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The present data show that SPN have a striking influence on thymus dependent T cells. The enhancing effect of gvh reactions on antibody formation against thymus dependent antigens give a good explanation for the antitumor effects of this substance.
Electron microscopy showed that commerical poly I: C consisted of molecules varying in length from less than 0.05 nm to more than 5 nm and also in morphology . To clarify the relationship between its molecular size and interferon-inducing activity, poly I: C was sonicated or fractionated by sucrose density gradient centrifugation, and the molecular length distribution and interferon-inducing activity of each preparation was determined in vivo and in vitro. The results showed that (1) poly I : C molecules 0.1-0.3 nm long were the most effective for interferon induction; (2) sonication of poly I : C reduced its molecular length and also the interferon-inducing activity, the degree of reduction varying in different fractions; and (3) the interferon-inducing activity of poly I: C of 0.1-0.3 nm obtained by sucrose density gradient centrifugation was higher than that poly I: C of corresponding length prepared by sonication.
Interferon and poly I : C inhibited the growth of influenza virus in organ cultures of foetal nasal mucosa, trachea, oesophagus and adult nasal mucosa. No antiviral effect was observed in decidua organ cultures. The combined use of interferon and poly I : C resulted in the enhancement of the antiviral effect.
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Mice with graft versus host reaction (GVHR) show a decreased production of serum interferon and that produced by the bone marrow and spleen cells and blood leukocytes in vitro upon inoculation with Newcastle disease virus. Interferon induction with lipopolysaccharide of Flexner bacteria resulted in activation of production of serum interferon and that induced in spleen cell and blood leukocyte suspensions. Serum interferon production after administration of poly(I) . poly(C) was similar in mice with GVHR and controls.
A comparative analysis of interferon and antiviral protein messenger RNAs was carried out. Differences in their biological activities and sedimentation coefficients were found. In RNA preparations from superinduced cells (cells treated with poly(I).poly(C) and antimetabolites) and from cells treated with interferon, messenger RNAs possesing interferon and antiviral activities were detected. The results suggest the existence of two types of mRNA (for interferon and antiviral protein, respectively) and support the hypothetic model of interferon action via an antiviral protein.
Dogs were able to produce only small quantities of circulating interferon after intraperitonal injection of Newcastle disease virus or polyinosinic-polycytidylic acid. Similarly, canine cell cultures produced very low concentrations of interferon in response to Newcastle disease virus or polyinosinic-polycytidylic acid and no detectable concentrations of interferon in response to pyran copolymer or tilorone hydrochloride. The antiviral substance met the physiochemical characteristics classically associated with interferon.
The diminution of immune response against SRBC induced in mice, by a prior injection of HRBC was counteracted by addition of certain immunostimulants to SRBC. The intensity of inhibition of antigenic competition was related to the quantity of immunostimulant added to SRBC. Some immunostimulants (B. abortus, lipopolysaccharide) were more active than others (C. parvum, Poly I : C). To inhibit antigenic competition immunostimulant had to be injected after or in mixture with SRBC never before.
Combined intraperitoneal treatment of mice with poly I: C and a polycationic modified polypeptide (poly-DMAE-glutamine) was investigated. It was established that the presence of appropriate amounts of poly-DMAE-glutamine produced markedly enhanced serum interferon levels as compared to those produced by poly I: C alone. Similar combinations injected into mice produced full protection against lethal doses of mouse-virulent Semliki forest virus.
It was found that the colony-forming capacity of parental bone marrow transplant (C57BL/6) was partially restored in the (CBA X C57BL/6) hybrid recipient irradiated with 800 rad when poly I -- poly C preparation was injected. The effect of poly I -- poly C injection on the colony formation was equivalent to addition of the thymus cells syngeneic with the marrow. In either case the number of splenic colonies was more than double that in the control. On the other hand, it was found that in a completely syngeneic system the number of splenic colonies was not influenced by the thymus cells and poly I -- poly C preparation. Poly I -- poly C doses ranging from 50 to 100 mug and thymus cell doses ranging from 4-10(6) to 8-10(6) did not increase the efficiency of the colony formation with a stable bone marrow dose transplant.
A second injection of 100 mug poly (rI) poly (rC) per mouse at 6 and 24 hours after the first injection stimulated additional peaks of interferon production. The dynamics of the process of accumulation and disappearance of interferon was similar to that after a single injection of poly (rI). poly (rC). Injection of the above dose 12 hours after the first injection induced no interferon production as it apparently coincided with the refractory state in interferon production. After pretreatment of poly (rI) poly (rC) with DEAE-dextran, the refractory phase occurred in 6 hours. Inoculation of Venezuelan equine encephalomyelitis virus as a second interferon inducer resulted in a repeated stimulation of interferon production both in animals and in tissue culture; however, interferon titres in this case were low. The use of an inactivated virus as a second interferon inducer stimulated interferon production to higher titres (5120 IU/ml) than a single injection of DEAE-dextran-treated poly (rI). poly (rC). It is possible that a combined use of poly (rI). poly (rC) and noninfectious virus as a second interferon inducer eliminates the development of the refractory state.
The dynamics of interaction of complexes of synthetic polynucleotides (polyinosinic and polycitidylic acid--poly (rI)-poly (rC), and polyguanylic and polycytidylic acid--poly (rG)-poly (rC)) with cells as well as the dynamics of interferon accumulation and development of antiviral effect against some RNA viruses were studied in primary chick embryo cell (CEC) cultures. Four phases were observed in the development of the antiviral effect of synthetic polynucleotides: adsorption, increase, marked antiviral effect and waning. The duration and extent of the antiviral effect depended upon the activity and the dose of the preparation and less so upon virus type. At the same time, the dynamics of the development of the antiviral effect in early stages differed significantly depending on the virus model.
Balb/3T3 mouse cells, normal and SV40-transformed, produced interferon when induced with Newcastle disease and influenza viruses; transformed cells failed to respond to double-stranded RNA inducers.
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The administration of sonicated fractions of f2 phage polyribonucleotides caused an increased weight loss and deterioration of the clinical state in female NZB mice. Discontinuance of the treatment resulted in an improvement of both the clinical state and the genetically determined autoimmune disorders of these mice. Some potential explanations of this effect are discussed.
In this review some interesting aspects of interferon and its present perspectives for a practical utilization in human viral infections and in oncological therapy are described. After an evaluation of general characteristics of IF, some particular problems are considered about this system as that of IF and poly I:C interaction with cellular membranes, genetic control of IF system, IF and its inducers influence on immune reactivity and human tumours cells IF inducing ability and sensitivity. Finally are described some data obtained in various Institutes with IF on human virosis and those obtained on human and animal oncology with IF and interferon inducers.