Interferon responses in schizophrenia and major depressive disorders.

The spontaneous and induced interferon (IFN) production in whole blood cultures was examined in 45 psychiatric inpatients and in 65 normal controls. Among inpatients there were 32 who were chronic schizophrenics (14 women, 18 men) and 13 who were severely depressed (11 women, 2 men). The analysis of the pooled results of assays in the heterogeneous population showed that leukocytes of the psychiatric patients produced significantly lower levels of IFN after stimulation with virus (NDV), lipopolysaccharide (LPS), and IFN spontaneously released without the inducers that control cells. In contrast, there was no difference between the psychiatric patients and controls in IFN response to phytohemagglutinin and phorbol myristate acetate (PHA + PMA). The results apparently confirmed observations made by Moises et al (1985) and Katila et al (1989). We have also tested our hypothesis that the statistics may mask the individual pattern of IFN response related to the specific psychiatric diagnosis, however. In fact, in the group of chronic schizophrenics we have found either high or low responders to all IFN inducers (NDV, PHA + PMA and LPS). Furthermore, the patients with high IFN response had dominant positive symptoms of schizophrenia (delusions, hallucinations, bizarre behavior and thought disorder). Whereas, in the patients with low IFN response the negative symptoms prevailed (asociality or withdrawal, flat affect, attention impairment, abolition or apathy). In plasma samples of schizophrenics, factors were detected that transferred a hypersensitivity to the IFN inducers to normal donor leukocytes. For instance, in leukocytes cultured in the presence of plasma from schizophrenics, there were 71% of high IFN responders after stimulation with NDV, versus 26% of high IFN responders in the presence of plasma from normal controls. We suggest that the factors may belong to the class of opioid peptides, which interact with the production of cytokines including IFNs.

Influence of selected antibiotics on interferon synthesis.

This paper discusses the influence of antibiotics - penicillin, streptomycin and mitomycin C - on interferon synthesis in vivo and in vitro. None of the antibiotics investigated was interferon inducer either in the suspension of human leukocytes or in the culture of cutaneo-muscular tissue from human embryo (HAT), or in mouse organism. However, the in vitro experiments revealed inhibitory effect of streptomycin and mitomycin C on the production of Newcastle disease virus (NDV) - stimulated interferon. Noteworthy is that the inhibition was most pronounced when the drug was administered simultaneously with the virus in the case of streptomycin or 24 h before the inducer in the case of mitomycin C. On the other hand, penicillin when introduced to the culture, exerted negligible modulatory effect on NDV-stimulated IFN.

Production of interferon in human fibroblast cultures: effect of temperature.

To obtain several harvests of interferon from the same culture the human fibroblasts have been incubated at various temperatures after the induction with virus. Preincubation of the culture infected with Newcastle Disease virus (NDV) at 37 degrees C for 8-10 hrs before the transfer of it to 25 degrees C resulted in the optimal harvest of interferon at 24th and 48th hrs after the induction. Also the preincubation of the culture infected with NDV for 8-10 hrs at 25 degrees C before its transfer to 37 degrees C resulted in better harvests of interferon than that obtained after the constant incubation at 37 degrees C. The same preparation of NDV could be used repeatedly 10 times without substantial loss of its interferon-inducing activity.

Production of interferon in human diploid cell cultures. II. Effect of various factors on interferon production in human diploid cell cultures.

Interferon was induced in primary human embryonic fibroblast cultures, using the Newcastle disease virus and synthetic polynucleotide poly I : poly C. Kinetics of interferon production were studied in this system, and optimal doses of some chemical factors which enhance interferon production were determined.

Effect of plant extracts on the in vitro interferon synthesis.

The extracts of roots and rhizomes of Angelica and Peucedanum genera, known in popular medicine for their various activities, were investigated in search of non-virus interferon inducers. It has been found that none of the extracts tested, induce interferon in human cell cultures. However, the extract from Peucedanum verticillare augmented the yield of interferon in the in vitro human fibroblast cell culture and human leukocytes suspensions when Sendai or NDV viruses were used as inducers. The increase of interferon yield was observed when the plant extract was administered at the time of interferon messenger RNA synthesis.

A method to assess the immunomodulating effects of the Tolpa Torf Preparation (TTP) by measuring the hyporeactivity to interferon induction and tumor necrosis factor response.

Tolpa Torf Preparation (TTP) is an immunomodulator which was found to be interferon (IFN) and tumor necrosis factor (TNF) inducer in human peripheral blood leukocytes (PBL). PBL cultures prepared from the blood of healthy volunteers taking 5 mg TTP tablet daily loose ability to respond to IFN induction by TTP, phytohemagglutinin (PHA) or lipopolysaccharide (LPS). The phenomenon of hyporeactivity or tolerance is characteristic of every IFN inducer described so far. In the TTP treated volunteers the tolerance developed during three weeks and it lasted one to two weeks. In comparison with the tolerance to the IFN induction the hyporeactivity to TNF induction developed slowly and it was only partial. Because the detection of the tolerance to IFN induction is a very sensitive indicator of TTP activity in vivo in patients taking the drug orally, we suggest that it may be applied to assess the mode of action, dosage and schedule of administration of the IFN-inducing immunomodulator.

Alterations in leukocytes induced by virus and interferon.

Alterations occurring in cells under an influence of interferon or viral interferon inducer were observed under the fluorescence microscope. The experiments were carried out with human leukocytes stained intravitally with acridine orange. From our observations it follows that both interferon as well as interferon inducer evoke morphological changes in leukocytes causing partial or complete disappearance of lysosomes in cytoplasm.

Synthesis of interferon in human leukocyte cells stimulated with influenza virus.

Strains of influenza A virus were tested for their ability to induce interferon synthesis in suspension of human leukocytes. Both, active as well as UV-inactivated strains were shown to be weak interferon inducers as compared to Newcastle virus. It appeared that interferon synthesis in human leukocytes was conditioned not by infectivity of the virus but by the presence of its surface antigens--hemagglutinin and neuraminidase.

Proteins in mouse embryonic cell (MEC) culture fluids following interferon induction.

A study was made on the proteins and interferon activity in supernatant culture fluids from mouse fibroblast cultures induced with Newcastle disease virus, and in controls. The studied materials showed low protein content, the concentration of proteins depending on the length of time from induction to their collection. Proteins from induced and control cultures were separated on CM-Sephadex C-50 and by electrophoresis in polyacrylamide gel. No difference was found in the character of proteins from control materials and from materials induced 24 hours after infection; the elution profile was the same, and the distribution of electrophoretic fractions was similar. Interferon activity was not accompanied by the appearance of a new protein fraction. However, 5--10 hours after induction differences were noted in electrophoretic mobility and a marked reduction in the number of protein fractions occurred in control and stimulated culture fluids.

Human interferons and their purification.

The present paper describes briefly the procedure used in our laboratory for the preparation of HuIFN-alpha. Induction of interferon was carried out in the suspension of human leukocytes from peripheral blood, using Newcastle virus as inducer. The optimal conditions to produce interferon were established in the media with and without serum. Moreover, the work reports the results of studies on the purification of HuIFN-alpha and HuIFN-beta interferons.

Effect of bacteriocins on interferon production.

The level of interferon induced with NDV in human diploid cell cultures treated with pyocins was decreased compared with the control culture. This effect was maximal when pyocins were given simultaneously with interferon inducers. In experiments in vivo it was shown that pyocin itself induced very small amount if any of interferon, but administered together with NDV inhibited production of circulating interferone in mice. Similar decrease of interferon production was found when other bacteriocins, namely pneumocin 114 or E-47 aerocin, were used.

Modulation of interferon synthesis with the drugs applied in bronchial asthma.

Investigations were carried out on 28 patients with nonatopic bronchial asthma treated with glycocorticosteroids or antibiotics and on 15 patients with atopic bronchial asthma treated with Alavac S vaccine. Leukocytes isolated from these patients by the method of Mogensen and Cantell were induced with Newcastle disease virus for interferon production, IFN was tested in the culture of human fibroblasts (HAT). The production of leukocytic IFN in glycocorticosteroids- and antibiotics-treated patients was shown to increase. On the contrary, the leukocytes from the patients 3 months treated with Alavac S exhibited suppressed production of the interferon.

Production of interferon by leukocytes from patients with atopic and nonatopic asthma.

Investigations were carried out on 62 patients with atopic and nonatopic asthma and 70 normal individuals. Leukocytes isolated according to the method of Mogensen and Cantell, were induced for interferon production with Newcastle virus, H strain for 24 h at 37 degrees C in a tube culture placed in rolling drum. Interferon was assayed in the culture of human fibroblasts (HAT). Leukocytes from patients with both types of asthma had reduced interferon-inducing activity. At acute viral infection, a transient increase of interferon titer was observed. The titer, however, never reached the values of interferon induced in leukocytes from healthy individuals.

Interferonogenic and antiviral effect of extracts from Erodium cicutarium. II. Modulatory activity of Erodium cicutarium extracts.

Methanol extract from Erodium cicutarium was shown not to induce interferon in a suspension of human leukocytes or in the cutaneo-muscular tissue of human embryo. It appeared to have no influence, either direct or cell-mediated, on interferon activity. However, it exerted stimulatory effect on the synthesis of interferon induced with Newcastle disease virus in cell cultures. The stimulation occurred irrespective of the time of methanol extract administration (before or after viral inducer). In the in vivo experiments, methanol extract injected intravenously induced interferon in mice. When given 24 h prior to Newcastle virus, it increased the titer of induced interferon determined in the animal serum collected 6 h after the virus injection. Besides, in the experimental viral infection in mice replication of influenza A virus in the lung tissue of infected animals was inhibited only when the mice were treated with methanol extract 24 and 48 h after infection with the virus.

Interferonogenic and antiviral effect of extracts from Erodium cicutarium.

Extracts from Erodium cicutarium L. Herit were tested for antiviral and interferon inducing properties. Both water extract and methanol extract as well as its fractions were observed to exert antiviral effect in relation to myxoviruses, Herpes virus type 1, Vesicular stomatitis and vaccinia virus. None of these extracts did induce interferon in a suspension of human leukocytes.

Production of interferon in human diploid cell cultures.

Eleven human diploid cell lines were compared for their ability to produce interferon in response to Newcastle Disease Virus. Sensitivity of the cultures of MM, Sindbis VSV and VR viruses was also studied. Human cells derived from various tissue of a single embryo responded variably to interferon inducer. Using selected viruses interferon production was studied in two systems, in cultures of leukocytes and in human embryonic cells.

Effects of some lipophilic carboxylic acid on release of interferon gamma from the human peripheral blood leukocytes.

Lipophilic carboxylic acids and their salts were tested for the ability of interferon induction in the cultures of human peripheral blood leukocytes. Of 13 tested organic compounds, two were selected: decyl-malonic acid and sodium salt of octylmethane-tri-(2-oxabutanoic)acid--which stimulated the synthesis of low amounts of gamma interferon.

Development and disappearance of tolerance to induction of interferon and tumor necrosis factor response in athletes treated with natural immunostimulant.

The effect of nonspecific immunostimulation was examined in 15 basketball players subjected to extensive physical effort. The Tolpa* Torf Preparation (TTP*), a natural immunostimulating drug, was applied orally, one 5 mg tablet daily, in two 21-day cycles, separated by 2-week hiatus. Blood samples were collected 4 times, after each of two TTP* cycles and after the first and second hiatus. Whole blood assay was used to determine the spontaneous and induced production of interferon (IFN) and tumor necrosis factor (TNF). The levels of the cytokines were measured by microbioassays. TTP* stimulated synthesis of IFN and TNF in the whole blood cultures. However, after the oral administraton of TTP* for 3 weeks the leukocytes of the athletes developed hyporeactivity to IFN induction by TTP* and to a lesser extent to another "superinducer"--a mixture of phytohemagglutinin and bacterial lipopolysaccharide. The hyporeactivity state disappeared spontaneously within 2 weeks. In contrast, the tolerance to TNF induction did not develop during the TTP* administration. The increase of immunoglobulins, mainly of IgM and IgG classes and an acute phase protein--alpha1-antitrypsin, was observed at the late phase of the treatment. We suggest that the cytokine levels may be early markers for immunoprophylaxis. Furthermore, high production of IFN and TNF may be associated with extensive physical effort.