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The aim of the study was to evaluate the clinical and interferon-modulating efficacy of a combination of rectal and topical dosage forms of IFN-α2b with antioxidants in the treatment of acute respiratory infections (ARIs) in comparison with other variants of antiviral therapy. Materials and methods. A total of 90 servicemen aged 19.2±0.9 years with uncomplicated forms of ARI were hospitalized not later than 48 hours after the onset of the disease. Patients were randomized into 3 groups of 30 people each. In the first group, patients received rectal suppositories containing IFN-α2b (1 million IU) and antioxidants (alpha-tocopherol acetate and ascorbic acid) twice a day for 5 days. In the second group, patients received intranasally a gel formulation containing IFN-α2b (36 000 IU/1 g) and antioxidants 3 times a day in addition to the above suppositories. In the third group, patients were prescribed umifenovir (reference drug) at dose of 200 mg 4 times a day for 5 days. The dynamics of regression of clinical manifestations of ARI in different groups, changes in concentrations of IFN-α and IFN-γ in blood plasma, as well as spontaneous and induced production of these cytokines by blood cells ex vivo were evaluated. After that, the patients were observed for another 3 months to register repeated cases of hospitalization for ARI. Results. Marked tendency to accelerate the regression of symptoms of intoxication and fever was observed when intranasal dosage form of IFN-α2b was administered to patients receiving the rectal form of this cytokine. The combination of rectal and topical dosage forms of IFN-α2b with antioxidants was more effective than monotherapy with the rectal suppositories in preventing repeated hospitalization for ARI. The above combination caused the most complete correction of induced production of IFN-α by blood cells ex vivo at its initial deviation from the norm. Conclusion. The obtained data indicate the expediency of using the combination of rectal and topical dosage forms of IFN-α2b with antioxidants for treatment of ARI.

The outcome of diseases accompanied or caused by mucostasis depends both on the restoration of drainage function of the airways and on the effectiveness of immune mechanisms against pathogens. N-acetylcysteine (NAC) is widely used as mucolytic and antioxidant remedy in clinical practice. In this regard, the data of the scientific literature on the direct and indirect effects of NAC on the mucosal immunity of the respiratory tract have been reviewed. NAC possesses pleiotropic immunomodulating properties, most of which contribute to the regression of clinical manifestations of acute and chronic inflammatory diseases of the respiratory tract. Biological and pharmacological effects of NAC include improvement in rheological properties of mucus, reduction of excess mucin production, restoration of mucociliary clearance and production of sIgA, suppression of excess production of IgE and IgG4, destruction of biofilms and inhibition of their formation, suppression of adhesion of pathogenic bacteria to epithelial cells, antioxidant activity, regulation of the production of pro-inflammatory and profibrotic cytokines. There was no convincing evidence that NAC is able to suppress any component of mucosal immunity. For final conclusions on this subject, further research are required.

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 CD3CD4cells, which in patients with CHC was larger than in those with CHB. In CHC and CHB patients, the counts of CD118lymphocytes 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 CD119cell counts were higher between CD4lymphocytes 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 CD3CD16CD56natural killer-like T (NKT) cells correlated with fibrosis severity. Patients with different degrees of LF showed no differences in the proportion of CD118and 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 CD4CD119lymphocytes between CD45cells 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.

This review analyzes whether it is expedient to use oral probiotics for the stimulation of immune response against pathogens in the respiratory tract. It considers a relationship between mucosal microbial colonization in different biotopes of the body and mucosal immunity in the respiratory tract. The principal and terminological controversial issues of colonic dysbiosis and the possibilities of using the medicines and products containing live commensals/symbionts to correct microbiota disturbances are examined. There are data on the degree of resistance and resilience of the colonic microbial community exposed to destabilizing factors, antibiotics in particular. The properties of probiotics that have been proven to enhance host response against pathogens and the phenomena that characterize these probiotics as immunomodifiers and distinguish them from other immunostimulating/immunomodulating agents are described. Criteria for choosing effective and safe oral probiotics to stimulate an immune response in the respiratory tract are formulated. Finally, we review the data on the clinical and immunomodulatory effects of dietary supplement containing a combination of three probiotic strains (Lactobacillus gasseri PA 16/8, Bifidobacterium bifidum MF 20/5 and Bifidobacterium longum SP 07/3) with vitamins and minerals as an agent to prevent and reduce the severity of acute and recurrent respiratory tract infections.

The paper analyzes the currently available data on the impact of respiratory viruses (RVs) on the exacerbations and clinical phenotype of chronic obstructive pulmonary disease (COPD), as well as on the molecular mechanisms of this impact. It emphasizes the role of acute respiratory viral infections (ARVI), primarily rhinovirus infections (RVI) as the most important triggers of COPD exacerbations and the causes of their severe and long-term course. Particular attention is given to ARVI-induced secondary bacterial infections that worsen COPD exacerbations. The mechanisms of how RVs potentiate chronic inflammation and remodeling of the airway, which are caused by tobacco smoke, are depicted. There are arguments that there is a much greater correlation of the acute episodes showing the more severe respiratory symptoms of COPD with ARVI than can be found by molecular methods for RV verification. The body’s genetic and/or acquired excessive response to viral invasion does not reflect the efficacy of antiviral defense and is an endogenous damaging factor in this situation. The role of RVs in the formation of the clinical phenotypes of COPD with frequent exacerbations remains debatable. The need for a search and more active practical introduction of means to prevent virus-induced COPD exacerbations appears obvious. In this regard, the authors identify chemical and mechanical polyvalent bacterial lysates for oral and sublingual administration. In addition to nonspecific stimulation of antiviral defense, these medicines induce antigen-specific mucosal and systemic reactions against bacterial pathogens. The role of ARVI pathogens in COPD exacerbations deserves a greater practical attention focused towards optimizing the treatment of this social disease.

On August 31,2023 in V.A. Nasonova Research Institute of Rheumatology a meeting of the Expert Council was held at which the principal investigators and co-investigators of the ARTNEO-2021 protocol "Multicenter randomized double-blind, placebo-controlled study of ARTNEO in patients with stage II-III primary knee osteoarthritis" was held. A consensus position was developed on the possibility and feasibility of using a combination of undenatured (native) type II collagen, methylsulfonylmethane, boswellic acids, vitamins C and D (ARTNEO complex) in clinical practice. Based on the results of the study, the use of the ARTNEO complex can be recommended as part of a complex therapy for patients with osteoarthritis as a course treatment with total duration up to 6 months. The results of the study can only be interpreted in relation to ARTNEO and cannot be transferred to preparations with a different composition.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. [ABSTRACT FROM AUTHOR]

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.

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.

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.

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.

Bacterial lysates may produce immunoregulatory effects in the inflammatory diseases that are not directly caused by infectious agents; they may also stimulate the immune response against pathogens which are not a part of the lysate composition. Imudon® is a polyvalent bacterial lysate that is available in orodispersible tablets. However, the influence of this drug product on aseptic inflammation and immune defense against the infectious agents, the antigens of which are not contained in this preparation have not been studied so far. The aim of this study, therefore, was to determine the anti-inflammatory and immunomodulating effects of Imudon® using the models of aseptic lymphadenitis (in Wistar rats) and pneumococcal pneumonia (in Balb/c mice), i.e., the conditions not related to the specific components of the bacterial lysate. Lymphadenitis was induced in rats by administration of λ-carrageenan into a cervical lymph node via an open operative approach. Whereas pneumonia was induced in mice by administering Streptococcus pneumoniae suspension intranasally. The choice of pneumococcus was determined by the absence of pneumococcal antigens in Imudon®, i.e., it cannot be a direct inducer of adaptive immune response against pneumococcal infection. Imudon® was administered intragastrically as a crushed tablet suspension following a therapeutic-preventive regimen (for 14 days daily until the induction of inflammation and for 3 [in the lymphadenitis model] or 5 days [in the model of pneumonia] in three doses thereafter). In the lymphadenitis model, Imudon® demonstrated both local and systemic anti-inflammatory responses manifested in the reduced number of circulating leucocytes and lower TNFα levels and by ameliorated histological features of inflammation in the operated lymph node. In rats, the anti-inflammatory effect was most pronounced when the product was administered at a dose of 2.2 mg/kg (equivalent to a human therapeutic dose) and 6.6 mg/kg. In the model of pneumonia, administration of Imudon® at 4.44 mg/kg (equivalent to a human therapeutic dose) and 13.32 mg/kg demonstrated a trend towards increased survival rate as compared to the control group. On Day 5 after infection Imudon® (4.44 and 13.32 mg/kg) decreased significantly the severity of inflammation and bacterial titer in the lungs. The titer of anti-pneumococcal immunoglobulins A in the bronchoalveolar lavage fluid were found to be higher in the Imudon® treated group (13.32 mg/kg) compared to control group. The results of this study showed high antiinflammatory and immunomodulatory activities of Imudon® and provided an insight into the mechanisms that underlie the clinical effects of this drug in various inflammatory diseases.

A meeting of the Discussion Club «Controversial and Unresolved Issues in the Treatment of Cough in Children in Outpatient Practice» with the support of the Pediatric Respiratory Society was held in Moscow on September 30 2017, bringing together leading Russian experts in pediatrics, pulmonology, immunology and otorhinolaryngology. There is the experts’ agreed opinion.

The review presents the criteria for a new classification of immunomodulatory drugs, which can be useful for a general practitioner. These criteria facilitate the selection of immunostimulant/immunomodulator in a specific clinical situation. Through the prism of these criteria, this paper provides information on the mechanisms and evidence of the prophylactic and, separately, therapeutic effectiveness of bacterial lysates, in particular OM-85 as one of the most studied and tested immunomodulators.

The prospects of treating patients with chronic rhinosinusitis were discussed, as well as the possibilities of prevention and complex therapy of the exacerbations of this disease.

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