Regulation of cell function in the macrophagal phagocytic system with salmozan

Salmozan has been shown to bring about changes in the phagocytic function of peritoneal macrophages, to produce a labilizing effect on the state of lysosomal membranes and to enhance the intensity of protein synthesis in peritoneal macrophages. The presence of relationship between the functional activity of the cells of the macrophagal phagocytic system, the resistance of the body to infections and the capacity for response to an antigenic stimulus has been revealed. The character of changes observed in this investigation has been found to depend on the interval between the injection of salmozan and the injection of sheep red blood cells or challenge with Listeria. The differences in the functional activity of the cells of the macrophagal phagocytic system, appearing under the influence of salmozan, can be attriduted to the action of this immunomodulating agent on various populations of peritoneal macrophages.     

Metabolic changes in the peritoneal macrophages of mice differing in the H-2 locus of histocompatibility after intraperitoneal administration of salmozan

The activity of 5'-nucleotidase in mouse peritoneal macrophages differing by histocompatibility locus H-2 after intraperitoneal injection of salmozan, an immunostimulating agent, has been studied. The character of changes in the activity of 5'-nucleotidase in peritoneal exudate macrophages after the intraperitoneal injection of salmozan has proved to be unrelated to the genotype of mice. The injection of salmozan induces a deep and prolonged decrease in the activity of 5'-nucleotidase in these macrophages. In mice of different strains changes in the activity of 5'-nucleotidase after the intraperitoneal injection of salmozan are of a linear type and can be approximated by a linear regression model.     

Differences in the receptor apparatus of resident and meat-peptone broth-stimulated macrophage populations detectable under the action of salmozan

The degree of expression of lectin-like receptors in resident (RPM) and peptone-elicited peritoneal macrophages (PE-PM) using salmozan as polysaccharide was investigated. Obtained results allow to suppose that salmozan screens lectin-like receptors in macrophages and SRBC. The salmozan screening of lectin-like receptors in macrophages and SRBC resulted in decrease of SRBC uptake level in RPM-subpopulation but did not alter it in PE-PM-subpopulation. The same effect was occurred with the intensified erythrocyte loading of this macrophage subpopulations. It is suggested that one of the functional differences of studied macrophage subpopulation consists in the largest expression of lectin-like receptors in RPM-subpopulation.     

Delayed hypersensitivity and nonspecific cellular immunity. The cytotoxic activity of macrophages, natural and antibody-dependent killer cells

The experiment on (BALB/cXC57BL)F1 mice, showing a high level of delayed hypersensitivity (DH) when sensitized with BCG vaccine and Staphylococcus aureus strain B-243, has demonstrated the influence of such sensitization and DH reaction induced by the injection of a specific antigen (old tuberculin or staphylococcal phagolysate) into the sensitized animals on the cytotoxicity of macrophages, natural killers (NK) and antibody-dependent killers (ADK). Sensitization with BCG vaccine alone results in an insignificant rise in the activity of these effector cells, and sensitization with S. aureus produces no changes at all. The pronounced activation of the cytotoxicity of macrophages, NK and, to a lesser extent, ADK has been observed in DH reaction induced by the injection of a specific antigen into the sensitized mice. In the course of DH reaction a rise in the activity of NK and ADK not only against tumor target cells, but also against microbial ones (Candida albicans and S. aureus) has been found to occur.     

Interaction of T-activin with peritoneal macrophages

The action of T-activin on peritoneal macrophages of CBA mice after its introduction into the animals has been studied. In intact mice the phagocytic activity of macrophages and their resistance to the cytopathogenic action of Salmonella typhimurium live cells remains unchanged. The injection of corpuscular pertussis vaccine into mice leads to a decrease in the resistance of macrophages to the action of salmonellae. The simultaneous injection of T-activin into mice in doses of 0.1 and 1.0 microgram per animal abolishes the damaging action of the vaccine. The analysis of the in vitro action of T-activin on macrophages of intact mice revealed that the preliminary incubation of cells with the preparation sharply increases their resistance to the action of salmonellae, while its introduction simultaneously with bacteria or after them rapidly leads to the death of macrophages. The action of T-activin is supposed to be linked with triggering the biosynthetic processes mediating the resistance of macrophages to the cytopathogenic action of salmonellae.     

Delayed hypersensitivity and nonspecific cellular immunity. The role of mono- and polynuclear phagocytes

Differences in the influence produced by sensitization with BCG vaccine and Staphylococcus aureus and by the reaction of delayed hypersensitivity (DH) induced, respectively, by the injection of old tuberculin and staphylococcal phagolysate on the phagocytic activity of peritoneal macrophages and blood leukocytes in different animals were experimentally demonstrated. A considerable activation of the bactericidal and ingesting functions of macrophages was observed in animals showing a pronounced DH reaction (rabbits, guinea pigs and mice), while in Wistar rats no such activation was noted. The latter showed no DH reaction after sensitization with BCG vaccine and the injection of the specific antigen. Among different strains of mice, the activation of macrophages occurred in the animals with the most pronounced DH reaction. Sensitization with BCG vaccine led to an insignificant sensitization of macrophages, and sensitization with S. aureus even suppressed the phagocytic activity of macrophages. The treatment of mice with antimacrophagal preparations (carrageenan, silica and trypan blue, but T-lymphocyte antiserum) before and after the injection of the specific antigen into the sensitized animals abolished the stimulation of anti-infection immunity.     

Delayed hypersensitivity and nonspecific cellular immunity. The conditions determining the maximally expressed immunity activity

In vivo experiments on the infection of mice with influenza A virus and Francisella tularensis and in vitro experiments on the bactericidal activity of macrophages have demonstrated the conditions leading to the maximally pronounced activation of immunity by means of preparations inducing delayed hypersensitivity (DH). The following conditions have been determined: the presence of pronounced DH previously to the injection of old tuberculin (OT) and staphylococcal phagolysate (SP) used as challenge antigens, the specificity and peculiar features of the antigenic structure of the challenge agent, the time of its administration after the course of multiple sensitizing injections of BCG and staphylococci, the dosage of OT and SP and the scheme of their administration, the desirability of their local use. The time of the maximum activation of cell-mediated immunity after the injection of OT and SP to sensitized animals with a high level of DH and the duration of such activation have been established.     

Action of hydrocortisone on the cytotoxic reactions in delayed hypersensitivity to microbial antigens

A study was made of the effect of hydrocortisone (HC) injected to animals with delayed hypersensitivity (DH) to BCG antigens on the cytotoxic activity of lymphocytes and production of lympho- and macrophage toxins. The cytotoxic test with the use of sensitized lymphocytes and preparation of lympho- and macrophage toxins were performed in vitro in the presence of specific microbial antigens. It was shown that HC exerts the most intense inhibitory action on the production of macrophage toxin. High doses of the hormone also inhibited the production of lymphotoxin. At the same time the cytotoxic activity of lymphocytes of the lymph nodes in DH was not inhibited by the employed doses of HC. No reduction was seen either in the sensitivity of autologous adhesive cells (macrophages) used as target cells for studying the cytotoxic activity of lymphocytes.     

Prolongation of the effect of immunostimulators as means of increasing resistance to causative agents of infection

Possible prolongation of the biological effect of some available immunostimulators such as prodigiozan, salmozan, polyribonate and thymalin by their sorption on aluminium hydrate was studied. It was shown that in comparison to the native immunostimulators the sorbed ones had a more pronounced biological action and provided a more prolonged increase in the host resistance to the causative agents of gas gangrene and typhoid fever. Using prodigiozan as an example it was demonstrated that the observed increase in the anti-infective activity of the sorbed drugs was associated with more intensive stimulation of some immunological factors involved in regulation of host nonspecific resistance. The results of the study are likely to indicate that it was experiment to further investigate the drugs to reveal their efficacy in other infection models and to optimize the schemes of their use.     

Information value of the indices of the nonspecific resistance of the body

A number of nonspecific resistance characteristics in mice, such as the total number of peritoneal exudate cells, the percentage and absolute number of macrophages, their cytochemical activity in the spontaneous tetrazolium test and cytochemical capacity, have been studied by comparison with the resistance of the animals to tularemia infection induced by Francisella tularensis, Ga?ski?'s vaccinal strain 15. Of these characteristics, the cytochemical capacity of peritoneal exudate macrophages, i.e. the total cytochemical activity of macrophages contained in a unit of volume, has been the most informative as regards the level of nonspecific resistance to this infection. Other characteristics under study cannot serve as criteria for the evaluation of the nonspecific resistance of the body to F. tularensis.     

Changes in the cellular reactivity of guinea pigs sensitized with Bacillus thuringiensis

Changes in the cell-mediated responsiveness of the body under the action of different variants of B. thuringiensis have been studied in experiments on guinea pigs. The data thus obtained indicate that the development of sensitization occurs in the animals, which is manifested by the increase of the sensitivity of leukocytes to the specific allergen and by the increase of the phagocytic activity of peritoneal macrophages. The most pronounced changes in the immune responsiveness of guinea pigs have been observed after the parenteral administration of B. thuringiensis var. galleriae.     

A reactivity to polyclonal stimulation of immunogenesis with salmozan after its repeated administration

The injection of 100 micrograms of salmozan (polysaccharide isolated from Salmonella typhi somatic O-antigen) or 50 micrograms of Escherichia coli lipopolysaccharide into mice induced a considerable increase in the number of antibody-forming cells in the spleen in response to the injection of sheep red blood cells (SRBC) 2-3 days later. This polyclonal effect was essentially weaker if the animals previously received 500 micrograms of salmozan (9-10 days prior to the injection of SRBC). The absence of reactivity was not linked with antibodies to salmozan or with some other serum factor. The lymphocytes of nonreactive mice proved to be capable of polyclonal response in the adoptive system, and at the same time the polyclonal response of intact lymphocytes to salmozan in the body of nonreactive irradiated mice was essentially weakened. The features making the above phenomenon similar to, as well as different from, the so-called "endotoxin tolerance" are analyzed.     

Sensitivity to mouse toxin and level of macrophage 5-nucleotidase activity]

It is shown that immunomodulator of bacterial origin salmozan causes alternations of sensitivity to mouse toxin in mice CBA. A correlation exists between the sensitivity to mouse toxin and the level of 5-nucleotidase of peritoneal exudate macrophages.     

The histological evaluation of the effect of Bacillus intermedius RNAse on the organs of immunogenesis in laboratory animals]

Histological changes in organs of immunogenesis of experimental animals after RNAse Bacillus intermedius treatment have been studied. The effect of RNAse on organs is revealed in activation of both cell and humoral immunity and factors of nonspecific resistance at early stage of reaction. The inhibition of immunological reactions and factors of nonspecific resistance takes place at later stages of enzyme action. The caused effects don't depend on catalytic enzyme activity.     

The heterogeneity of the alveolar macrophages of guinea pigs immunized subcutaneously with a vaccinal strain of Yersinia pestis]

The study of alveolar macrophages obtained from guinea pigs at different periods after the subcutaneous immunization with Y. pestis vaccine strain has revealed the heterogeneity of these macrophages in their bactericidal activity with respect to Y. pestis and in their resistance to the cytopathic action of this microorganism, as well as in the content of lysosomes and in the expression of receptors on the cell surface. The study has shown that subcutaneous immunization does not lead to the redistribution of subpopulations and to changes in their digestive activity.     

Cytotoxic action of immune lymphocytes on "adherent" cells (macrophages) of autologous system lymph nodes during delayed hypersensitivity]

A study was made in the autologous system of the cytotoxic action of immune lymphocytes on the "adherent" cells (macrophages) of the lymph nodes of guinea pigs in delayed hypersensitivity (DH) to the streptococcus antigens and tuberculoproteins. Death of a considerable number of the "adherent" cells in cultivation of a suspension of cells of the lymph nodes of animals sensitized with the culture of streptococcus or BCG in the presence of specific antigen (thermo-stable streptococcus fraction or tuberculin, respectively) alone. Detection of death of the "adherent" cells in the autologous system can be used as one of specific and sensitive tests in studying the DH.     

The role and proposed mechanism by which oestradiol 17β-hydroxysteroid dehydrogenase regulates breast tumour oestrogen concentrations

Synthesis of the biologically active oestrogen, oestradiol, within breast tumours makes an important contribution to the high concentrations of oestrogens which are present in malignant breast tissues. In breast tumours, oestrone is preferentially converted to oestradiol by the Type I oestradiol 17β-hydroxysteroid dehydrogenase (E2DH). Several growth factors, such as insulin-like growth factor Type I, and cytokines, such as Tumour Necrosis Factor (TNF), have been shown to stimulate E2DH activity in MCF-7 breast cancer cells. As little is known about the regulation of Type I E2DH expression and activity in other breast cancer cell lines, the expression and activity of this enzyme was examined in other oestrogen receptor positive and also oestrogen receptor negative breast cancer cell lines. As it is possible that E2DH activity may be limited by co-factor availability, the effects of exogenous co-factors on enzyme activity in these cell lines was also investigated. For T47D and BT20 breast cancer cells, the addition of exogenous co-factors was found to enhance enzyme activity. TNF, in addition to stimulating E2DH activity in MCF-7 cells, also increased activity in T47D and MDA-MB-231 cells, although to a lesser extent than in MCF-7 cells. An investigation of signalling pathways involved in the regulation of E2DH activity revealed that stimulation of both the protein kinase C (PKC) and PKA pathways may be involved in regulation of E2DH activity. As several growth factors and cytokines have now been found to be involved in regulating E2DH activity, the role that macrophages and lymphocytes have in supplying these factors and the mechanism by which these factors may stimulate tumour growth, is also reviewed.     

Effect of delayed hypersensitivity due to Staphylococcus or BCG vaccine on the sensitivity of animals to infection with heterologous bacteria or influenza virus

Experiments on mice of different strains have demonstrated that sensitization with BCG vaccine slightly increases resistance to infection with Francisella tularensis, Escherichia coli 819 and influenza A2 virus in mice of those strains which are capable of developing a high level of delayed hypersensitivity (DH). On the contrary, sensitization with Staphylococcus aureus b-243 decreases this resistance. A sharp increase in resistance to infection has been achieved in sensitized animals receiving DH-inducing specific antigen (old tuberculin or staphylococcal phagolysate) 24 hours before inoculation. This increased resistance to infection is due mainly to the eliminating capacity of the reticuloendothelial system and not to the bactericidal factors of the serum. The level of sensitization and the manifestation of DH reaction have been found to be genetically determined and to govern the degree of activation of nonspecific immunity.     

Effect of endogenous and synthetic sex steroids on the clearance of antibody-coated cells

Steroid hormones may influence the clinical expression of immunologic disease; however, their mechanism of action is uncertain. By using an experimental model, we studied the effect of sex steroids on the clearance of antibody-coated cells by macrophages in the spleen and liver. Progesterone significantly inhibited the clearance of IgG-coated E by splenic macrophages, whereas no effect was observed on the clearance of heat-altered E. This effect of progesterone was observed at serum concentrations which are attained during human pregnancy and the menstrual cycle. Furthermore, when splenic macrophages were isolated from progesterone-treated animals, they expressed decreased Fc gamma R activity. In addition, structural analogs of progesterone which have diminished glucocorticoid and progesterone activity retained this effect on macrophage Fc gamma R. In contrast, the estrogens estradiol and estriol as well as a structural estrogen analog with minimal estrogenic activity, 1,3,5(10)-estratrien-3,16 beta-diol, enhanced splenic macrophage Fc gamma R-dependent clearance. This action of estradiol could be partially inhibited by the antiestrogen tamoxifen. However, estradiol did not affect the C3-dependent clearance of IgM-coated E by hepatic macrophages. Concurrent administration of estradiol and progesterone demonstrated that the action of estradiol was predominant. These studies indicate that sex steroids alter splenic macrophage Fc gamma R function in vivo. This result may explain the alteration of disease activity in some human immunologic disorders during changes in hormonal state. Furthermore, analogs of progesterone and estrogen, as well as antiestrogens, which minimally affect the sex organs, retain the ability to alter splenic macrophage Fc gamma R function.     

Changes in the bactericidal activity of macrophages from mice with various degrees of resistance to Salmonella typhimurium infection as affected by interferon

The bactericidal activity of mouse macrophages with different sensitivity to Salmonella infection has been studied. The sensitivity of BALB/c mice to S. typhimurium infection is associated with the low bactericidal activity of their macrophages. The introduction of interferon stimulates the bactericidal activity of macrophages sensitive to Salmonella infection of mice, which sharply enhances the resistance of the animals to this infection.