INDUCTORS OF INTERFERON (Latin inductor entering; interferon; synonym interferonogena) — big group of the agents of various origin causing formation of interferon in the fabrics and cells which were affected by these agents. Originally only viruses and their nucleinic to - you since in experiences with use of viruses there was an established fact of education were considered as Nominative interferon (see). However further it was revealed that Inductors of interferon, except viruses, can be many bacteria and their endotoxins, mycoplasmas, rickettsiae, and also various chemical connections; on activity they can be highly effective or moderate.
I. Highly effective inductors:
1. The RNA-containing viruses of animals.
2. The DNA-containing viruses of animals.
3. Viruses of plants, bacteria, fungi.
4. Natural two-filamentous RNA. 5. — weed synthetic two-filamentous polyribonucleotides (And) — weed (C), etc.
II. Moderate inductors:
1. Bacteria (Brucella, Salmonella, Serratia, Bordetella, Hemophilus, Francisella, Listeria).
4. Toxoplasma, plasmodiums and other protozoa.
6. Allogenic cells.
7. Lipopolisakharida of bacteria (endotoxins, lipid And).
8. Polysaccharides of fungi (mannan, galaktozomannan).
9. High-molecular polymers: a) polycarboxyarmour (piranovy copolymers, copolymers on the basis of vinylpyrrolidone, polikrilata and polymethacrylates), b) polysulphates (polyvinylsulphate), c) polyphosphates (fosforilirovanny polysaccharides, polynucleotides).
10. Low-molecular weight compounds: a) antibiotics (cycloheximide, Kanamycinum), b) tiloron, c) dibenzylfuran, d) main dyes.
11. Mitogenetic agents (phytohemagglutinin, concanavalin A, etc.).
In definition of the nature And. and. mistakes were made. So, statolon, reckoning before as polysaccharide with polianionny structure — a product of Penicillium stoloniferum, it was dvukhtyazhevy RNA of the virus which is reproduced in a fungus, passed edges at destruction of a fungus into extracts. Are received And. and., being artificially synthesized polianionny connections, napr, the pyrane representing copolymer of ether apple to - you and divinyl alcohol, and polycytidylic to - t — weed dvukhtyazhevy copolymers of gomopoliribonukleotid among which the greatest activity copolymer polyinosinic has (And) — weed (C), etc.
A large number already found and again revealed And. and. taking into account their possible use in practice of medicine allowed to formulate requirements, the Crimea they shall answer: to be non-toxic for the recipient, not to have antigenic properties, to be removed without inclusion in a genome of a cell producer of interferon, to have considerable efficiency both on tension, and on duration of interferonindutsiruyushchy action, to allow a possibility of introduction them in an organism in the simplest way, not to have cancerogenic properties.
The mechanism of formation of interferon
the Mechanism of formation of interferon is complex process, and the hypotheses explaining this mechanism are rather conditional. The initial stage of induction is still unsolved. Existence of a large number of inductors, various by the nature, allows to assume also various options of this first stage. So, in case of induction of synthesis of interferon a virus the last gets into a cell, is deproteinized (though need of this deproteinization) and then either any component of a virus, or the product formed in the course of a virus reproduction is authentically not established (e.g., a replicative form of virus RNA), cause derepression of a cellular genome (its site responsible for synthesis of interferon) and formation of information RNA for interferon. When And. and. polyanions after their penetration into a cell served, presumably there was derepression of synthesis of IRNK for interferon owing to the competition of these polyanions to interfazny DNA for communication with the histones causing repression of the DNA matrix function; as a result there was an opportunity for synthesis of this RNA. It is necessary to emphasize that the general for any mechanism of synthesis of interferon is obligatory derepression of that site of cellular DNA, as a result transcriptions (see) to-rogo there is a synthesis of IRNK for interferon.
The further mechanism of formation of interferon is also not clear yet. However assume that as a result of broadcast of the formed IRNK (see. Broadcasting ) the predecessor of interferon — preinterferon which in the course of functioning of a number of enzymes turns into interferon (scheme) is synthesized. At the same time accumulation of interferon in turn induces derepression of a so-called regulatory gene, owing to functioning to-rogo synthesis of «regulatory» protein whose «duty» is the termination of transformation of preinterferon into interferon is provided. Perhaps, there is also other mechanism of inhibition of synthesis of interferon. So, the formed inhibitor of an interferonoobrazovaniye breaks a stage of broadcasting in this process, and he or acts as RNK-aza, or somehow unites to IRNK for interferon and owing to this fact efficiency in the course of broadcasting oppresses her. Suppression of synthesis of «regulatory» protein, e.g., by processing of cells Actinomycinum of D and cycloheximide after already begun process of synthesis of interferon leads to increase in products of interferon in 100 and even 1000 times (a phenomenon of super-induction in products of interferon).
The begun synthesis of interferon lasts certain time, and then comes to an end in spite of the fact that in cells its inductor continues to remain. Repeated influence during this period And. and. does not lead to resuming of synthesis of interferon. This phenomenon of inability of cells and fabrics both in an organism, and out of it to answer with production of interferon repeated influence And. and. received the name of a refrakternost to induction of interferon.
Is the cornerstone of the mechanism of a refrakternost sharp oppression of a cellular genome, derepression to-rogo the used inductor is not able to provide.
Ability to products of interferon is recovered after certain time. So, in an organism of an animal induction of interferon starts over again leading to its products 72 hours later, full loss of a refrakternost happens only in 5 — 7 days. In culture of cells loss of a refrakternost is inherent only in the growing cultures when cell fission takes place. Apparently, both the phenomenon of a refrakternost, and its loss are connected with the corresponding dynamics of change of amount of regulatory protein for products of interferon. The phenomenon of a refrakternost most likely can be rather serious obstacle on the way of practical use And. and. and in medical practice.
Various cells have unequal ability to answer induction of interferon. Leukocytes were the most active producers of interferon in comparison with other types of cells of an organism. It formed the basis for use of leukocytes of blood of donors by production of interferon (human). In quality And. and. in this case usually take the inactivated viruses of the Newcastle disease or Sendai. It is necessary to notice that mono - and polinukleara of peritoneal exudate serve as more active producers of interferon, than the leukocytes received directly from blood.
Impact on induction of interferon is exerted by the most various factors. It is rather well known about increase in products of interferon induced by viruses in the conditions of more high temperature, low level of pH, existence in the environment of cultivation of blood serum. Efficiency of induction of interferon and after pretreatment of cells producers exogenous interferon increases ("priming - effect"). Products of interferon depend on age of the person and animals, embryos of hens, and also on duration of cultivation of in vitro of cellular cultures. The research conducted by V. D. Solovyov and T. A. Bektemirov showed that if among adults the individuals incapable of products of interferon (though the size of these products was subject to considerable individual fluctuations) were not revealed, then most of the inspected children aged till 1 year was weak producers of interferon. The exception was made by newborns, products of interferon leukocytes of which above, than at children of more advanced age. With age interferonprodutsiruyushchy ability increased, reaching a maximum by 12 — 18 years. According to authors, immaturity or inferiority of such protective mechanism what the interferonoobrazovaniye is, and serves one of factors of the raised susceptibility of a children's organism to a viral infection and heavier course of respiratory viral infections at children. At people 60 years are more senior the interferonoobrazovaniye is also sharply lowered.
A large number various by the nature And. and., high performance of products of interferon caused by them in an organism of the recipient allowed to raise a question of a possibility of use of these inductors in clinic. As interferon has the expressed specific specificity of protective action concerning the owner (producer) and besides efficiency of use of interferon in many respects depends on its concentration and safety in the place of manifestation of its anti-virus activity, there was a question of replacement of exogenous interferon endogenous, i.e. formed in that organism, in Krom its anti-virus activity shall be shown. Thanks to studying of a large number various And. and. the conclusion was made that copolymer polyinosinic can become the most probable for use in clinic drug and polycytidylic to - — weed t (And) — weed (C). This connection was highly effective in experiences on rodents at intranasal, hypodermic and intraperitoneal ways of its introduction.
It is necessary to emphasize, however, that interferonindutsiruyushchy ability is not absolute. So, tiloron, the inducing synthesis of interferon in an organism of rodents, had no this ability at introduction to monkeys and the person. Pauly (I) — weed (C) — one of the most effective And. and. in cellular cultures (including cells of the person) and at rodents — it was very weak And. and. at the person and primacies. For example, in observations on volunteers weed rather low protective effect (And) — weed (C) it was revealed at a rinovirusny infection and smaller at infection with an influenza virus of A2 (Hong Kong) 68; at the same time interferon managed to be found in blood serum of people after deep inhalation weed (And) — weed (C).
Highly effective And. and. primacies had complexes weed (And) — weed (C) with poly-l - a lysine, received the name of screened polynucleotides. The role of poly-l - a lysine in this complex came down to protection weed (And) — weed (C) from the destroying effect of the hydrolases which are contained in blood serum of people and primacies.
It should be noted that to copolymer weed (And) — weed (C) a certain toxicity is inherent: as a result of its introduction to dogs blood coagulation was broken, hemorrhages in a liver and a necrosis of hepatic cells were noted. However, according to researchers, this circumstance is not an obstacle for a wedge, tests of synthetic polyribonucleotides in quality And. and., as the difference between toxic and effective (interferonindutsiruyushchy) doses is rather big. Besides, before passing to wide a wedge, to use of these connections, it is necessary to carry out careful studying of influence of synthetic polyribonucleotides (as a matter of fact synthetic nucleinic to - t, i.e. alien genetic information) on the genetic device of a cell. Especially this potential danger at introduction of screened polyribonucleotides which as it was noted above, are steady against effect of hydrolases increases.
Use synthetic And. and. opens recent trends in studying of interferon and in development of chemotherapy of viral infections. There is real a possibility of establishment of the chemical structures causing induction of interferon, a possibility of opening of molecular mechanisms of this induction. For development of chemotherapy of viral infections receiving synthetic And. and. means creation of new type of antiviral chemotherapeutic drugs which will be able to provide bystry development of highly effective protection practically against any viruses owing to extremely wide range of antiviral activity of the formed interferon. And. and. manifestations of an immune response of an organism have also promoting effect and on others (in addition to an interferonoobrazovaniye).
Bibliography: Bektemirov T. A. and Bektemirova M. S. Artificial inductors of interferon, Vopr, virusol., No. 2, page 131, 1973, bibliogr.; P. N. jambs of an irovnov 3. I. Virus-induced immunity, M., 1972; Education and effect of interferon, under the editorship of M. K. Indulen, etc., Riga, 1972; With about-lovyev V. D. and Balangding I. G. Kletka and a virus, M., 1973, bibliogr.; Nightingales V. D. and Bektemirov T. A. Interferon in the theory and practice of medicine, M., 1970, bibliogr.; But M. of a. Armstrong J. A. Interferon, Ann. Rev. Microbiol., v. 29, p. 131, 1975.
I. G. Balangding.