuclease in interferon-treated HeLa cells infected with reovirus.

Abstract: Treatment with interferon protected HeLa cells from infection with reovirus. This virus apparently activated an antiviral mechanism that was detected by the presence of (2'-5')oligoadenylate [(2'-5')An] in intact cells. The (2'-5')An was previously shown to activate an endoribonuclease, RNase L. We measured (2'-5')An by a sensitive competition-binding assay in cells infected at different multiplicities and for different lengths of time. Nanomolar concentrations of (2'-5')An were detected in cells infected at a multiplicity of greater than 5 after 2 h of infection, the time at which the infecting virions were uncoated. The level of (2'-5')An increased up to 6 h postinfection but declined afterward. To establish whether viral mRNAs were cleaved by RNase L, we analyzed the RNA extracted from infected cells by a highly specific hybridization assay on Northern blots. Full-sized reovirus mRNAs were detected in control infected cells, but not in interferon-treated infected cells, at 6 h postinfection. At this time, a nuclease activity could be detected in these cells by demonstration of cleavage of rRNA, degradation of cellular mRNA, and polysome breakdown in the presence of emetine. Since this inhibitor freezes ribosomes, cleavage of mRNA between ribosomes could only be accounted for by an endonuclease, presumably RNase L.

Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. I.

Abstract: Interferon-sensitive (745) and interferon-resistant (3Cl-8) Friend leukemia cells (FLC) are highly tumorigenic for DBA/2 mice. The phenotype of interferon sensitivity or resistance does not change with in vivo passage. Daily administration of mouse interferon markedly enhanced the survival time of mice injected with either 745 or 3Cl-8 cells. Use of quantitative methods for determining the number of FLC (colony formation in agarose and immunofluorescence) permitted us to show that potent, partially purified or highly purified mouse interferon (s.a. 0.5 to 1 × 109 u/mg protein) induced a 100- to 1,000-fold decrease in the number of tumor cells in the peritoneal cavity in the days following inoculation of 745 or 3Cl-8 cells. Interferon decreased the number of FLC even when treatment was initiated at a time when tumor cells were multiplying exponentially in the peritoneal cavity. There was no evidence that interferon acted as an inducer of FLC differentiation in vivo. The finding that interferon was equally effective in mice inoculated with interferonresistant cells as in mice inoculated with interferon-sensitive cells suggests that in this experimental system interferon does not act directly on the tumor cells, but that the interferon-induced antitumor activity is mediated by the host.

Control of the ppp(a2'p)nA system in HeLa cells. Effects of interferon and virus infection.

Abstract: HeLa cells have an unusually high level of ppp(A2′p)nA synthetase(n = 2 to ≥4) even in the absence of interferon treatment. In accord with this ppp(A2′p)nA and ppp(A2′p)nA-mediated ribosomal RNA cleavage occur naturally in response to encephalomyocarditis virus infection in control as well as in intcrleron-treated cells. Despite this, in the absence of interferon treatment, encephalomyocarditis virus grows well In these cells. A possible explanation for this paradox is that the ppp(A2′p)nA dependent RNase is lost or inactivated at later times post-infection in control but not in interferon-treated cells. It appears, therefore, to bc the prevention by interferon of the virus-mediated inhibition of the ppp(A2′p)n-dependent nuclease rather than the absolute level or induction of the ppp(A2′p)nA synthetase which is crucial for the activity of the ppp(A2′p)nA system in HeLa cells. These results provide evidence for a further level of control in the ppp(A2′p)nA system and show that limited ppp(A2′p)nA-mediated ribosomal RNA cleavage alone is not sufficient to cause;in inhibition of virus growth.

Oxygen intermediates are triggered early in the cytolytic pathway of human NK cells

Abstract: The mechanism of tumour cell destruction by natural killer (NK) cells or other lymphocytes is not understood. NK cells appear to represent a primitive anti-tumour surveillance system more analogous to macrophages than lymphocytes. Free oxygen radicals (O-2, OH) and H2O2 are thought to be involved in cell destruction by macrophages and therefore we looked for similar cytocidal intermediates of oxygen in NK cells. These highly reactive molecular species can easily be detected in the presence of luminol by the emission of light. We show here that highly enriched human NK cells respond to NK-sensitive but not NK-insensitive tumour cells with a rapid burst of oxygen metabolites as detected both by chemiluminescence and cytochrome c reduction. Agents which can prevent chemiluminescence and cytochrome c reduction, such as superoxide dismutase (SOD), reduced NK-mediated cytolysis and agents which increased chemiluminescence, such as interferon, also increased NK-mediated cytolysis. These results suggest that the production of oxygen species may be the earliest event to occur in the NK cell following tumour cell contact, and these products are involved in NK-mediated cytolysis.

Replication of lactate dehydrogenase-elevating virus in macrophages. 1. Evidence for cytocidal replication.

Abstract: Summary A primary infection of peritoneal macrophage cultures with the lactate dehydrogenase-elevating virus (LDV) results in productive infection of 3 to 20% of the cells. When cultures were incubated in the absence of macrophage growth factor (MGF), LDV production ceased after a single cycle, but in cultures in which macrophage replication was stimulated by the presence of MGF LDV production continued for several weeks at a low level, representing not more than 1% of that observed during the acute phase. Significant amounts of interferon were not present in either acutely or persistently infected cultures, and treatment of persistently infected cultures with anti-interferon globulin or superinfection with LDV did not significantly stimulate LDV replication. Macrophage cultures established with peritoneal macrophages from LDV-infected mice also showed only a low level of LDV replication and were resistant to superinfection by LDV. Mouse hepatitis virus, Semliki Forest virus and vesicular stomatitis virus, on the other hand, replicated normally in LDV-persistently infected macrophage cultures. LDV replication was relatively resistant to interferon whether added to the cultures or generated endogenously by infection with Newcastle disease virus or defective-interfering (DI) particles of vesicular stomatitis virus. Temperature-sensitive mutants or DI particles of LDV were not detected in LDV-persistently infected cultures or chronically infected mice. The results support our hypothesis that the decrease in LDV production in mice or macrophage cultures at the end of the acute phase results from the destruction of the subpopulation of macrophages that is permissive for LDV, and that the low level persistent infection involves the passage of the virus to new permissive cells that are generated continuously, although at a low rate, from non-permissive precursor cells.

Cytotoxic T lymphocytes produce immune interferon in response to antigen or mitogen.

Abstract: Interferon (IFN) was found to be secreted by cloned lines of murine cytotoxic T lymphocytes in response to mitogenic or antigen specific stimulation. The IFN produced was shown to be of the immune type based on its sensitivity to pH 2.0 and on the ability of an antiserum to immune IFN to neutralize the antiviral activity.

Evidence for a protective role of interferon in resistance to murine cytomegalovirus and its control by non-h-2-linked genes.

Abstract: Murine cytomegalovirus (MCMV) induces rapid production of a partially pH 2-stable type 1 interferon, the serum level of which is controlled by non-H-2-linked host genes. The production of high, intermediate, and low levels of interferon was found in C3H/He, C57BL/10, and BALB/c mice, respectively, and the use of H-2 congenic mice on the BALB/c or C57BL/10 background showed that H-2-associated genes were not involved. Administration of large (up to 200,000 U) daily doses of partially purified type 1 (alpha plus beta) interferon failed to protect low-producer BALB/c or BALB.K strains from lethal infection. Treatment of the higher (C3H/He) or intermediate (C57BL/10) producer strains with anti-type 1 interferon antibody significantly reduced their resistance to the virus; however, such treatment had no effect on the low-producer BALB/c strain. The decreased resistance of anti-interferon-treated C3H/He mice was accompanied by a transient reduction in serum interferon titers, decreased activation of natural killer cells, a markedly enhanced viremia, and increased viral titers in the liver. These data strongly support a protective role of interferon in defense against MCMV in certain strains of mice. Furthermore, these data suggest that previous observations of a correlation of non-H-2-linked, genetically determined resistance to MCMV with activation of natural killer cells may have its basis in the genetic control of interferon induction by MCMV.