The effect of therapy with cytostatics and immunomodulators on mitotic pathology in Lewis tumor cells in mice]

The effect of cytostatics (methylnitrosourea and methotrexate), immunomodulators (thymalin and reaferon) and their combinations on the mitotic pathology of mice Lewis tumour cells was studied. It was revealed that chemotherapy with these agents changed the interrelation between mitotic phases and somewhat enhanced the incidence of pathologic mitoses mainly connected with the damage of mitotic apparatus. Immunomodulators differently affected the cytostatic activity of antitumour agents that may be associated with their mechanisms of action.     

Effect of immunomodulators of varying nature on the expression of lymphocyte markers in melanoma patients]

The influence of immunomodulators such as tactivin, thymalin, gangliin and translam on expression of lymphocyte markers in patients with melanoma was studied. It was shown in vitro that sensitivity of the lymphocyte receptors of melanoma patients to the immunomodulators was individual and depended on the initial level of the marker expression and the drug properties. Preliminary determination of sensitivity of the immunoregulatory cells to the immunomodulators lays the basis for the use of adequate immunocorrecting therapy in the complex treatment of oncologic patients. Gangliin and translam are membrane active compounds influencing the structure and function of lymphocytic membranes. They are considered as a promising class of immunomodulators with diverse spectra of immunotropic action and various fields of practical use.     

Correction of immune response using purified staphylococcal toxoid and likopid in the secondary immunodeficiency induced by Coxsackie virus B3

The action of immunomodulators, purified staphylococcal toxoid (PST) and lycopid, on secondary immunodeficiency state developing during infection caused by Coxsackie virus B3 was studied. This defect was manifested by delayed hypersensitivity to sheep red blood cells (SRBC) and the suppression of neutralizing antibodies to poliomyelitis virus. Depending on the scheme of the experiment, PST normalized the defects of immune response to SRBC or poliovirus, increased suppression or showed no activity. Lycopid corrected the defects of humoral response to SRBC. The combination of PST and lycopid was found to produce no increase of suppression. The suggestion was made on the expediency of combination of two (and probably more) immunomodulators for increasing the efficiency of correction of secondary immunodeficiency.     

Liposomes in Host Defense Mechanism: A Key Role for Macrophages

Abstract

Liposomes can be used as carriers for antigens, immunomodulators and cytotoxic drugs. Such liposomes may serve as a tool to manipulate immune and non-immune host defense mechanisms. In most cases their effects are mediated by macrophages. Macrophages seem to be involved in humoral (antibody) responses and in cytotoxic T-lymphocyte responses. They are also important in non-immune defense mechanisms against foreign invaders and altered self. Which macrophages can be influenced by the liposome encapsulated molecules depends on the administration route of the liposomes. The macrophages ingest the liposomes. Once within the cell, lysosomal phospholipases disrupt the phospholipid bilayers. In this way, encapsulated molecules are released in the cell. Such liposome delivered molecules can be processed (antigens), activate the macrophage (immunomodulators) or disturb the metabolism of the cells (cytotoxic drugs). That the latter inhibition of macrophage functions may result in immunopotentiation is explained by the fact that certain macrophages are regulating immune functions by suppression.     

Bacteria-phagocyte interactions: emerging tactics in an ancient rivalry

Abstract Although phagocytes appear to have a redundancy of both oxidative and non-oxidative killing mechanisms, nevertheless, bacterial pathogens are still able to evade these defenses in vivo and cause lethal infection. As the mechanisms by which phagocytes function have become detailed at the molecular level, both the recognition of specific bacterial virulence determinants and their effects at specific sites in the phagocytes are also being identified. Knowledge of these interactions may permit the use of immunomodulators either to neutralize these virulence determinants or to enhance the bacterial capabilities of the phagocyte.     

Combined experimental use of vaccine against acute human encephalomyelitis and immunomodulators]

Combined use of vaccine and immunomodulators such as ridostin, inosiplex and polyribonate against acute encephalomyelitis of humans (AEMHs) was studied. It was shown that low immunogenic doses of the vaccine did not provide a protective action against the virus of AEMHs while after administration of the vaccine in combination with the immunomodulators there was protection in all the groups of the animals exposed to the low immunogenic doses of the vaccine during the first immunization. It was noted in regard to all the combinations of the immunomodulators and vaccine used in the low immunogenic doses that the level of the increase in the titer of the virus-specific antibodies, the proliferative activity to the specific antigen and mitogens and of interferon induction depended on the immunomodulator type. At the same time, it was found that the marked production of interferon within the first 24 hours observed after the use of the combination of inosiplex, ridostin and the vaccine resulted in increased activity of natural killer cells and lower proliferative activity of cells and production of virus-specific antibodies. This was indicative of the necessity of choosing the immunomodulators, their doses and time of the administration in relation to the immunization.     

Lipid emulsion therapy in women with recurrent pregnancy loss and repeated implantation failure: The role of abnormal natural killer cell activity

Altered immune and/or inflammatory response plays an important role in cases of recurrent pregnancy loss (RPL) and repeated implantation failure (RIF). Exacerbation of the maternal immune response through increased NK cell activity and inflammatory cytokines can cause embryo rejection leading to abortion or embryo implantation failure. Immunosuppressors or immunomodulators can help or prevent this condition. Currently, lipid emulsion therapy (LET) has emerged as a treatment for RPL and RIF in women with abnormal NK cell activity, by decreasing the exacerbated immune response of the maternal uterus and providing a more receptive environment for the embryo. However, the mechanisms by which the intralipid acts to reduce NK cell activity are still unclear. In this review, we focus on the studies that conducted LET to treat patients with RPL and RIF with abnormal NK cell activity. We find that although some authors recommend LET as an effective intervention, more studies are necessary to confirm its effectiveness in restoring NK cell activity to normal levels and to comprehend the underlying mechanisms of the lipids action in ameliorating the maternal environment and improving the pregnancy rate.     

Olfactory stress and modification of phagocytosis in peripheral blood cells of adult male mice]

Data on pheromonal influence on phagocytic activity of leukocytes in peripheral blood of adult randombred and CBA male mice have been obtained. The identified mouse pheromone 2,5-dimethylpyrazine was used, which induces some physiological effects associated with reproduction in both mouse males and females. Significant differences in spontaneous level of phagocytosis were between inbred CBA and randombred animals: the frequency of phagocytic cells was lower in CBA males by 1.4 times. The substance tested here induces phagocytosis in randombred (by 1.7 times) males. A low dose of 2,5-dimethylpyrazine (similar to the natural pheromone concentration) induces a higher increase in phagocytic activity by leukocytes. Possible mechanisms of pheromonal action on phagocytosis are discussed with the perspectives of finding highly effective immunomodulators among mammalian pheromones.     

Plants as potential sources of natural immunomodulators

In recent years, the immunomodulating properties of plants are being studied extensively with greater interest due to the growing awareness on immune system modulation and to achieve the desirable effects on disease prevention. Several plant remedies well-known in traditional medicine exert their anti-infective effects not only by directly affecting the pathogen, but also by stimulating natural and adaptive defense mechanisms of the host. Therefore plant-remedies have become versatile means with improved immunotherapy. The aim of this review is to highlight the efficacy of available literature evidences on natural immunomodulators of plant origin. In addition, several aspects on plants and their phytoconstituents responsible for immunomodulation have been discussed. A brief explanation has also been given on the use and efficacy of chemical immunomodulators. Moreover, this review also discusses biological screening methods for various plant-based immunodrugs that focus on revealing the mechanism involved in immunomodulation. Hence, botanicals, the diverse chemical complexes, could provide appropriate combinations of synergistic moieties useful in immune drug discovery. In this article, we reviewed the importance of traditional medicines as natural products related to immunodrugs.     

Immunomodulating properties of interferon inducers

Data on the immunomodulating activity of interferon inductors are presented. It was revealed that the inductors increased the animal vaccinal response. Schemes for combined use of the interferon inductors and immunomodulators were developed. The immunomodulators were shown to increase the host interferon response evident from synergistic increasing of the interferon titers or prolongation of interferon circulation in blood of the animals. The efficiency of the schemes for combined use of the interferon inductors and immunomodulators was obvious from stimulation of the antibody production. As a result the time of the antibody circulation in blood increased. The effect of the combined use of the immunomodulators and interferon inductors was studied. The combined use of the preparations significantly increased the average life-span of the animals and the rate of their survival.     

Effects of modulators and cytostatics on catabolism of I-125 desoxyuridine in tumors (express-method of antineoplastic modulator screening)]

El-4 and P-815 murine tumor cells labelled by 125I-deoxyuridine or 51Cr were administered in 7-day subcutaneous syngeneic tumors or subcutaneously. At the same time different groups of mice were treated by LPS plus MDP, beta-C7H15-MDP, dexal-MDP, polyacrylamide-MDP-phosphatidylethanolamine, adriblastin or cyclophosphamide. It was shown that cytostatics and immunomodulators significantly delayed catabolism and withdrawing of 125I-deoxyuridine (that has not been incorporated in DNA) from tumor cells. This delay was correlated with the inhibition of tumor nodes growth rate. It is concluded that influence of cytostatics and immunomodulators on catabolism and withdrawing rate of 125I-deoxyuridine from tumor cells relates to their cytostatic effect and may be used at the earliest screening step of immunomodulator analysis.     

Pharmacologic study of inflammatory processes. Modification of polynuclear neutrophil chemotaxis]

A study of rat polymorphonuclear chemotaxis has been made by a direct microscopic method and the effect of inflammatory reactions induced by carrageenan, calcium pyrophosphate and complete Freund's adjuvant has been studied. In addition the action of various drugs such as cholera toxin, colchicine, prostaglandins and certain immunomodulators, was investigated. The results have been analysed with special regard to the role of chemotaxis in inflammatory responses.     

The blood system and the organism adaptation to extreme factor

The formation of blood system adoptive reaction in many cases is defined by the type of action and the condition of hemopoietic inductive microenvironment: hemodynamics of hemopoietic tissue, functional conditions of bone marrow macrophages, mast cells and glycosaminoglycans content. The shift in hemodlobin fraction occurs in extreme conditions requiring an increased gas transport by the blood. In case of tissue lesion, lymphocytes stimulate their regeneration. Morphogenetic function of lymphoid cells may be alerted by immunomodulators. Blood cells participate in angiogenesis, and this property may be used for vessel grafts production.     

Monoclonal antibodies and other biologic agents in the treatment of asthma

Asthma represents a syndrome of airway inflammatory diseases with complex pathology. The immunologic pathogenesis is being increasingly revealed and provides opportunity for targeted biological intervention. Current experience with immunomodulators as targeted therapy in asthma is described in this literature review. Targeted therapies have included strategies to activate dendritic cells through the TLR-9 receptors, to interrupt the action of T_H2 cytokines with cytokine blockers and monoclonal antibodies, to promote development of T_H1 responses, to block IgE mediated pathways and to block TNFα. Omalizumab is the only biological therapy that has an approved indication in asthma at this time. An improved understanding of the heterogeneity of asthma should allow for specific targeting of different disease phenotypes specific therapies including immunomodulators.Key words: cytokine blockers, dendritic cell, monoclonal antibodies, immunomodulators, T_H2 cells, T_H1 cells, airway inflammation, IgE, omalizumab     

Monoclonal antibodies and other biologic agents in the treatment of asthma

Asthma represents a syndrome of airway inflammatory diseases with complex pathology. The immunologic pathogenesis is being increasingly revealed and provides opportunity for targeted biological intervention. Current experience with immunomodulators as targeted therapy in asthma is described in this literature review. Targeted therapies have included strategies to activate dendritic cells through the TLR-9 receptors, to interrupt the action of T_H2 cytokines with cytokine blockers and monoclonal antibodies, to promote development of T_H1 responses, to block IgE mediated pathways and to block TNF –α. Omalizumab is the only biological therapy that has an approved indication in asthma at this time. An improved understanding of the heterogeneity of asthma should allow for specific targeting of different disease phenotypes specific therapies including immunomodulators.     

The effect of immunomodulators on the immunogenicity of TNF-blocking therapeutic monoclonal antibodies: a review

Therapeutic monoclonal antibodies have revolutionized the treatment of various inflammatory diseases. Immunogenicity against these antibodies has been shown to be clinically important: it is associated with shorter response duration because of diminishing concentrations in the blood and with infusion reactions. Concomitant immunomodulators in the form of methotrexate or azathioprine reduced the immunogenicity of therapeutic antibodies in rheumatoid arthritis, Crohn disease, and juvenile idiopathic arthritis. The occurrence of adverse events does not increase when immunomodulators are added to therapeutic antibodies. The mechanism whereby methotrexate and azathioprine influence immunogenicity remains unclear. Evidence-based consensus on prescribing concomitant immunomodulators is needed.     

How vaccinia virus has evolved to subvert the host immune response

Viruses are obligate intracellular parasites and are some of the most rapidly evolving and diverse pathogens encountered by the host immune system. Large complicated viruses, such as poxviruses, have evolved a plethora of proteins to disrupt host immune signalling in their battle against immune surveillance. Recent X-ray crystallographic analysis of these viral immunomodulators has helped form an emerging picture of the molecular details of virus-host interactions. In this review we consider some of these immune evasion strategies as they apply to poxviruses, from a structural perspective, with specific examples from the European SPINE2-Complexes initiative. Structures of poxvirus immunomodulators reveal the capacity of viruses to mimic and compete against the host immune system, using a diverse range of structural folds that are unique or acquired from their hosts with both enhanced and unexpectedly divergent functions.     

Tumor necrosis factor and its induction by bacterial endotoxins

Using suitable immunomodulators (Corynebacterium parvum vaccine, Zymosan or muramyl dipeptide), lipopolysaccharides (LPS) from various members of the family Enterobacteriaceae (Escherichia, Salmonella, Serratia, Shigella) were tested on rabbits in relation to the production of tumor necrosis factor (TNF). TNF was determined by means of the serum titration of L-929 cell cultures in the presence of Actinomycin D, this with resulting titres of 3.2 x 10(3) to 5.1 x 10(4) IU TNF/ml. Analogous titres were noted after the action of denatured LPS (ie LPS subjected to alkaline hydrolysis or H2O2).     

Various aspects of the chemotherapy of bacterial infections

The principles of rational antibiotic therapy in modern conditions are considered. The mechanism of action of the main antibiotics widely used for the treatment of infectious diseases and indications to the use of combined antibiotic therapy are analyzed. Good prospects for the use of immunomodulators and agents inhibiting microbial cell enzymes in a number of pathological conditions are shown.