Evaluation of amyxin effect in prophylaxis of acute respiratory viral infections

The results of the evaluation of the oral inductor of endogenic interferon (amyxin), manufactured in Russia are presented. The use of amyxin was found to produce a drop in morbidity in acute respiratory virus infections (ARVI) among medical workers 3.4 times, i.e. the preparation exhibited a pronounced prophylactic effect with respect to ARVI. The use of the preparation was accompanied by a decrease in the number of manifest forms of ARVI. Persons given the preparation often had ARVI in a mild or asymptomatic form.     

The role of immunocytes in the production of interferon in response to its induction by aromatic hydrocarbons]

Interferon (IF) was synthesized in animals by diverse populations of immunocytes in response to induction by various low molecular weight aromatic hydrocarbons. The level of the involvement of either population of the immunocytes in IF production is determined by the chosen inductor. IF induction by acridanone L-1 was mainly observed in macrophages and B-lymphocytes. T-Cells actively participated in IF synthesis induced by amyxin, a representative of the fluorenone group. IF synthesized by lymphocytes of human peripheral blood in response to L-1 was completely neutralized by antiserum to alpha-IF while IF induced by amyxin in the same culture was a mixture of alpha- and beta-IFs at a ratio of 3:1.     

Interferon in the modulation of the immune response in pyelonephritis caused by Staphylococci and Pseudomonas aeruginosa

In experiments on mice the influence of mouse serum interferon, type I, on immune response in pyelonephritis caused by staphylococci and P. aeruginosa has been studied. The immunomodulating action of interferon and its therapeutic effectiveness have been shown to depend on the etiology of the disease. When injected intraperitoneally in a dose of 1,000 ED, interferon produces a pronounced therapeutic effect in pyelonephritis caused by P. aeruginosa and no effect in pyelonephritis of staphylococcal etiology. Type I interferon introduced in the dose used in this investigation has no influence on the killer activity of spleen lymphocytes, enhances the activity of the complement and the production of antibodies, produces a leukopenic effect and, depending on the etiology of pyelonephritis, exerts influence on the activity of dehydrogenases, the number of EAC- and E-rosette-forming cells, the oxidation metabolism of neutrophils and their phagocytic activity.     

Interferon inhibits DNA Synthesis induced in Mouse Lymphocyte Suspensions by Phytohaemagglutinin or by Allogeneic Cells

IN addition to its well known antiviral activity, interferon has recently been shown to inhibit the multiplication of tumour and mammalian cells in cell culture^1–6. We report here the inhibition by interferon of DNA synthesis induced in mouse spleen lymphocytes by the non-viral stimuli phytohaemagglutinin (PHA) and allogeneic lymphocytes. These findings are in accord with our contention that interferon affects cell function and, furthermore, they suggest that by acting on lymphocytes, interferon plays a role in the immunological response of the host.     

Interferon activation of the production of a factor increasing the bactericidal properties of mouse macrophages

It has been established that the administration of homologous interferon to mice activates the production by splenocytes of a factor increasing the bactericidal properties of macrophages in the peritoneal exudate. The activation effect was dose-dependent. The maximum production was noted on day 3 after the injection of interferon, type I, or its inducers. Cell-producers of the factor are mainly lymphocytes.     

Activity of dsRNA-dependent protein kinase in rat lymphoid cells under the effect of X-ray irradiation

The activity of dsRNA-dependent protein kinase, which is the key enzyme of the interferon signal system, was studied in the rat spleen and thymus lymphocytes under the influence of X-ray irradiation at 0.5 and 1 Gy doses and interferon inducers administration. An increase of the enzyme activity was established in the presence of FGA, concanavaline A, poly(I).poly(C) in vitro. The effect is intensified under the irradiation by 0.5 Gy dose. The protein kinase activity in lymphocytes is amplified in proportion to poly(I).poly(C) concentration, that was most pronounced in the irradiated animals. The comparative analysis of the action of interferon inducers on the dsRNA-dependent protein kinase activity was carried out. Two biological systems were used: in vivo (when the preparations were injected to the experimental animals) and in vivo (under the preincubation of isolated lymphocytes with the inducers). It was shown that the combined action of radiation and interferon inducers causes the stimulation of dsRNA-dependent protein kinase activity.     

Effect of exogenous interferon on the transplantation reactions of mice]

The authors studied the influence of the serum obtained at various periods after the administration of interferon inductors (New castle disease virus, amino ethylisothiouronium, E. coli endotoxin) on the rate of rejection of the skin or cell transplant of mice C3H and CBA, and also CC57Br. The allogenous skin transplant perished more rapidly; there was also an acceleration of elimination of allogenous lymphoid cells, suppression of colony formation by the cells of allogenous bone marrow in the spleen of the irradiated recipient in administration of the serum obtained at the period of maximal content of interferon induced by the Newcastle disease virus and by amino ethylisothiouronium. The cytotoxic activity of lymphocytes of mice CC57Br against the allogenous target cells rose in the presence of these sera. The serum containing interferon induced with E. coli endotoxin failed to influence the rate of the allotransplant rejection and did not increase the cytotoxic activity of lymphocytes.     

Interferon: effects on the immune response and the mechanism of activation of the cellular response.

The discovery of interferon in 1957 by Drs. Isaacs and Lindenmann led to major revisions in the concepts of man's defenses against viral infections. There are at least two types of interferon. Along with their antiviral properties, they have recently been shown to exert a suppressive effect on the humoral and cellular immune response; they affect both B and T lymphocytes. A variety of substances, including virus, polyribonucleotides, and mitogens for T lymphocytes, are good interferon inducers. T lymphocytes seem to be necessary for these inducers to exert their immunosuppressive effects. The immunosuppressive effects of interferon inducers suggests that interferons may be mediators of suppressor T lymphocyte effects. In the virus system, interferon does not exert its antiviral effects by direct action on the virus, but rather derepresses a cell gene that results in the production of an antiviral protein. This antiviral protein is probably the mediator of inhibition of virus replication. This is a complex sequence of events that results in the interaction of interferon with the cell membrane and the resulting production of the antiviral state in the cell. This review will examine the various steps of this involved process.     

Increase in the sensitivity of leukemia cells, incubated in interferon, to the effect of immune serum]

L-1210 AND P-388 leukemic cells were incubated in three types of interferon, i.e. L-cell interferon and two types of lymphocyte interferon (induced in the lymph node lymphocytes of intact mice and the lymphocytes obtained on the 10th day after intraperitoneal injections of 5-10(7) L-1210 cells). "False" interferon obtained by the method analogous to that of obtaining L-cell interferon, excluding the viral induction, was used for control. Cells incubated in interferon proved to be more sensitive to the action of the cytotoxic antibodies than those treated with "false" interferon. Treatment of the cells with lymphocytic interferon induced on the lymphocytes of immune mice increased their sensitivity even more in comparison with the cells treated with interferon obtained from intact mice.     

Effect of interferon type I on the in vivo persistence of Salmonella typhimurium

The influence of type I interferon on the persistence of S. typhimurium in the body of mice has been studied. The injection of the preparation of interferon has been shown to be conductive to the survival of the animals and to reduce the time of Salmonella persistence in the body. The injection of interferon enhances the phagocytic activity of macrophages in the peritoneal exudate of mice.     

Formation of immune interferon and blast transformation in stimulated cultures of human lymphocytes

Lymphocyte blast transformation (LBT) and interferon (IF) production were studied in 55 phytohemagglutinin- and dry purified tuberculin-stimulated lymphocyte cultures obtained from normal subjects (7 adults and 24 children). A relationship has been disclosed between LBT and interferon production. However, in some of the culture with marked LBT there occurred a defective IF production. On the contrary, with suppressed PHA-induced transformation, IF production was within normal. The role of the interferon production test for estimation of the functional activity of human lymphocytes is discussed.     

Heterogeneity of mouse lymphocytes in interferon production upon influenza virus challenge in culture

Heterogeneity of mouse lymphocytes with respect to interferon production upon influenza virus challenge in culture was studied. Spleen cells produced much more interferon than thymocytes or mesenteric lymph node cells. Spleen cells mainly responsible for interferon production belonged to the hydrocortisone-sensitive population. When spleen lymphocytes were separated into seven fractions by centrifugation on a serum albumin density gradient, they were found to differ greatly in interferon producing capacity; a small fraction of intermediate density, representing a few percent or less of the total lymphocytes, produced markedly high levels of interferon.     

Nonsensitized lymphocytes produce leukocyte interferon when cultured with foreign cells.

Nonsensitized human lymphocytes produce interferon when cultured with either transformed or normal heterologous cells. De novo RNA and protein synthesis was not required in a foreign cell for it to act as the inducer. The interferon produced has been characterized as being leukocyte type rather than immune or fibroblast type.     

T-lymphocyte function and sensitivity to interferon in trisomy 21

Previous studies have shown that cells from subjects with trisomy 21 have enhanced sensitivity to the antiviral effects of interferon, presumably because of the location of the gene, IfRec, coding for the species-specific response to interferon on chromosome 21. Interferon is also known to have many other effects including the ability to inhibit the proliferation of many types of cells. To determine whether proliferating trisomic lymphocytes are more sensitive to the antiproliferative effect of interferon we have investigated, using healthy noninstitutionalized subjects with trisomy 21, the ability of interferon to inhibit the proliferation of lymphocytes stimulated with phytohemagglutinin P(PHA), concanavalin A (Con A), and tetanus toxoid. The trisomic subjects had normal numbers of peripheral blood leukocytes, and normal numbers and proportions of T and B lymphocytes. The production of interferon by PHA-stimulated trisomic T lymphocytes was normal. Trisomic lymphocytes also had normal proliferative responses to PHA and Con A. There were no differences between the inhibitory effects of interferon on the proliferation of PHA-stimulated trisomic and normal lymphocytes. However, trisomic lymphocytes stimulated with low doses of Con A did display significantly enhanced sensitivity to the antiproliferative effects of interferon. In contrast to normal lymphocytes, trisomic lymphocytes were not stimulated to proliferate by tetanus toxoid, and exposure to interferon resulted in enhancement, rather than inhibition, of DNA synthesis.     

Interferon inhibitor in the blood of patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) patients at advanced stages of the disease have an interferon inhibitor in the blood circulation. This inhibitor can block antiviral activity of all three types of human interferons and can significantly reduce the synthesis of interferon alpha by the treated lymphocytes obtained from normal healthy individuals. Available evidence suggests that inhibitor activity is neither because of the antibody to interferon nor due to high level of protease-like activity in the plasma. The inhibitor has also been shown to be effective in eliminating the interferon-mediated enhancement of natural killer cell activity. Interferon inhibitory activity was not detected in any of the sera taken from normal healthy individuals. Identification and characterization of interferon inhibitor has direct bearing upon effective utilization of interferons in the clinic.     

Target cells for interferon production in human leukocytes stimulated by sendai virus.

Whole leukocytes, mononuclear cells, polymorphonuclear cells (PMN), MONOCYTES, PURIFIED LYMPHOCYTES, AND T (rosette-forming cells, RFC) and non-T (nonrosette-forming cells, nonRFC) lymphocytes isolated from the human peripheral blood were stimulated by Sendai virus, respectively, and examined for interferon production in their culture fluids. High levels of interferon were produced by mononuclear cells, but not by PMN. Removal of monocytes from the mononuclear cell population did not affect at all the levels of interferon produced, although it strongly suppressed interferon induction by polyinosinic-polycytidylic acid (poly IC) and mitogenic response to phytohemagglutinin (PHA) of the lymphocytes. Purified monocytes and T lymphocytes were unresponsive to the virus. In contrast, a population of purified non-T lymphocytes produced high levels of interferon. Addition of monocytes to the interferon-producing non-T lymphocytes did not affect the levels of interferon produced. No detectable levels of interferon were produced in the mixture of T lymphocytes and monocytes. It is concluded that non-T lymphocytes may be a major target for interferon induction of human leukocytes by Sendai virus.     

Enhancement by interferon of natural cytotoxic activities of lymphocytes from human cord blood and peripheral blood of aged persons.

Effects of interferon on natural (or “spontaneous”) cytotoxicity of lymphocytes from cord blood and peripheral blood of aged persons were tested in a chromium-release assay against RSb target cells. These natural cytotoxic activities were enhanced by leukocyte and fibroblast interferon as shown in adult lymphocytes.     

Proportion of lymphocytes forming E, EA, and EAC rosettes following treatment with human interferon preparations in vitro

The proportion of lymphocytes forming E, EA, and EAC rosettes after treatment with human interferon preparations in vitro was measured. While interferon increased the percentage of lymphocytes forming E rosettes, the percentage of cells forming EA rosettes was diminished. The proportion of lymphocytes forming EAC rosettes was not altered to any major extent by interferon treatment. The same effects were observed when fibroblast interferon, purified to homogeneity with regard to molecular weight, was used.     

The Defensive Role of the Interferon System

The evidence relating the interferon system to the infectious process has been examined. The available evidence supports the view that the interferon system is an important component of the body''s nonimmune defenses, which are probably the major causes of recovery from already established virus infections of body tissues. The interferon system can also serve to limit virus spread through the bloodstream. Factors which may influence the interferon system and thereby influence virus infection have been considered. Finally, evidence is presented which indicates that the interferon system is one of the determinants of virulence of certain viruses and is one of the determinants of some persistent virus infections.     

Effect of human recombinant interferon on cytotoxic activity of natural killer (NK) cells and monocytes

Studies have been performed on the in vitro immunologic effects of homogeneous recombinant human leukocyte interferon, IFLrA. Large granular lymphocytes, enriched for natural killer (NK) cell activity, were pretreated wtih IFLrA or natural interferon preparations and then tested for augmentation of NK activity and of antibody-dependent cell-mediated cytoxicity (ADCC). Monocytes were tested for cytolytic and cytostatic activity in 48–72 hr radioisotopic assays performed in the presence or absence of interferon. Treatment with IFLrA caused significant augmentation of NK, ADCC, and monocyte-mediated cytotoxic activities. Even 10 units of IFLrA induced augmentation of NK activity, and 100 units or more boosted monocyte-mediated activity. The effects in each of these assays were species-specific, with no detectable effects on the activity of mouse effector cells. These results indicate that homogeneous recombinant interferon has potent in vitro immunomodulating effects and thus provide a basis for carefully examining the in vivo effects of this protein on host defenses in forthcoming clinical trials with cancer patients.