[Cytotoxic action of the chemical substances found as admixtures in medical immunobiological preparations]. / Tsitotoksicheskoe deistvie khimicheskikh veshchestv, soderzhashchikhsia v vide primesei v nekotorykh meditsinskikh immunobiologicheskikh preparatakh.

The cytotoxic action (CTA) of chemical substances contained as admixtures in medical immunobiological preparations on human diploid cells has been studied. Such chemical substances as rivanol and merthiolate in admissible concentrations show the highest degree of CTA. The results obtained in this investigation indicate that different concentrations of chemical substances may produce equal CTA; thus, thiolate in toxic in a dose of 0.8 microgram/ml; the same CTA is produced by aluminium sulfate in a concentration of 500 micrograms/ml. Small doses of chemical substances, producing no explicit manifestations of the cytotoxic effect, may have latent CTA determined by additional methods of investigation. CTA may be manifested as lethal, sublethal and latent cell lesions. In working out regulations on the test for CTA it is expedient to indicate admissible residual amounts of chemical substances contained in finished medical immunobiological preparations, considering that these amounts must be incapable of producing CTA in cell cultures. The conclusion has been made on the expediency of denoting small amounts of chemical substances capable of producing latent CTA as tentatively tolerable doses.

[Use of a diploid cell line for detecting the toxic components in medical immunobiological preparations]. / Ispol'zovanie diploidnoi linii kletok dlia vyiavleniia toksichnykh komponentov v meditsinskikh immunobiologicheskikh preparatakh.

Besides specific antigens medical immunobiological agents (MIBA) contain chemical compounds (formaldehyde, aluminium hydroxide and mercury salt, merthiolate) in permissible concentrations. Therefore, the investigation of MIBA and their components should involve methods studying the effect of chemical compounds on cells and their structural components. For this purpose WHO recommends to use cell cultures. The results obtained show that cell cultures (constant and diploid lines) allow the differentiation in the degree of toxicity of chemical compounds constituting MIBA. Merthiolate had the strongest irreversible lethal effect. The technique can prove useful for more accurate evaluation of toxicity in inactivated bacterial and viral vaccines as well as in serum preparations. Cell culture can be successfully used for the detection of toxic components in vaccines and serum drugs, with the final safety tested by their injection to animals.

Acquired immunity and allergy of cells cultured in vitro.

It is in the reinoculated cell line FL that the sensitivity of cells under the action of a small dose of diphtheria toxin (DT) changes to the toxin itself as well as to the Coxsackie enterovirus. (B-5). After surviving the infection and getting again "healthy", the cells have acquired simultaneously an elevated sensibility to DT and reduced susceptibility to B-5 transmissible even in long passages. These acquired properties are a transient phenomenon, after a certain number of passages the culture returns to initial stage with all properties inherent in the initial line of cells: with regard to DT in 10 months, to coxsackie virus in 7 months. The stage of elevated sensibility to DT and reduced susceptibility to B-5, however, may be not only renewed but also considerably prolonged and even strengthened by repeated contact of cells with a small dose of DT. The small dose of DT is the first delusion of the toxin not provoking any visible morphological changes in the monolayer. The experimental data obtained render it possible to presume that application of reinoculated cell cultures offers a promising method for studying manifestations of laws governing the third factor of immunity and allergy at the level of cells.

[Preparation of diagnostic sera to enteroviruses 69, 70 and 71 having medical importance]. / Prigotovlenie diagnosticheskikh syvorotok k énterovirusam 69, 70 i 71, imeiushchim meditsinskoe znachenie.

The use of enteroviruses, types 69, 70 and 71, purified with freon and concentrated with polyethylene glycol, for immunizing rabbits, following 4 immunization schedules, has made it possible to obtain active virus-neutralizing diagnostic sera with antibody titers of up to 1:2560, 1:806 and 1:9123, respectively.

[Participation of Coxsackie B viruses in the occurrence and recurrence of infectious-allergic myocarditis (a serological study)]. / Uchatsie virusov Koksaki B v vozniknovenii i retsidivirovanii infektsionno-allergicheskogo miokardita (serologicheskoe issledovanie).

The serological study of sera from patients with infectious allergic myocarditis and from healthy persons has revealed essential differences in the occurrence and titers of antibodies to Coxsackie virus B. In patients with infectious allergic myocarditis the infectious process has been found to be significantly more frequently linked with Coxsackie viruses B, serovars 2 and 4.

[Detection of antibodies against enterovirus 71 in the sera of Moscow residents]. / Vyiavlenie antitel protiv énterovirusa 71 v syvorotkakh zhitelei Moskvy.

Twenty three out of 55 serum samples obtained from subjects aged 20-55 years have proved to be seropositive, 15 of the positive serum samples (i.e. more than 50%) possessing the titer greater than or equal to 1:16. The presence of specific antibodies in the sera of the inhabitants of Moscow suggests that either enterovirus 71 or some other virus whose antigens are partly identical to those of enterovirus 71 apparently circulates among the population of Moscow.

[Evaluation of the toxic action of prophylactic and therapeutic preparations on cell cultures. III. The detection of toxic properties in medical biological preparations by the degree of cell damage in the L132 continuous cell line]. / Otsenka toksicheskogo deistviia profilakticheskikh i lechebnykh preparatov na kul'turakh kletok. Soobshchenie III. Vyiavlenie toksicheskikh svoistv v meditsinskikh biologicheskikh preparatakh po stepeni povrezhrdeniia kletk v perebvivaemoi linii L132.

The methods of the quality control of medical biological preparations, including tests on animals, do not ensure the complete absence of toxicity in a final product. The use of the method of "subcultures with the introduced preparation" makes it possible to determine the toxicity of both specific and nonspecific components of vaccines and sera from the number of dead and damaged cells. The toxic action of preparations kills and damages the cells at the site of injection, thus inducing the formation of autoantigens whose effect on the body cannot be predicted. Thus thimerosal, commonly used as preservative, has been found not only to render its primary toxic effect, but also capable of changing the properties of cells. This fact suggests that the use of thimerosal for the preservation of medical biological preparations, especially those intended for children, is inadmissible.

[Evaluation of the toxic action of prophylactic and therapeutic preparations on cell cultures of different types and origin. II. The cytotoxic action of adsorbed DPT vaccine and its components on cells of the continuous L132 line]. / Otsenka toksicheskogo deistviia profilakticheskikh i lechebnykh preparatov na kulturakh kletok raznogo vida i proiskhozhdeniia. Soobshchenie II. Tsitotoksi-cheskoe deistvie vaktsiny AKDS i ee komponentov na kletki perevivaemoi linii L132.

Different batches of the same preparation manufactured at the same enterprise, or at different enterprises, in accordance with the same manufacturing regulations have been found to be capable of producing a damaging effect of different intensity on the continuous cell culture L132. The titers vary, according to their cytotoxic effect, from 1 : 32 to 1 :2048. The components of B. pertussis antigens and thimerosal solutions have been found to produce the most pronounced cytotoxic effect on the cells. The comparison of the results of the titration of adsorbed DPT vaccine in cell cultures with clinical manifestations has shown correlation between a greater degree of cell damage in vitro and severe local reaction. Therefore, in the process of the quality control of preparations cell cultures provide more sensitive tests than laboratory animals, which is confirmed by our data obtained in revealing the toxic properties of adsorbed DPT vaccine and its components.

[Efficient rabbit immunization schemes for obtaining diagnostic sera against adenoviruses]. / Ratsional'nye skhemy immunizatsii krolikov dlia polucheniia diagnosticheskikh syvorotok protiv adenovirusov.

Virus-neutralizing and hemagglutinating antibodies in higher titers can be obtained by using the schemes designed for long-term immunization of rabbits, while complement-fixing antibodies in higher titers accumulate in the blood serum after the injection of the antigen into lymph nodes.

[Effect of specific antibodies on active immunity development in those inoculated with an antirabies vaccine]. / Vliianie spetsificheskikh antitel na vyrabotku aktivnogo immuniteta u privitykh antirabicheskoi vaktsinoi.

The study of the effect of gamma globulin introduced in different doses (0.5 and 0.25 ml/mg) in combination with Fermi rabies vaccine (observations on humans were made) and with cerebral rabies vaccine inactivated by UV irradiation (in animal experiments) demonstrated that the injection of the higher doses of gamma globulin resulted in lower geometrical mean of antibody titers. Therefore, in combined administration of rabies vaccine and gamma globulin for postexposure rabies prevention it is advisable to reduce the dose of gamma globulin by one-half.

[Rational method for producing sera with high titers of virus-neutralizing antibodies. Part III]. / Ratsional'nyi metod polucheniia syvorotok s vysokimi titrami virusnei tralizuiushchikh antitel. Soobshchenie III.

The effect of a number of nonspecific stimulators of immunogenesis (complete-Freund's adjuvant, complete adjuvant prepared from Soviet made components, arlacel with vaseline oil, aluminium hydroxide) on the immune process has been studied. The highest titers of virus-neutralizing antibodies have been obtained with the use of complete Freund's adjuvant land complete adjuvant prepared from Soviet components (X=1 : 54040 and X=1 : 40960, respectively).

[Effect of different doses of diphtheria exotoxin on the properties of L929 and HeLa cells]. / Deistvie razlichnykh doz difteriinogo ekzotoksina na svoistva kletok L929 i HeLa.

Various forms of interaction between diphtheria exotoxin and the continuous L and HeLa cell lines were revealed, depending on its doses: toxic, subtoxic and small (following the subtoxic dose). Cells of the same origin, treated with these doses, develop similar changes in some of their properties, differing only in their "survival" time, the period of adaptation and the time of entering the phase of active proliferation. the systems of cells, having simultaneously low susceptibility to infection with some RNA-containing viruses (L cells with low susceptibility to vesicular stomatitis virus and HeLa cells with low susceptibility to Coxsackie B5 virus) and high susceptibility to repeated treatment with diphtheria exotoxin, have been obtained.

[Effect of small doses of diphtheria exotoxin on cell cultures]. / Deistvie malykh doz difteriinogo ékzotoksina na kul'tury kletok.

High diphtheria exotoxin concentrations induced irreversible injuries to all the cultures under study (L, HeLa, spcv pzM). However, its final titres in the mentioned cells differed. HeLa and pzM cells, being highly sensitive, can be recommended for titration of dipheria exotoxin, instead of the expensive guinea pig tests. Low (subtoxic) doses produced cytoproliferative action and caused changes of the cell properties.

[1st stage of infectious allergy]. / Pervaia stadiia infektsionnoi allergii.

In administration of bacterial exotoxins (diphtheria, botulinic) to guinea pigs in doses of 1/100 Dlm at an interval of one hour there developed a typical sickness with the lethal outcome in the course of 2-3 days from the beginning of the exotoxin administration. Low bacterial exotoxin doses induced allergic reaction of the organism before the cell producing specific antibodies began to act in defence. Lymphatic system cells responded rapidly to the low doses of bacterial exotoxins, but the process of formation of cells producing antibodies failed to reach mature plasmocytes, and no antibodies formed. With increase of the interval between the administration of low bacterial exotoxin doses to 24 hours specific antibodies did form, but these antibodies failed to protect the animals which were in the state of infectious allergy. The first stage of infectious allergy induced by low bacterial doses was nonspecific. Animals which were in the state of infectious allergy to diphtheria exotoxin perished of low botulinic (exotoxin) doses, and vice versa.