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Aim. To study the anti-allergic effects of ruzam, an extract from the culture of a thermophilic Staphylococcus aureus strain, in an in vivo model of asthma and its influence on degranulation of mast cells and basophils in vitro.Materials and methods. Allergic asthma in guinea pigs was reproduced by two intraperitoneal injections of ovalbumin followed by a series of inhalations of this antigen for 1.5 months. Ruzam (6 μg / kg) or a reference drug (sodium cromoglycate, 3 mg / kg) was administered daily via a nebulizer during the last 6 days of immunization. One day after completion of inhalations with ovalbumin and compared drugs, changes in the airways were assessed using cytological, morphometric, and histologic methods. Rabbit blood basophils and rat peritoneal mast cells were used to determine the effect of ruzam on IgE-independent degranulation induced by the compound 48 / 80 in vitro. The effect of ruzam was compared with that of hydrocortisone hemisuccinate. Basophils from the blood of ovalbumin-sensitized guinea pigs were used to evaluate the effect of the drug on IgE-dependent degranulation induced by ovalbumin. Granules of mast cells and basophils were detected by alcian blue staining to calculate the degranulation index.Results. In the asthma model, ruzam reduced the degree of airway obstruction by increasing the bronchoalveolar lavage volume returned and suppressed neutrophilic and eosinophilic inflammation, while mobilizing other effector cells of the anti-pathogen immunity (lymphocytes and macrophages). Ruzam has proven to have a stronger anti-allergic effect than sodium cromoglycate by several parameters. At concentrations of 8.4–840 μg / ml, ruzam inhibited degranulation of mast cells and basophils, induced by the compound 48 / 80, equally to hydrocortisone hemisuccinate (10–3 M). At concentrations of 280 and 420 μg / ml, ruzam dose-dependently inhibited ovalbumin-induced degranulation of basophils in sensitized guinea pigs.Conclusion. The anti-allergic effect of ruzam was confirmed in test systems in vivo and in vitro. We speculate here that the TLR2 signaling pathway may be involved in biological and pharmacological effects of this drug.

Aim. To compare the clinical efficacy and influence on interferon (IFN) production / sensing of drugs with immunemediated antiviral effects, which potentiate type 1 (T1) immune responses, in the treatment of acute respiratory infections (ARI) in patients with allergic rhinitis.Materials and methods. 146 ARI patients with remission of seasonal allergic rhinitis were divided into 4 cohorts. In addition to symptomatic therapy, patients received either 2,000 IU of IFNγ in each nasal passage 5 times a day; or rectal suppositories containing 106 IU of IFN-α2b and antioxidants (AO) twice a day, and a gel with IFN-α2b and AO intranasally 3 times a day; or 400 mg of pidotimod per os twice a day; or 125 mg of tilorone per os on days 1, 2, 4, and 6. The severity of ARI was determined daily as the sum of 10-point scores for 15 symptoms. Serum concentrations of IFNα and IFNγ and the ability of blood cells to produce these cytokines ex vivo spontaneously and upon stimulation with Newcastle disease virus or phytohemagglutinin were studied using enzyme-linked immunosorbent assay (ELISA). The proportions of circulating lymphocytes expressing type I IFN receptor subunit 2 (CD118) or IFNγ receptor α-chain (CD119) were determined by flow cytometry.Results. ARI symptoms in all cohorts generally regressed in a similar way. However, from day 5 of the treatment, pidotimod relieved symptoms more effectively than other drugs. In patients treated with tilorone, the regression of ARI manifestations was delayed in the first two to three days, followed by rapid symptom reduction. An initial decrease in the induced production of IFNγ was found in patients treated with pidotimod, and a tendency to a decrease in this parameter was noted in other cohorts. The induced production of IFNγ after the treatment in all groups did not differ from that in healthy donors. No significant changes and differences in the proportions of CD118+ and CD119+ lymphocytes were found between the cohorts, except for a decrease in the number of CD118+ cells after the treatment with tilorone. In patients treated with IFN-α2b + AO, the proportions of CD119+ and CD118+ lymphocytes tended to increase slightly.Conclusion. Drugs that promote the development of T1 over T2 immune responses are a useful option for treating ARI in patients with allergic rhinitis.

Immune cells and molecules, as well as synaptic transmission molecules play a regulatory role in the communication pathways of the entire body when it is necessary to engage all body resources in the fight against infections or tumor cells wherever they appear. In potential allergy, the neuroimmune network controls allergen tolerance maintenance at both local and systemic levels.The review focuses on different neurotransmitters and our understanding of a balance and imbalance between the immune system and the nervous system in allergic inflammation, including allergic rhinitis. However, the pathogenesis of the two endotypes of rhinitis (conventional allergic rhinitis and local allergic rhinitis) and the impact of the neuroimmune network on it remain unresolved.

We studied the effect of tilorone on the dynamics of IFNα, IFNγ, and IL-1β levels in the lung tissue and blood serum in relation to viral load in the lungs of BALB/c mice with pneumonia caused by influenza virus A/Aichi/2/68 (H3N2). Tilorone was administered per os in doses of 40, 150, and 540 μg per mouse 6, 30, and 78 h postinfection, which simulated the drug regimen used in the clinic for the treatment of influenza and acute respiratory viral infections in Russia and post-Soviet countries. Tilorone reduced viral load with the maximum amplitude (2-3 lg) after 1-2 administrations. The results of studying the dynamics of the cytokine levels in the infected animals in general support the previous hypothesis that, in repeated dosing, tilorone enhances the IFN response (compensates for its deficiency) at the early stages of acute respiratory viral infections and suppresses (damps) excessive production of IFN and proinflammatory cytokines at the later stages.

Lack of anti-infective protection is one of the reasons for the occurrence of purulent-inflammatory diseases of the skin, soft tissues and purulent-septic complications in the postoperative period. Immunocorrective therapy is extremely relevant in surgical practice, and it can be used both for the prevention and treatment of postoperative complications. In this regard, special attention should be paid to low molecular weight fragments of peptidoglycan of cellular bacteria muramyl peptides. The study included 65 patients with purulent inflammatory diseases, of which 35 men aged 2355 years with chronic recurrent pyoderma (ostiofolliculitis, folliculitis, sycosis, furunculosis), and 30 patients aged 18 to 65 years with purulent inflammatory diseases of soft tissues, mainly abscesses and phlegmons of various localization without pronounced concomitant pathology. The examination included 26 patients with purulent-septic complications in the postoperative period. The patients included in the study were divided into 2 equal groups: 1 is the main group, in which patients received intramuscularly Polimuramil 200 mg daily for 5 days in addition to treatment; Comparison group 2, in which patients received only standard treatment. The clinical symptoms of pyoderma were assessed from day 0 to day 7, then on day 14, after 1 and 6 months of the study. Blood samples were taken from all patients for hematological and immunological studies. The timing of the appearance of granulations was monitored daily. The inclusion of Polimuramil in the complex treatment of pyoderma accelerated the regression of the main clinical manifestations of the disease and promoted the induction of stable remission. In patients with soft tissue infections, Polimuramil increased the degree of regression of the depth and area of the wound and accelerated the appearance of granulations. The clinical efficacy of Polimuramil in patients with purulent-septic complications in the postoperative period correlated with a decrease in CRP and procalcitonin levels. The study confirms the effectiveness of Polimuramil in the treatment of purulent-inflammatory diseases and purulent-septic complications in the postoperative period and its high immunomodulatory potential (8 figs, 2 tables, bibliography: 5 refs).

The traditional view of immunoglobulin (Ig) production only by B-lymphocytes and plasma cells has been revisited. Non-lymphoid tumor cells can also synthesize and secrete Ig with unidentified specificity. Expression of Ig genes was detected in the cells of malignant neoplasms of epithelial origin, such as breast carcinoma, colorectal cancer, prostate cancer, as well as in epithelial tumor cell lines. mRNA of the IgG1 heavy (H) chain constant region, sterile Iɣ-Cɣ transcript, H and light (L) chains of IgG, V(D)J recombination of H and L chain gene segments, as well as RAG1 (recombination-activating gene 1) and RAG2 enzymes, which are required for V(D)J recombination, were found in cancer cell lines and resected carcinoma tissues. IgG produced by cancer cells can be involved in the invasion and metastasis of these cells through interaction with E-cadherin, as well as with the metastasis-associated protein MTA1. Tumor-derived IgG plays an important role in malignant progression via activation of platelets by interacting with their FcγRIIa receptors and inducing the production of low levels of reactive oxygen species. The level of IgG in malignant neoplasms is positively correlated with proliferation markers, stage of progression, growth and survival of the tumor. These data modernize the current views on the mechanisms of carcinogenesis and create the basis for the search for new diagnostic and prognostic markers in malignant neoplasms, as well as methods of their target therapy. Further in-depth studies of the phenomenon of Ig production by tumor cells will contribute to more effective practical application of the accumulated knowledge in this field.

We studied the effect of a combination of three muramylpeptides from gram-negative bacteria (Polymuramyl) on hematological parameters, morphology of the spleen, and serum cytokine level in mice with B16 melanoma treated with cyclophosphamide. Intraperitoneal administration of cyclophosphamide to tumor-bearing animals sharply reduced the number of leukocytes, especially neutrophils, in the blood and depleted the cellular composition of the spleen white pulp. Subsequent three daily intramuscular injections of Polymuramyl in doses of 70 and 860 ng/mouse for 3 days, as well as subcutaneous injection of the reference drug filgrastim (granulocytic CSF) in a dose of 12 μg/mouse partially corrected hematopoietic disorders and restored the cellular composition of the spleen. Granulocytic CSF more effectively replenished the content of mature neutrophils in the blood, while Polymuramyl restored the content of stab neutrophils. In contrast to granulocytic CSF, administration of Polymuramyl was followed by an increase in the level of granulocyte-macrophage CSF and a tendency to an increase in the serum content of IL-6, which indicates the involvement of these cytokines in the hematopoietic activity of Polymuramyl.

It has long been known that Bacillus CalmetteGurin (BCG) vaccine provides nonspecific protection against many non-mycobacterial infections, which has been discussed in the last decade through the prism of the concept of trained immunity. Within the framework of this concept, a persistent increase in resistance to various pathogens, which occurs after an infectious disease or exposure to certain microbial agents, is associated with epigenetic reprogramming of innate immune cells and their bone marrow progenitors. The COVID-19 pandemic has drawn attention of scientists and practitioners to BCG as an inducer of trained immunity. A number of epidemiological studies have suggested a negative association between the coverage of the population with BCG vaccination and the burden of SARS-CoV-2 infection. A series of independent clinical studies of the effectiveness of this vaccine in non-specific prevention of COVID-19 has been initiated in different countries. Recently, the key role of cytosolic NOD2 receptors in BCG-induced trained immunity has been proven. This actualizes the search for effective immunoactive preparations for prevention of respiratory infections in the pandemic among low molecular weight peptidoglycan fragments of the bacterial cell wall, muramylpeptides (MPs), which are known to be NOD2 agonists. The review highlights the proven and proposed linkages between BCG, MPs, NOD2 and trained immunity in the light of the COVID-19 pandemic. Analysis of the data presented indicates the prospects for preclinical and clinical studies of MPs as potential drugs for nonspecific prevention of SARS-CoV-2 infection and/or other respiratory infections in risk groups during the pandemic. First of all, attention should be paid to glucosaminylmuramyl dipeptide, approved for clinical use in Russia and a number of post-Soviet countries for the complex treatment and prevention of acute and recurrent respiratory infections.

Topical calcineurin inhibitors (TCI) have emerged from the shadow of topical corticosteroids as another first-line remedies for treating acute flares of atopic dermatitis (AD). The effectiveness of TCI in maintenance therapy is also undeniable. The wider use of TCI increases the relevance of the issue of their safety. The adherence of physicians and their patients to the treatment with TCI is constrained by a controversial FDA black box warning against these drugs based on the theoretical risk of skin tumors, especially lymphoma. This warning, formulated in 2005, has been repeatedly refuted. However, there have been studies that at least partially supported cautious use of TCI. In recent years, the results of large cohort prospective studies clarifying the issue of oncological safety of TCI have been published. The review highlights the results of various studies with optimistic, pessimistic and balanced conclusions regarding the safety of TCI, primarily their effect on tumorigenesis, in order to better inform physicians about the benefit/risk balance when using these drugs in AD patients. The data presented in this review indicate that there is no increased risk of melanoma and other forms of skin cancer in TCI users, but these data do not completely rule out the risk of skin lymphoma. However, the very low level of potential risk to an individual patient gives physicians the right to neglect this risk when choosing TCI as a treatment option for AD.

Introduction. The majority of cases of habitual miscarriage are closely related to impaired maternal immune tolerance. Experimental mice models of abortion, where the critical time points are established to monitor pregnancy progression, are widely used to study the pathogenesis of early reproductive loss. However, the relationship between the embryonic development and extraembryonic structures with the immune microen-vironment is not well understood. The aim of the study is to compare the morphofunctional characteristics of the uteroplacental unit and embryo in early pregnancy in mice with experimental spontaneous, induced, and potentiated abortions. Materials and methods. Allogeneic physiological pregnancy was modeled using ♀CBA × ♂BALB/c mice mating. Spontaneous abortions were reproduced by mating ♀CBA × ♂DBA/2 mice. Induced abortions and potentiated abortions were triggered by intraperitoneal administration of the immunomodulator ß-heptylglycoside muramyl dipeptide (MDP) to pregnant females on gestation day (gd) 5 and gd 7 mated in following combinations ♀CBA × ♂BALB/c and ♀CBA × ♂DBA/2, respectively. Mice were withdrawn from the experiment on gd 8, then uterine horns and uteroplacental units were isolated. The material was fixed in 10% neutral formalin, and standard processing was performed for histological examination. In equatorial sections, the cross-sectional area of uteroplacental unit was measured, and maternal, embryonic, as well as extraembryonic structures were analyzed. An immunohistochemical assay with rabbit polyclonal anti-CD68 antibodies was conducted to detect macrophages, then the density of CD68+ cells per 1 mm2 of the decidual area was determined. Results. On day 8 of pregnancy, in the groups of induced and potentiated abortions cross-sectional area of the uteroplacental units was decreased compared with the groups of physiological pregnancy and sponta-neous abortions. Induced and potentiated abortions demonstrated vasodilation in the mesometric decidua zone and stagnation of blood in the blood vessels, compaction of trophoblast, and hemorrhage in decidua basalis whether spontaneous abortions showed occluded maternal vessels surrounded by edematous and vacuolated trophoblast cells.At the early stages of modeling of spontaneous and immuno-dependent abortions, disturbances in the devel-opment of the embryo and extraembryonic structures were revealed, ranging from initial signs of resorption to the destruction of the embryo and membranes.In viable embryos, density indices of CD68+ macrophages in the decidual membrane of the uteroplacental units did not differ significantly in all miscarriage cases, CD68+ cells were not detected in cases of embryo-nal resorption. Conclusion. The MDP treatment in a period after completion of implantation and before forming a mature placenta (gd 5–7) results in the inducing or the potentiating abortions in CBA females mated with by Balb/c or DBA/2 males, respectively. In both cases, we revealed disturbed chorion morphogenesis and embryonic development to the extent of its complete resorption and the absence of CD68+ macrophages in resorbed embryos’ microenvironment on day 8 of pregnancy. Keywords: miscarriage, models, muramyl dipeptide β-heptylglycoside, uteroplacental unit, macrophages, immunotolerance

Introduction: The prevalence of chronic inflammatory airway diseases is rising. Their treatment with corticosteroids increases infection risk, while overuse of antimicrobial agents may increase morbidity and antimicrobial resistance. Nonspecific immunomodulatory compounds alter immune responses to both infectious and atopic challenges. These compounds may offer an alternative approach for symptom reduction and prophylaxis against both infections and exacerbations in chronic inflammatory airway disease.Areas covered: We assessed the available data on the efficacy of nonspecific immunomodulators including bacterial lysates, synthetic compounds, and vaccines in chronic rhinosinusitis (CRS); allergic and non-allergic rhinitis; chronic obstructive pulmonary disease (COPD), and asthma. A search of PubMed was carried out using the 'Clinical Trials' filter for each condition and immunomodulatory product detailed below, where available, data from meta-analyses were reported.Expert opinion: Pre-clinical data has revealed a coherent mechanistic path of action for oral immunomodulators on the respiratory immune system, principally via the gut-lung immune axis. In patients with asthma, allergic rhinitis, CRS, and COPD immunomodulatory therapy reduces symptoms, exacerbations, hospitalizations, and drug consumption. However, data are heterogeneous, and study quality remains limited. A lack of high-quality recent trials remains the major unmet research need in the field. ispartof: EXPERT REVIEW OF RESPIRATORY MEDICINE vol:14 issue:6 pages:603-619 ispartof: location:England status: published

Spontaneous proliferative activity of splenocytes in female CBA mice and the response of these cells to antigens of allogeneic male BALB/c and DBA/2 mice in a mixed splenocyte culture were evaluated by 3H-thymidine incorporation in different pregnancy models. ♀CBA×♂BALB/c mating was used for modeling physiological pregnancy. Spontaneous abortions were reproduced by abortion-prone ♀CBA×♂DBA/2 mating. In order to simulate immunostimulant-induced and immunostimulant-potentiated abortions, 0.83 mg/kg muramyl dipeptide β-heptylglycoside was intraperitoneally injected to CBA females mated with BALB/c or DBA/2 males, respectively, on gestation days 5 and 7. The increase in the rate of embryo resorption in the models of spontaneous, induced, and potentiated abortions occurred against the background of an increase in the level of spontaneous proliferation of splenocytes and a decrease in their reactivity to paternal antigens on gestation day 9.

The effect of a bacterial lysate complex IRS 19 on local and systemic manifestations of inflammation was studied in a rat model of aseptic lymphadenitis. Injection of λ-carrageenan into the cervical lymph node via surgical approach caused an increase in the thickness of the capsule, disturbances in histoarchitecture, the appearance of necrosis foci, histiocytosis of subcapsular and cerebral sinuses in the lymph node, as well as an increase in the level of TNFα in the blood serum and the number of circulating leukocytes and neutrophils. Course intranasal administration of bacterial lysate complex in this model dose-dependently reduced the level of these markers of the systemic inflammatory response and the severity of microstructural disorders in the affected lymph nodes. Thus, bacterial lysate complex after intranasal administration produces a systemic anti-inflammatory effect that goes beyond the respiratory tract.

The aim of the present study was to evaluate the clinical efficacy of a standardized combination of three muramyl peptides containing a residue of meso-diaminopimelic acid (Polymuramyl), as well as effects of this immunomodulator on the lymphocyte subpopulation profile, function of circulating neutrophils, and concentrations of serum immunoglobulins in the patients with chronic recurrent pyoderma. Thirty-five men (34.5±10 years) with exacerbation of chronic pyoderma (osteofolliculitis, folliculitis, sycosis, furunculosis) were randomized into two groups matched by age and clinical manifestations of the disease. In the comparison group (n = 17), the patients received standard treatment. In the main group (n = 18), in addition to the same standard treatment, the patients received intramuscular injections of Polymuramyl at a dose of 200 mg daily from day 1 to 5 of the study. The overall assessment of the treatment efficacy was performed on the day 14, and at 1 and 6 months of observations. Induction and maintenance of complete clinical remission were assessed as “significant improvement”; induction and maintenance of partial remission were considered to be “improvement”; persistent signs of skin inflammation and lack of remission were assessed as “lack of effect”. Immunological parameters were studied on days 0 and 14, and then at 1 and 6 months of the study. Addition of Polymuramyl to the standard treatment caused a marked tendency towards increased proportion of the patients with «significant improvement» or «improvement» on the day 14: total ratio of the patients with any clinical improvement was 24% higher, and the relative number of the patients with "lack of effect" was five-fold lower than in the comparison group (p=0.076). A trend towards improved clinical efficacy, according to the above criteria, was maintained after 1 and 6 months of the study. At 6 months of the follow-up, the proportion of patients without pustules/furuncles in the main group (9 out of 18) exceeded that in the comparison group (3/17, p = 0.047). Significant inter-group differences and dynamics of indicators of neutrophil functions, subpopulation composition of lymphocytes and concentrations of immunoglobulins in serum were not detected. However, in the main group after the 6-month observation, there was an upward trend in the absolute number of T-cells due to CD3+CD4+ subpopulation, as well as serum IgA concentration. The results of this study are in accordance with previously published data, thus indicating the ability of Polymuramyl to accelerate regression of clinical manifestations of chronic pyoderma and induce sustained remission of this disease. At the same time, the design of present investigation and the timing of taking biological samples for laboratory tests did not allow to register significant changes in most of the studied systemic immunological parameters under the influence of immunomodulator, except for the previously described modulation at the level of pro- and anti-inflammatory cytokines.

We studied the effect of a combination of three muramylpeptides from gram-negative bacteria (Polymuramyl) on hematological parameters, morphology of the spleen, and serum cytokine level in mice with B16 melanoma treated with cyclophosphamide. Intraperitoneal administration of cyclophosphamide to tumor-bearing animals sharply reduced the number of leukocytes, especially neutrophils, in the blood and depleted the cellular composition of the spleen white pulp. Subsequent three daily intramuscular injections of Polymuramyl in doses of 70 and 860 ng/mouse for 3 days, as well as subcutaneous injection of the reference drug filgrastim (granulocytic CSF) in a dose of 12 μg/mouse partially corrected hematopoietic disorders and restored the cellular composition of the spleen. Granulocytic CSF more effectively replenished the content of mature neutrophils in the blood, while Polymuramyl restored the content of stab neutrophils. In contrast to granulocytic CSF, administration of Polymuramyl was followed by an increase in the level of granulocyte-macrophage CSF and a tendency to an increase in the serum content of IL-6, which indicates the involvement of these cytokines in the hematopoietic activity of Polymuramyl.

Lowgrade cutaneous inflammation, which persists after induction of remission of atopic dermatitis (AD), determines the risk of repeated relapses and progression of the disease. It has been well established that subclinical inflammation in the skin of atopic patients may be inhibited by topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI), and proactive courses of these drugs prolong remission of the disease. In terms of prolonged application, TCI have some advantages over TCS in the context of safety. However, the routine use of TCI in AD is constrained by many practitioners who do not accept the concept of subclinical chronic inflammation and the strategy of maintenance antiinflammatory therapy on areas prone to repeated relapses, as well as obsolete myths about the association of TCI application with increased risk of cutaneous lymphoma. The review presents modem data on the pathophysiology of AD with a focus on subclinical skin inflammation, which persists after regression of acute manifestations of the disease, and the possibilities of suppressing this inflammation with TCI. Data on the safety of TCI for longterm use and the absence of prooncogenic potential are given. In addition, the relevance and expediency of pimecrolimus use in children under 2 years of age are emphasized.

Probiotics have long been considered not only as a way of correcting intestinal dysbiosis but also as a promising immunomodulatory solution. Over the past years, the evidence base for their effectiveness in the prevention and treatment of immuneassociated human diseases has substantially increased, the previously described mechanisms were specified and new components of the immunocorrective effect of probiotic bacteria, including those belonging to the genus Lactobacillus, have been deciphered. The meta-analytical findings and systematic reviews leave no doubt about the advisability of using certain probiotics, primarily Lactobacillus rhamnosus GG (LGG), in children for the treatment and prevention of various forms of acute diarrhea, including those associated with the administration of antibacterial agents, as well as for the prevention of respiratory infections. The results of testing the strain to be used as an adjuvant vaccine and a way of preventing atopic dermatitis are encouraging. The review analyzes the specific characteristics of present-day children who are more susceptible to allergic and infectious diseases, effector molecules of lactobacilli and signaling pathways that ensure their immunomodulatory effect, the main areas of therapeutic and preventive application and safety of probiotics, with a focus on LGG as one of the most studied and tested strains. In addition, the clinical efficacy of the synbiotic Normobakt L, a combination of LGG (4 × 109) plus fructooligosaccharides (800 mg),which has been approved in Russia for use in children with rotavirus infection against a background of atopic dermatitis, is demonstrated

We have studied the effect of a combination of three natural muramylpeptides containing a meso-diaminopimelic acid residue (polyramyl) on the subpopulations of circulating T cells, spleen morphology, and leukocyte level in the blood of C57Bl/6 mice with cyclophosphamideinduced immunosuppression. Intraperitoneal injections of cyclophosphamide in a dose of 100 mg/kg on days 1, 3, 5, and 7 of the experiment reduced leukocyte count and the relative number of CD4+ T cells in the blood, and also depleted the cellular composition of splenic white pulp on day 10. Subcutaneous injections of polyramyl in a dose of 200 μg/mouse on days 8 and 9 practically completely restored blood leukocytes count and morphology of the splenic white pulp. Moreover, administration of polyramyl induced marked tendency to increase in the relative number of CD4+ T cells and CD4/CD8 ratio in mice with cyclophosphamideinduced immunosuppression.

The discovery of the trained immunity phenomenon, which explains adaptive characteristics of the components of the innate immunity, not only to modernizes our understanding of the fundamentals of anti-infectious defense, but also contributes to further progress in the development and more rational selection and use of immunomodulatory agents. Induction of memory within the innate immune response is the basis of long-lasting immunomodulating effects of some non-specific immunomodifiers, which either contain ligands for innate immunity receptors or modulate the immune response pathway mediated by these receptors. For the first time, the mechanisms of action of pidotimod (a synthetic dipeptide with immunomodulatory properties) have been re-examined in the light of the trained immunity phenomenon.

Muramyl dipeptide β-heptylglycoside (C7MDP) was administered to non-pregnant CBA female mice and pregnant mice after non-abortion-prone mating (CBA×BALB/c) and mating associated with a high rate of spontaneous abortion (CBA×DBA/2). In non-pregnant females, C7MDP increased the production of IL-2, IL-4, IL-5, IL-6, IL-17, IFNγ, TNFα, and GM-CSF at constant production of IL-1α and IL-10. C7MDP increased the production of IL-10 and IL-17 and suppressed the production of IFNγ on day 8 of gestation in non-abortion-prone mouse couples and stimulated the synthesis of IL-4 and IFNγ, reduced IL-5 production, and slightly increased IL-1α secretion after abortion-prone mating. On day 14 of gestation, C7MDP elevated the yield of IL-2, IL-4, IFNγ, TNFα, and GM-CSF in CBA×BALB/c and CBA×DBA/2 couples and IL-17 in the fi rst variant of mating.

Aim To determine whether there is a correlation of the composition of circulating lymphocyte subpopulations, the serum concentrations of interferon (IFN)-α, IFN-γ, and IFN-λ3, and the lymphocyte expression of types I and II IFN receptors with the species of a disease pathogen and the degree of liver fibrosis (LF) in patients with chronic hepatitis B (CHB) and in those with chronic hepatitis C (CHC). Subjects and methods The investigation enrolled 44 patients with CHC, 9 patients with CHB, and 13 clinically healthy donors. The degree of LF in the patients was determined using transient elastography. The composition of peripheral blood lymphocyte subpopulations was examined; the concentrations of IFN-α, IFN-γ, and IL-28B were estimated. Results Lymphocyte counts were higher in patients with CHC and in those with CHB than those in healthy donors; and the number of neutrophils was lower. There were no differences between the groups in the composition of lymphocyte subpopulations with the exception of the number of CD3+CD4+ cells, which in patients with CHC was larger than in those with CHB. In CHC and CHB patients, the counts of CD118+ lymphocytes were higher than those in healthy donors. Patients with CHB and those with CHC did not differ between themselves and from healthy donors in the expression of CD119 on the lymphocytes. In CHC patients, the relative CD119+ cell counts were higher between CD4+ lymphocytes than those in healthy donors. The serum levels of IFN-α and IFN-γ in CHC and CHB patients were similar, but higher in healthy donors. The concentration of IL-28B genotype in patients with CHC was twice as high as in those with CHB, but the differences were statistically insignificant. The number of lymphocytes increased with the progression of fibrosis; that of neutrophils decreased. There was an inverse relationship between platelet counts and LF severity. Multiple comparisons of the clusters of patients with different degrees of LF revealed no differences in the number of major lymphocyte subpopulations. However, the number of CD3+CD16+CD56+ natural killer-like T (NKT) cells correlated with fibrosis severity. Patients with different degrees of LF showed no differences in the proportion of CD118- and CD119 cells between lymphocytes and in the serum levels of IFN-α, IFN-γ, and IL-28B levels. Patients with grade IV LF displayed a higher proportion of CD4+CD119+ lymphocytes between CD45+ cells than did those with grade III LF. Conclusion Several new clinical and laboratory trends were identified and the nature and extent of previously described hematological and immunological changes were clarified in CHC or CHB patients with various degrees of LF. Some indicators may be used as additional criteria for the prognosis of the above forms of hepatitis, and a number of newly described facts suggest that it is necessary to revise the protective/phlogogenic value of types I, II, and III IFNs in chronic viral hepatitis C and B.

Phenyl, p-tolyl, and p-tert-butylphenyl β-1-thio-N-acetylglucosaminides were synthesized by the treatment of thiophenols with peracetate of α-D-glucosaminyl chloride in the presence of triethylamine or under the conditions of phase-transfer catalysis with quaternary ammonium salts. The compounds synthesized were used for obtaining of glycosides of 4,6-O-isopropylidene-N-acetylmuramic acid, which were coupled with L-Ala-D-Glu(NH2)-OBzl and then deprotected to obtain the target aryl β-thioglycosides of N-acetylmuramyl-L-analyl-D-isoglutamine (MDP). The aryl β-thioglycosides of MDP were found to stimulate an antibacterial resistance toward Staphylococcus aureus in mice. The reliable induction of the spontaneous activity of natural killers in the population of blood mononuclear cells was observed only for phenyl β-thio-MDP at a dose of 200 µg/ml.

Symmetric secondary linear alcohols were proposed as aglycones for the synthesis of lipophilic glycosides of β-N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). Pentadecan-8-ol, nonadecan-10-ol, and tricosan-12-ol were glycosylated by the oxazoline method. Based on the corresponding glucosaminides, alkyl β-glycosides of 4,6-O-isopropylidene-N-acetylmuramic acid were synthesized and coupled with the dipeptide. Deprotection of isopropylidene groups by acidic hydrolysis and catalytic hydrogenolysis of benzyl esters resulted in the target muramyldipeptide glycosides. Nonadecan-10-yl and tricosan-12-yl β-MDPs at doses 2 μg/mice most effectively stimulated antibacterial resistance in mice against Staphylococcus aureus. In contrast to the previously synthesized undecan-6-yl β-MDP, pentadecan-8-yl, nonadecan-10-yl, and tricosan-12-yl β-MDPs demonstrated direct cytotoxicity toward tumor cells K-562 and blood mononuclear cells.

The effects of oral treatment with Aralox phytopreparation containing Aralia mandshurica (Araliaceae) and Engelhardtia chrysolepis (Juglandaceae) extracts on some parameters of lipid metabolism was studied in women with nondiabetic obesity receiving low-caloric diet. Our randomized placebo-controlled study comprising 32 volunteers showed that aralox treatment led to a decrease in total body weight and fat weight, reduced perilipin content in adipocytes and plasma triglyceride content, and stimulated activity of hormone-sensitive lipase.

The following glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) were synthesized: β-4-tert-butylcyclohexyl MDP, β-2-(adamant-1-yl)ethyl MDP, β-2,2-diphenylethyl MDP, and β-2-(p-biphenyl) ethyl MDP. The starting peracetylated β-N-acetylglucosaminides were prepared by the oxazoline method. They were converted into 4,6-O-isopropylidene-N-acetyl-D-muramic acids, which were coupled with L-Ala-D-Glu(NH2)OBn. The target glycopeptides were obtained after their deprotection. The stimulation of the anti-infection resistance of mice against Staphylococcus aureus by the MDP glycosides was studied.

Hexyl, octyl, and cyclohexyl β-glycosides and heptyl and cyclohexyl α-glycosides of muramyl dipeptide (MDP) were synthesized. Tests in vitro and in vivo revealed lower immunostimulating activities of MDP α-glycosides in comparison with the corresponding β-glycosides and MDP itself. In the case of alkyl β-glycosides, differences in hydrocarbon chain lengths (C4–C8) and in aglycone (aliphatic chain and aliphatic or aromatic ring) exerted no substantial effect on the immunostimulating activity.

We studied the capacity of 9 new muramyl dipeptide glycosides to stimulate mouse resistance to experimental sepsis induced by intraperitoneal injection of salmonella typhimurium culture. Preventive intraperitoneal injections of muramyl dipeptide β-glycosides better improved survival of infected animals compared to the original (unmodified) muramyl dipeptide and muramyl dipeptide α-glycosides. The most effective drug muramyl dipeptide β-heptylglycoside injected during sepsis development also reduced animal mortality, decreased bacterial contamination of the viscera, and increased phagocytic activity of peritoneal macrophages in infected animals.

We studied the effect of new muramyl dipeptide glycosides with different structure of aglycon and configuration glycoside bond on spontaneous and mitogen-induced proliferation of mouse splenocytes and production of interleukin-2 by these cells. Biological activity of muramyl dipeptide beta-glycosides with aliphatic, carbocyclic, adamantile, and phenol aglycons is higher than that of the original compound, while alpha-glycosylation decreases the immunostimulating effect of this glycopeptide.

We studied the capacity of anomeric pairs of alpha- and beta-dodecyl, alpha- and beta-(1-pentylhexyl), and alpha- and beta-cyclododecyl glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide) to stimulate the nonspecific resistance of mice to intraperitoneal infection of Staphylococcus aureus and Escherichia coli cultures. Intraperitoneal pretreatment with the test substances in a wide dose range increased survival of infected animals. No differences were found between the biological effects of alpha- and beta-dodecyl and alpha- and beta-(1-pentylhexyl) glycosides of muramyl dipeptide. An inverse relationship was found between stimulatory activity and dose of alpha- and beta-cyclododecyl glycosides of muramyl dipeptide during sepsis caused by Staphylococcus aureus.

We compared the effects of Tamerit, Polyoxidony, and Licopid on spontaneous and lipopolysaccharide-stimulated production of interleukin-1 and tumor necrosis factor by mouse peritoneal macrophages in vitro. The test preparations were equally potent in stimulating nonactivated cells. Licopid produced a costimulatory effect on macrophages primed with endotoxin. Tamerit in different doses suppressed cytokine production by cells. Polyoxidony in low doses activated, but in high doses suppressed this process.

Immunomodulatory activity of five new synthetic muramyl dipeptide (MDP) derivatives (β-heptylglycoside-MDP, β-hexadecylglycoside-MDP, polyacrylamide-MDP, polyacrylamide-MDP-phosphatidylethanolamine, and dexal-MDP) is studiedin vitro in different test systems.

Effects of 11 original glycoside derivatives of muramyl dipeptide on the production of interleukin-1 and tumor necrosis factor by mouse peritoneal macrophages were studied. The relationship between macrophage activation evaluated by induction of these cytokines and configuration of glycoside bond and aglycon structure of MDP was revealed.

The effects of 3-aminophthalhydrazide and carrageenan on reparative regeneration and expression of CD117 by liver cells after partial hepatectomy were studied in mice. 3-Aminophthalhydrazide stimulated regeneration of the liver and increased the count of CD117(+) hepatocytes. By contrast, carrageenan inhibited liver reparation and CD117 expression.

Decrease in the absolute count of T lymphocytes in the peripheral blood (mainly CD4+ cells), activation of humoral immunity with accumulation of immune complexes, and suppression of the neutrophil metabolic activity were detected in patients with chronic glomerulonephritis in the presence of opisthorchis invasion. Imbalance in the serum concentrations of cytokines produced by T-helper subpopulations (predominance of Th products) was detected.

The interaction between two homologous muramyl dipeptide derivatives (β-heptylglycoside and β-hexadecylglycoside) and model membranes and internalization of these derivatives into K562 human erythroleukemia cells are studied. It is suggested that the difference in the interaction of these homologs with model membranes and in their immunomodulating activities result from different hydrolipophilic balance of these perorations.

We studied the capacity of 9 new muramyl dipeptide glycosides to stimulate mouse resistance to experimental sepsis induced by intraperitoneal injection of salmonella typhimurium culture. Preventive intraperitoneal injections of muramyl dipeptide beta-glycosides better improved survival of infected animals compared to the original (unmodified) muramyl dipeptide and muramyl dipeptide alpha-glycosides. The most effective drug muramyl dipeptide beta-heptylglycoside injected during sepsis development also reduced animal mortality, decreased bacterial contamination of the viscera, and increased phagocytic activity of peritoneal macrophages in infected animals.

We studied the effect of new muramyl dipeptide glycosides with different structure of aglycon and configuration glycoside bond on spontaneous and mitogen-induced proliferation of mouse splenocytes and production of interleukin-2 by these cells. Biological activity of muramyl dipeptide beta-glycosides with aliphatic, carbocyclic, adamantile, and phenol aglycons is higher than that of the original compound, while alpha-glycosylation decreases the immunostimulating effect of this glycopeptide.

Effects of 11 original glycoside derivatives of muramyl dipeptide on the production of interleukin-1 and tumor necrosis factor by mouse peritoneal macrophages were studied. The relationship between macrophage activation evaluated by induction of these cytokines and configuration of glycoside bond and aglycon structure of MDP was revealed.

The ability of β-heptylglycoside muramyl dipeptide (glymuride) to stimulate nonspecific resistance in mice is studied. Glymuride prevents the death of up to 80% animals intraperitoneally infected withSalmonella typhi in a dose of 100 LD50. Glymuride is effective in both oral and intravenous administration. The ED50 for these routes of administration are calculated.