Glatiramer acetate (GA) is approved for the treatment of multiple sclerosis (MS). However, the mechanism of action of GA in MS is still unclear. In particular, it is not known whether GA can modulate the pro-inflammatory Th17-type immune response in MS. We investigated the effects of original GA (Copaxone ® , Teva, Israel) and generic GA (Timexone ® , Biocad, Russia) on Th17- and Th1-type cytokine production in vitro in 25 patients with relapsing-remitting MS and 25 healthy subjects. Both original and generic GA at concentrations 50–200 μg/ml dose-dependently inhibited interleukin-17 and interferon-γ production by anti-CD3/anti-CD28-activated peripheral blood mononuclear cells from MS patients and healthy subjects. This effect of GA was reproduced using purified CD4 + T cells, suggesting that GA can directly modulate the functions of Th17 and Th1 cells. At high concentrations (100–200 μg/ml), GA also suppressed the production of Th17-differentiation cytokines (interleukin-1β and interleukin-6) by lipopolysaccharide (LPS)-activated dendritic cells (DCs). These GA/LPS-treated DCs induced lower interleukin-17 and interferon-γ production by autologous CD4 + T cells compared to LPS-treated DCs. These data suggest that GA can inhibit Th17-immune response and that this inhibitory effect is preferentially exercised by direct influence of GA on T cells. We also demonstrate a comparable ability of original and generic GA to modulate pro-inflammatory cytokine production.

1 -ФГБУ "Научно исследовательский институт эпидемиологии и микробиологии имени почетного академика Н.Ф.Гамалеи" Минздрава России: 123098, Москва, ул. Гамалеи, 18; 2 -ФГБУ "Научно исследовательский институт вирусологии им. Д.И.Ивановского" Минздрава России: 123098, Москва, ул. Гамалеи, 16; 3 -ФГБУ "НИИ пульмонологии" ФМБА России: 105077, Россия, Москва, ул. 11 я Парковая, 32, корп. 4 РезюмеЦелью работы явился анализ респираторных вирусов и цитокинов в индуцированной мокроте больных с фенотипом "бронхиальная астма (БА) и хроническая обструктивная болезнь легких (ХОБЛ)" вне обострения и антигенов Mycoplasma pneumoniae и антител к микоплазмам и хламидиям в сыворотке крови. В образцах индуцированной мокроты у пациентов с фенотипом "БА + ХОБЛ" выяв лены респираторные вирусы (риновирусы группы А, респираторно синцитиальный вирус и аденовирус), в крови -антигены микоплазм и / или антитела к M. pneumoniae и Chlamydia pneumoniae. Респираторные инфекции были ассоциированы с дисбалансом интерферонов (IFN) 1-3 го типов и противовирусного белка МхА. При отсутствии экспрессии гена IFN β в 58,3 % образцов детектировались РНК IFN α и в 42,9 % -РНК IFN λ. Показан дефицит функциональной активности IFN α и γ. Ключевые слова: фенотип "бронхиальная астма и хроническая обструктивная болезнь легких"; риновирусы; респираторно синцитиаль ный вирус; аденовирус; микоплазмы; хламидии; интерферон 1-3 го типов; белок МхА; обратная транскрипция с полимеразной цепной реакцией в реальном времени; агрегатгемагглютинация; иммуноферментный анализ. Respiratory viruses and bacteria SummaryThe aim of the study was to analyze respiratory viruses and cytokines in induced sputum samples, serum Mycoplasma pneumoniae antigens and anti Mycoplasma and anti Chlamydia antibodies in stable patients with bronchial asthma and chronic obstructive pulmonary disease (COPD) pheno type. Methods. RNAs of rhinovirus, respiratory syncytial virus, metapneumovirus, types 1, 2, 3, and 4 influenza viruses, coronaviruses ОС43, Е229, NL63, and HKUI; DNA of group B, C and E adenoviruses and bocavirus were detected by real time PCR with hybridization and fluorescent detec tion. Serum IgG, IgM and IgA antibodies against C. pneumoniae were detected with indirect microimmunofluorescence assay. Mycoplasma pneu moniae antigens were detected with aggregate hemagglutination method. Results. In patients with asthma plus COPD phenotype, three respiratory viruses were detected in sputum, such as rhinovirus, respiratory syncytial virus and adenovirus; antigens of and / or antibodies against M. pneumo niae and Chlamydia pneumoniae were also detected in blood sera. The respiratory infections were associated with imbalanced ratio of interferon types I, II, III and MxA antiviral protein. In patients with no expression of IFNβ gene, IFNα RNA was detected in 58.3% of samples and IFNλ RNA was detected in 42.9 % of samples. Decreased functional activities of IFNα and IFNγ were found.

Scientific Relevance: Mucosal immunity plays a major role not only in the prevention but probably also in the outcome of COVID-19. An enhanced production of secretory immunoglobulin A (sIgA) might contribute to the activation of the immune response mechanisms. Study Objective: To assess the levels of sIgA produced by epithelial cells in the nasal and pharyngeal mucosa and those measured in salivary gland secretions and to study the course of COVID-19 following the intranasal or subcutaneous administration of a bacteria-based immunostimulant agent. Materials and Methods: This study included 69 patients, aged between 18 and 60, who had moderate COVID-19 infection. They were divided into two groups: Group 1 (control group) included 39 patients who received only background therapy, and Group 2 was made up of 30 patients who received background therapy in combination with the Immunovac VP4 vaccine, a bacteria-based immunostimulant agent, which was given for 11 days starting from the day of admission to hospital. The levels of sIgA were measured by ELISA in nasal epithelial swabs, pharyngeal swabs, and salivary gland secretions at baseline and on days 14 and 30. Results: The convalescence phase of moderate COVID-19 was associated with a decrease in sIgA levels in nasal swabs, persistently high sIgA levels in salivary gland secretions, and no changes in pharyngeal swabs with the levels similar to those in healthy subjects. The addition of an immunostimulant agent to combination therapy for patients with COVID-19 stimulates the production of sIgA in the nasal and pharyngeal compartments, reduces C-reactive protein (CRP) levels and shortens the duration of fever and the length of hospital stay. Conclusion: Using an immunomodulatory agent containing bacterial ligands in therapy for COVID-19 patients enhances the production of sIgA in the nasal and pharyngeal compartments and improves the course of the disease.

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