Immunobiological properties of granulocytemacrophage colony-stimulating factor and synthetic peptides of his active center

Granulocyte-macrophage colony-stimulating factor (GM-CSF) belongs to the group of growth cytokines (hematopoietins) that regulate proliferation and differentiation of myeloid lineage cells. Recently, a lot of new data have accumulated, indicating the presence of a number of previously unknown biological effects in GM-CSF and synthetic peptides of its active center, which open up new prospects for their wide clinical use.The review outlines current understanding of the structure, functions, and mechanisms of GM-CSF action and concerns the structure of its receptor. The GM-CSF producer cells are characterized, as well as target cells (effector cells) responding to this cytokine are also presented. The known mechanisms of intracellular signaling involved into the GM-CSF/receptor interaction are described. The main pleiotropic effects of this cytokine as a factor of hematopoiesis and an immunostimulating agent are characterized. The previously known and recently found immunobiological effects of this cytokine, its recombinant forms and synthetic analogues of its active center are discussed.Participation of GM-CSF in hematopoiesis and differentiation of myeloid cells, the effects of this cytokine on the functional activity of immunocompetent populations (lymphocytes, macrophages, neutrophils, dendritic cells) and tissue cells were characterized. The influence of GM-CSF on the development and course of infectious and inflammatory processes, its role in the creation of combined vaccines is reviewed. Clinical data on usage of GM-CSF and its recombinant forms in hematology, immunology, oncology, reproductive medicine and in the treatment of systemic autoimmune processes and infectious diseases are presented.The recently discovered immunobiological properties of synthetic peptides derived from active center of GM-CSF are summarized, indicating that they exhibit immunotropic and hematopoietic effects, as well as antimicrobial activity against Gram-negative and Gram-positive bacteria, viruses, and tissue repair (effect on the rate of wound healing), which is not typical to the whole GM-CSF molecule. We discuss the prospects for clinical applications of synthetic GM-CSF analogue (ZP2 peptide), and an opportunity of creating new cosmetics and pharmaceuticals with combined immunostimulating, antimicrobial and reparative properties on its basis.The review expands the view on potential usage of cytokine therapy in the treatment of various infectious and non-infectious diseases in humans, and is addressing a wide range of specialists working in the field of allergology and immunology, infectology and regenerative medicine

Role of lipid metabolic disturbances for the mechanisms of immune dysregulation and endothelial dysfunction in early forms of chronic cerebrovascular insufficiency

It is known that the immunological component of nearly any dysregulatory pathology is manifested by the development of new functional systems providing adaptation reactions, as well as by the presence of allostasis, reflecting other forms that are different from the normal parameters, and variants of mutually supporting relationships that occur at different structural and functional levels of the body. A long stay in the areas of military campaigns inevitably has a negative impact on the re-adaptation for civilian life, and it is accompanied by occurence of pathological functional connections that lead to dysregulation of the basic functions, including those of nervous and immune systems. In this regard, we studied the features of immune cell functioning in the patients with early forms of chronic cerebral ischemia accompanied by hyperlipoproteinemia, and we have made a comprehensive assessment of the factors characterizing morphological and functional state of endothelium. A representative survey included 87 patients who participated in the Afghan campaign with early forms of cerebral circulatory failure. The subjects exhibited objective and subjective signs of underlying vascular disease, typical to the earliest manifestations of chronic cerebrovascular insufficiency (CVVN) manifesting as headache, dizziness, noise in the head, memory impairment, decreased performance. All the patients underwent a comprehensive examination, i.e., expanded lipidogram, determination of vasoactive factors in the blood and cultural fluid, the number of circulating desquamated endotheliocytes, thus reflecting morphological signs of endothelial damage, additional ultrasound Doppler sonography of the main vessels, transcranial Doppler and electroencephalography were carried out.It is known that endothelial cells are independently capable of modulating vascular tone, depending on the current clinical condition, and it may be also subjected to remodeling rearrangements with involvement into the pathological process, e.g., in atheromatosis. In this regard, endothelial dysfunction is a key factor in developing vascular pathology, affecting the systemic level. According to results of the study, it has been established that the main progression mechanism for the early forms of CVVN is the development of endothelial dysfunction. The condition has multifactorial genesis in which immune mechanisms are directly involved. Hyperlipoproteinemia established in more than 90% of cases, is one of the most important metabolic triggering factors for development of immune reactions, which is also promoted by imbalance of vasoform and thrombogenic factors, by presence of oxidative and nitrosative cellular stress markers which generally contribute to increase in cerebral vascular remodeling and the basis for the formation of organic pathology of the central nervous system

ACTUAL ISSUES OF MASTOPATHY DIAGNOSTICS IN LARGE INDUSTRIAL CITY OF CHELYABINSK REGION

Urban ecological problems are associated with industrial pollution emissions, waste of metallurgical production, unhealthy lifestyle and reproductive behavior lead to a steady rise in cancer pathology in theChelyabinskregion. Women in early reproductive age living in areas of ecological concern with suspected mastopathies, exhibit significantly higher levels of tumor markers associated with the tumor cell membranes of (CA19-9, SA15-5, CA125), CEA (carcinoembryonic antigen). Therefore, it seems necessary to perform massive laboratory programs for oncological screening, especially, among young working population, in order to identify breast diseases, and to arrange appropriate risk groups at this basis, aiming for development of effective preventive measures for the future

CYTOMETRIC ANALYSIS OF THE SPECTRUM SUBPOPULATION OF T LYMPHOCYTES IN THE EARLY FORMS OF CHRONIC BRAIN ISCHEMIA VETERANS OF MODERN WARS

Formation of the earliest forms of chronic brain ischemia veterans of modern wars accompanied by an increase in the systemic circulation of the population of T lymphocytes and monocytes, reflecting the activation of central mechanisms lymphopoiesis. In step vascular encephalopathy is an increase in circulating pool of T lymphocytes expressing the activation markers early positive reflecting readiness cells to IL-2 dependent proliferation. When progessirovanii chronic brain ischemia decreased levels of circulating T-regulatory cells, which may reflect a violation of self-tolerance in relation to brain antigens

Immune phenotype of tissues from exudative lesions of Reinke’s space

Non-inflammatory exudative lesions of Reinke’ pos space present the most common cause of phonation disorders in representatives of vocal professions. The leading role in pathogenesis of this disorder is given to the nearly complete absence of lymphatic drainage of Reinke space and local deposition of tissue fluid. The mechanisms of its progression are of particular importance when determining the condition of mucosaassociated laryngeal tissue. The aim of our work was to evaluate the parameters of immunohistochemical lymphocyte typing in exudative lesions from the Reinke’s space. Materials and methods: The main group consisted of 40 patients, at the mean age of 43.2±2.1 years, exhibiting tumor-like exudative lesions of Reinke’s space. The biopsy material was taken from the vocal folds, including polyps, vocal nodules and Reinke’s edema. Myxoid and angiomatous types of the polyps were separately assessed. Videofibrolaryngoscopy was performed using an Olympus TYPE 150 bronchofibroscope (Germany). Morphological studies were carried out using a DMRXA microscope (Leika, Germany) by means of the ImageScopeM computer program (Germany). The uniformly treated sections were stained with Hematoxylin & Eosin (Biovitrum, Russia). Immunohistochemical quantitative assessment of the main T cell populations (CD3+, CD4+, CD8+), B cells (CD20+), histiocytes (CD68+), and the cells expressing bcl-2 and p53 cell regulators was carried out automatically using the BenchMarkXT immunohistotainer (Ventana, USA). The results were expressed as U/mm2. Results and Discussion. Some special features of cellular immunophenotype were revealed in exudative lesions of Reinke’s space. Reinke’s edema was characterized by high content of CD3+ lymphocytes, CD4+, CD8+, CD20+, p53 positive cells of the basal epithelium, as well as low numbers of CD68+, bcl-2 positive lymphocytes and cells of the basal epithelium. Myxoid type of polyps was characterized by low content of CD3+, CD4+, CD8+, CD20+ lymphocytes, bcl-2 positive lymphocytes and basal epithelium cells, CD68+ monocyte-macrophage cells, and high amounts of p53 positive basal epithelial cells. In the angioma-type polyps, we have registered low contents of CD3+, CD4+, CD8+, CD20+ lymphocytes, high numbers of monocyte-macrophage CD68+ cells, MMP-9+, bcl-2 positive lymphocytes, and low content of p53 positive cells of basal epithelium. The samples from the vocal nodules were characterized by low content of CD3+, CD4+, CD8+, CD20+ and p53 positive basal epithelial cells; high numbers of CD68+ cells (monocyte-macrophage series), MMP-9+ and bcl-2 positive lymphocytes

CHARACTERISTICS OF CELLULAR COMPARTMENT CHANGES OF IMMUNE SYSTEM IN THE PATIENTS WITH CHRONIC POLYPOUS RHINOSINUSITIS DEPEND ON EFFICIENCY OF DRUG THERAPY

Despite numerous attempts to control the course of chronic rhinosinusitis with nasal polyps (CRSwNP) by means of pharmacological treatment and new surgical approaches, the majority of patients experience lifelong persistence of this disorder, at recurrence rates of 50-60% within 18 months after surgical treatment. Since CRSwNP is a chronic persistent inflammatory process, it affects the entire body condition, including the state of systemic immune response. An elevation of NK (CD3-CD16+CD56+), activated NK (CD8+CD3-), NKT cells (CD16+CD56+CD3+), Treg (CD4+CD25brightCD127low to neg) cells and activated T-lymphocytes (CD3+CD25+) was revealed elsewhere among all the patients with CRSwNP, using a flow ytometry method. There was no difference between various disease phenotypes. We analyzed the status of cellular component of systemic immunity, dependent on clinical course of the disease and efficiency of the administered therapy of CRSwNP. The patients were divided into three subgroups. The follow-up period was 1 year. The first group comprised the patients who showed positive dynamics after conservative therapy, resulting into regression of nasal polyps and their grade than a year ago. The second group included the patients in whom the size of polyps remained the same. The third group included the patients with higher incidence of nasal polyps than a year ago.We have shown a decrease of Treg, NKT cells, NK and activated NK, cytotoxic T-lymphocytes (CD3+CD8+), activated T-cell numbers in clinical group 3 with aggressive growth of polyps and low effect of standard therapy, which may cause deterioration of the immune system cellular populations, accompanied by presence of persistent productive inflammatory process of nasal cavity and paranasal sinuses. In the second group, a significant elevation of total lymphocyte number, total and activated T cells, T helpers (CD3+CD4+), cytotoxic T lymphocytes, NK and NKT cells was shown. Meanwhile, a decrease in absolute number of activated NK was observed despite the NK growth. Therefore, we can assume that the mechanism of their activation was disturbed and compensated by production of NKT cells and cytotoxic T lymphocytes. Moreover, we have shown in this group that the absolute number of Treg cells is increased; and these cells had a suppressive influence on effector cells of adaptive immune response, thus inducing incomplete elimination of infectious agents, which contribute to permanent incomplete course of inflammatory process. Chronic inflammatory process in CRSwNP affects systemic cellular immunity depending on the morbidity characteristics in the course of pathological process. The maximal intensity of systemic cellular immunity is observed in the group of patients that require permanent basic drug therapy. In case of aggressive CRSwNP and failure of standard drug therapy, we observed a decrease in absolute numbers of effector cells, along with decreased Treg lymphocyte numbers which may explain inefficient immune regulation of inflammatory process and medical interventions in this group of patients

Features of the immune status of patients with acute coronary syndrome who underwent СOVID-19, depending on the number of cytotoxic T lymphocytes (CD8⁺)

The 2019 coronavirus disease (COVID-19) pandemic has had an unprecedented impact on health and economies around the world. Direct myocardial injury and cytokine storm, leading to destabilization of preexisting plaques and accelerated formation of new plaques, are two mechanisms that trigger the acute coronary syndrome in COVID-19. There is insufficient data on the immune status of patients with acute coronary syndrome who have undergone COVID-19. The aim of the study was to study T and B cell, humoral immunity depending on the number of cytotoxic T lymphocytes (CD8+) in patients with acute coronary syndrome who underwent COVID-19. Materials and methods of research: 65 men with unstable angina pectoris and acute myocardial infarction (acute coronary syndrome) from 40 to 65 years old, who had previously had COVID-19, were examined. A study of peripheral blood was carried out: complete blood count (Medonic device, Sweden), general and specific IgM, IgG, IgA, compliment fragments (Vector Best, Russia). Subpopulations of T and B lymphocytes were determined by flow cytometry. In persons with acute coronary syndrome who underwent COVID-19 with predominantly normal and elevated levels of cytotoxic T cells, a more severe course of the disease was observed: patients with acute myocardial infarction prevailed, they had longer mortality, longer treatment duration, and stent thrombosis was more common. In patients with elevated cytotoxic T cells, there was a maximum increase in erythrocytes, hemoglobin, hematocrit, lymphocytes of both the total number and subpopulations – T helpers, T-NK lymphocytes, NK lymphocytes, T lymphocytes of early and late activation, B1 and B2 lymphocytes, index of NBT-induced test. In patients with normal levels of NK cells, compared with other groups, there was an increase in spontaneous NBT activity and index, a significant decrease in C3a and C5a complement fragments. Prevalence of stent thrombosis and mortality in the group of patients with normal levels of cytotoxic T cells may indicate torpidity of the immune system in these patients with poor outcomes

Clinical diagnostic criteria of efficiency for combined etiopathogenetic therapy in patients with chronic Epstein–Barr virus infection

Treatment of chronic viral infections accompanied by permanent virus persistence in the target epitopes of the oral cavity, skin, urogenital tract is complicated by virtual lack of available drugs exerting combined systemic virulicidal and immunomodulatory effects. Here we demonstrate clinical and immunological efficacy of combined therapy in treatment of Epstein–Barr virus (EBV)-associated chronic infections. The aim of the study was to evaluate the clinical and immunological efficacy of combined etiopathogenetic therapy using the Acegram cosmetic product in patients with EBV-associated chronic infections. Materials and methods. There were enrolled 40 patients monitored before treatment as well as 20 patients followed up after combination therapy (cycle therapy consisted of oral valaciclovir (Valtrex) applied at dose of 500 μg twice a day for 10 days, glucosaminylmuramyldipeptide (Licopid) — 10 mg 2 twice a day for 10 days, topical irrigation for mucous membranes with granulocyte-macrophage colony-stimulating factor active center-derived peptide (Acegram-spray) 3 times a day for 10 days. If necessary, treatment courses were repeated 20 days after the onset. All patients were examined for the presence of EBV genomes in the oral fluid and blood using the qualitative and quantitative polymerase chain reaction (PCR) using the DNA technology test system (Russia) on a DT-Lite device prior treatment and 30, 60 days post-therapy time points. In addition, serum samples were analyzed for level of class G immunoglobulins specific to the EBV nuclear and capsid antigens by using enzyme immunoassay (test systems manufactured by CJSC Vector Best, Russia) as well as immune status (clinical methods, enu flow cytometry evaluation of the phagocytic activity of neutrophils, ELISA method). Results. Use of single or two course combination therapy in subjects with fully eradicated EBV carriage associated with reversed clinical symptoms was accompanied by recovered immune system status (T and B cells, T-helper cells, CD3+ CD25+  cells, phagocytosis parameters). A non-invasive approach proposed for controlling virus elimination in the oral fluid by using polymerase chain reaction method may serve as to objectively monitor therapeutic efficacy

Seroprevalence of sars-cov-2 antibodies in symptomatic individuals is higher than in persons who are at increased risk exposure: The results of the single-center, prospective, cross-sectional study

The present study aimed to assess antibody seropositivity prevalence among symptomatic individuals and individuals with a high risk of occupational exposure to SARS-CoV-2. Participants from Chelyabinsk (Russian Federation) who were at an increased risk of exposure to SARS-CoV-2 (high-risk group, n = 1091) and participants who either had symptoms consistent with COVID-19 or were suspected to have experienced COVID-19 in the past (symptomatic group, n = 692) were enrolled between 28 September and 30 December 2020. Blood samples were tested by enzyme-linked immunosorbent assay D-5501 SARS-Cov-2-IgG-EIA-BEST and D-5502 SARS-Cov-2-IgM-EIA-BEST (AO Vector-Best, Novosibirsk, Russia). The overall seropositivity rate was 28.33–28.53%. SARS-CoV-2 antibodies were detected in 17.23% (adjusted prevalence of 17.17–17.29%) of participants in the high-risk and 45.95% (adjusted prevalence of 45.91–46.24%) in the symptomatic group. Higher IgG and IgM titers were observed in women compared to men, as well as in participants in the symptomatic group compared to those in the high-risk group. The results indicate that the seroprevalence among residents in several Russian regions is low (28.38%) and inadequate to provide herd immunity. The lower seroprevalence among participants in the high-risk group may be attributed to the enforcement of healthcare protocols and the use of adequate personal protective equipment. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.The reported study was funded by RFBR and NSFC (project No.20-515-55003), by the NSFC (project No. 82161138003), and partly by the Government contract of the Institute of Immunology and Physiology (AAAA-A21-121012090090-9)

GROWTH OF BIOLOGICAL MARKERS OF AGING AND ALLOSTASIS IN VETERANS OF THE AFGHAN WAR CONFLICT WITH EARLY FORMS OF CHRONIC BRAIN ISCHEMIA

We investigated the rate of biological aging, the levels of stress hormones and regulatory cytokines in Afghan war veterans and civilians with early forms of chronic brain ischemia. The study established acceleration of aging according to biological age indicators, earlier clinical onset of early forms of chronic cerebrovascular diseases associated with the processes of posttraumatic disregulation of cerebral and systemic vascular tone, the accumulation of "allostatic load” in the form of hypercortisolemia, growth regulator and angiogenic cytokines in veterans of the Afghan conflict