Myeloid-derived suppressor cells (MDSCs) are an immunosuppressive population involved in pathological processes associated with chronic inflammation. In recent years, the role of these cells in the regulation of a number of non-pathological processes, in particular, in the development of vaccine-induced immune response, has been actively discussed. This work was aimed at investigating the role of MDSC in the development of an immune response in old mice immunized with an inactivated whole virion SARS-CoV-2. Immunization of old animals induced an increase in the relative content of B cells and the production of specific antibodies to S1 and N proteins of SARS-CoV-2 in titers comparable to those of young animals. At the same time, elevated MDSC levels in aged animals negatively correlated with the level of CD8+ T cells. Splenic MDSCs in old animals were characterized by increased production of reactive oxygen species compared to young animals. In vitro experiments showed that MDSC depletion increased antigen-specific production of IFNγ by CD4+ T cells. The data obtained suggest a negative role for MDSC in regulating the T-cell vaccine-induced response to inactivated SARS-CoV-2 and encourage further studies in this direction, which may be a key to developing approaches to increase the efficacy of vaccines against SARS-CoV-2 in at-risk groups.

Preventive vaccination is a crucial strategy for controlling and preventing infectious diseases, offering both effectiveness and cost-efficiency. However, despite the widespread success of vaccination programs, there are still certain population groups who struggle to mount adequate responses to immunization. These at-risk groups include but are not restricted to the elderly, overweight individuals, individuals with chronic infections and cancer patients. All of these groups are characterized by persistent chronic inflammation. Recent studies have demonstrated that one of the key players in immune regulation and the promotion of chronic inflammation are myeloid-derived suppressor cells (MDSCs). These cells possess a wide range of immunosuppressive mechanisms and are able to dampen immune responses in both antigen-specific and antigen-nonspecific manner, thus contributing to the establishment and maintenance of an inflammatory environment. Given their pivotal role in immune modulation, there is growing interest in understanding how MDSCs may influence the efficacy of vaccines, particularly in vulnerable populations. In this narrative review, we discuss whether MDSCs are able to regulate vaccine-induced immunity and whether their suppression can potentially enhance vaccine efficacy in vulnerable populations.

Abstract According to WHO, the acquired secondary form of hematopoietic-depressive states increases the risk of death in people with cancer, infectious, and hormonal diseases. The choice of drugs that stimulate the proliferative activity of bone marrow cells is limited. The stimulus to the search for hematopoietic-stimulating compounds among pyridine derivatives was the manifestation of the activity of the cerebroprotective drug Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) to restore the granulocytes and B-lymphocytes homeostasis in clinical practice. The hematopoietic-stimulating activity of the newly synthesized compound Complex of 5-benzyl-7-(o-fluorobenzylidene)-2,3-bis(o-fluorophenyl)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c]pyridine complex with β-cyclodextrin (BIV) was studied on a model of cyclophosphamide-induced myelodepression in C57BL6/J mouse line. The BIV compound demonstrated a stimulating effect on the process of restoring the level of Ly-6G+ Ly-6C+ granulocytes, monocytes/macrophages, CD19+ B-lymphocytes in the bone marrow, exceeding the activity of the reference drug Methyluracil. The BIV compound did not affect on the proliferative activity of c-kit (CD117+)-expressing cells, CD3e+ pre-T-lymphocytic cells and Ter-119+ erythroid cells in the bone marrow. The total number of bone marrow myelokaryocytes in the experimental groups was significantly higher than in the intact group. The pronounced hematopoietic-stimulating effect of the BIV compound gives in the future the prospect of development as a drug used for the treatment of B-lymphocytic and granulocytic-macrophage hematopoietic-depressive states.

Coronavirus disease 2019 (COVID-19) is a potentially life-threatening infection characterized by excessive inflammation, coagulation disorders and organ damage. A dysregulated myeloid cell compartment is one of the most striking immunopathologic signatures of this newly emerged infection. A growing number of studies are reporting on the expansion of myeloid cells with immunoregulatory activities in the periphery and airways of COVID-19 patients. These cells share phenotypic and functional similarities with myeloid-derived suppressor cells (MDSCs), which were first described in cancer patients. MDSCs are a heterogeneous population of pathologically activated myeloid cells that exert immunosuppressive activities against mainly effector T cells. The increased frequency of these cells in COVID-19 patients suggests that they are involved in immune regulation during this infection. In this article, we review the current findings on MDSCs in COVID-19 and discuss the complex role of these cells in the immunopathology of COVID-19.

Impaired NK cytotoxicity has been linked to poor cancer prognosis, but its mechanisms are not clearly established. Increasing data demonstrate that NK cells lose cytotoxicity after interaction with NK cell-sensitive tumor cells. In this paper, we provide evidence that the human adenocarcinoma cell line MiaPaCa2 and TNFα and TGFβ-treated MiaPaCa2 cultures (MiaPaCa2-TT) induced functional anergy of NK cells via FGL2 protein. MiaPaCa2-TT cultures decreased expression of IFNγ, CD107a, DNAM-1, and stimulated expression of PD1 by NK cells, as well as inhibited their cytotoxic activity in a greater manner compared to the parental culture. More importantly, we found that co-cultivation with anergized NK cells decreased expression of IFNγ and CD107a by naïve NK cells, which supports the hypothesis of NK cell functional anergy transmission. The obtained results suggest a mechanism by which tumor cells may inhibit cytotoxic functions of tumor-infiltrating and circulating NK cells in cancer.Abbreviations: CFSE: Carboxyfluorescein diacetate succinimidyl ester; CSCs: Cancer stem cells; FGL2: Fibrinogen-like protein 2; mAbs: Monoclonal antibodies; MiaPaCa2: Human adenocarcinoma cell line; MiaPaCa2-ТТ: Adenocarcinoma cell line MiaPaCa2 cells stimulated with TNFα and TGFβ-1; PI: Propidium iodide; TGFβ: Transforming growth factor beta; TME: Tumor microenvironment; TNFα: Tumor necrosis factor alfa.

NK cells play an important role in the pathogenesis of atherosclerosis, using their cytotoxic mechanisms that promote the initiation, progression, and rupture of atherosclerotic plaques that leads to acute myocardial infarction. However the data about their cytolytic activity in post-infarction period remain controversial. The aim of this work was to study the dynamics of changes in the NK cell cytolytic activity within three weeks after acute myocardial infarction in connection with the level of circulating immune complexes in the peripheral blood. Material and methods. 16 healthy donors and 35 patients after the development of acute myocardial infarction (AMI) on the 1st, 7th and 21st days was studied for the NK cell cytolytic activity of the mononuclear fraction of peripheral blood, evaluated by the cytolysis of erythroleukemia K-562 cells in vitro and levels of serum circulating immune complexes (CIC) using the method of precipitation with polyethylene glycol-6000. Results and discussion. In the most patients, AMI led to functional anergy of NK cells, but in the smaller part of patients, the increase in their cytotoxicity was observed. The post-infarction period was characterized by an increased content of CIC, the level of which positively correlated with the development of functional anergy of NK cells. Possible mechanisms for the development of both functional anergy and an increase in NK cell activity in the post-infarction period are discussed. Keywords: аcute myocardial infarction, NK cells, circulating immune complexes.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Induction of a novel myelo-lymphoid progenitor during acute malaria infection critically dependent on interferon γ signaling Alexandre J Potocnik, Nikolai N Belyaev, Douglas E Brown, Ana-Isabel Garcia Diaz, Aaron Rae, William Jarra, Joanne Thompson, Jean Langhorne

It is well documented that age-related impaired functioning of immunocompetent cells is associated with an increase in the rates of chronic inflammatory diseases. Recently, an ability of melatonin to modulate inflammatory processes by regulating leucocyte recruitment has been demonstrated. However, to date, no studies have attempted to determine the impact of melatonin on the expression of CD62L by lymphocytes. CD62L, also known as L-selectin, is required for the entry of lymphocytes into secondary lymphoid organs, sites of tumor growth and chronic inflammation through high endothelial venules. Here, we investigated the effect of melatonin at physiological concentrations on the expression of CD62L by T and NK cells in vivo and in vitro. We demonstrated that NK and CD3(+) T cells obtained from the spleen of aged mice were characterized by decreased expression of CD62L compared to young mice. Melatonin administration up-regulated the levels of surface CD62L on NK and T cell populations in aged mice under non-inflammatory conditions and on CD8(+) T cells in aged mice with chronic inflammation. Pre-incubation with melatonin prevented the reduction in CD62L expression by CD8(+) T cells induced by the co-cultivation of peripheral blood mononuclear cells with human pancreatic adenocarcinoma cell line (MiaPaCa-2). The obtained results suggest that melatonin can modulate lymphocyte homing into lymph nodes and sites of chronic inflammation and, therefore, can stimulate immune responses in chronic inflammatory conditions associated with aging.

Heavy metal pollution is rapidly increasing in the environment. It has been shown that exposure to vanadium and chromium is able to alter the immune response. Nevertheless, the mechanisms by which these metal pollutants mediate their immunomodulatory effects are not completely understood. Herein, we examined the effect of ammonium metavanadate and potassium dichromate on the development of an inflammatory response caused by subcutaneous injection of turpentine oil. We demonstrated that pretreatment of rats with ammonium metavanadate and potassium dichromate for two weeks prior to initiation of the inflammatory response resulted in a wider zone of necrosis surrounding the site of inflammation. The acute inflammatory process in the combined model was characterized by elevated serum levels of IL-10 and decreased serum levels of IL-6 as compared to rats not treated with ammonium metavanadate and potassium dichromate. Ammonium metavanadate and potassium dichromate administration induced a decrease in the proportion of splenic His48HighCD11b/c+ myeloid cells accompanied by a reduced infiltration of the wound with neutrophils. Further analysis showed decreased proportions of CD3+CD4+IFNγ+ and CD3+CD4+IL-4+ T cells in the rats with combined model as compared to inflamed rats not treated with ammonium metavanadate and potassium dichromate. The data suggest that consumption of vanadium and chromium compounds disrupts the inflammatory response through an altered balance of pro- and anti-inflammatory cytokines and inhibition of effector T cell activation and neutrophil expansion.

Regulatory T cells (Tregs) play a major role in tumor escape from immunosurveillance by suppressing effector cells. The number of Tregs is increased in tumor sites and peripheral blood of breast cancer patients. However, the data regarding phenotypic and functional heterogeneity of Treg subpopulations in breast cancer are limited. The present study aimed to investigate the number and suppressive potential of Tregs that possess natural naïve-(N nTregs), effector/memory-like (EM nTregs), and Tr1-like phenotypes in breast cancer patients and healthy women.

Recent data have demonstrated that chronic inflammation is a crucial component of tumor initiation and progression. We previously reported that immature myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity toward effector T cells were expanded in experimental chronic inflammation. We hypothesized that elevated levels of MDSCs, induced by chronic inflammation, may contribute to the progression of tumor growth. Using the Ehrlich carcinoma animal model, we found increased tumor growth in mice with chronic adjuvant arthritis, which was accompanied by a persistent increase in the proportion of splenic monocytic and granulocytic MDSCs expressing CD62L (L-selectin), when compared to tumor mice without adjuvant arthritis. Depletion of inflammation-induced MDSCs resulted in decreased tumor growth. In vitro studies demonstrated that increased expression of CD62L by MDSCs was mediated by TNFα, elevated concentrations of which were found in tumor mice subjected to chronic inflammation. Moreover, the addition of exogenous TNFα markedly enhanced the suppressive activity of bone marrow-derived MDSCs, as revealed by the ability to impair the proliferation of CD8+ T cells in vitro. This study provides evidence that chronic inflammation may promote tumor growth via induction of CD62L expression by MDSCs that can facilitate their migration to tumor and lymph nodes and modulation of their suppressor activity.

Increased serum concentrations of tumor necrosis factor α (TNFα) and transforming growth factor β-1 (TGFβ-1) in the blood of patients with pancreatic cancer (PC) have previously been demonstrated. In addition, exogenous exposure to these cytokines promotes various cancer cell invasive and cancer stem cell (CSC) phenotypes. However, their importance in pancreatic CSCs remains elusive. In the present study, the effects of TNFα and TGFβ-1 on the human PC cell line MiaPaCa-2 were examined. Using flow cytometry, it was revealed that TNFα and TGFβ-1 synergistically increase cluster of differentiation (CD) 44v6, CD133 and ATP-binding cassette transporter G2 (ABCG2) expressing populations in adherent tumor cell culture conditions. Furthermore, a similar trend was observed in cells pretreated with these cytokines grown in sphere forming culture conditions. Similar to previous studies, TNFα treatment increased the proportion of epidermal growth factor receptor (EGFR) expressing cells in adherent culture, and this data was further supported by the results of the sphere formation assay, in which the subculture with a high proportion of EGFR expressing cells exhibited the most efficient sphere forming ability. However, the proportion of vascular endothelial growth factor receptor 1 (VEGFR1) expressing cells did not increase upon treatment with these cytokines individually or in combination. This data was subsequently supported by the results of the wound healing assay in which cytokine treatment did not increase the migration of cells. The MTT cell proliferation and cytotoxicity assay revealed that TNFα + TGFβ-1 treatment significantly increased cell proliferation and daunorubicin resistance, but not gemcitabine resistance. In conclusion, the data of the current study provide a mechanistic association between TNFα, TGFβ-1 and the CSC properties of MiaPaCa-2 cells. In addition, it suggests that targeting TNFα and TGFβ-1 is beneficial for improving the therapeutic efficacy of treatments for patients with PC.

Myeloid-derived suppressor cells (MDSCs) are important negative regulators of immune processes in cancer and other pathological conditions. We suggested that MDSCs play a key role in pathogenesis of chronic inflammation, which precedes and, to a certain extent, induces carcinogenesis. The present study aimed at investigation of MDSCs arising during chronic inflammation and light-at-night (LN)-induced stress, which is shown to accelerate chronic diseases.

Failure of antitumor immunity in cancer was shown to be mediated by myeloid-derived suppressor cells (MDSCs), which are considered to be one of the key factors contributing to the development of malignant diseases. Therefore, the development of pharmacological approaches to effectively eliminate MDSCs in organisms carrying growing tumors is a promising pathway for potential treatment. For this purpose we propose alpha-fetoprotein (AFP) conjugated with a cytotoxic agent as a vector molecule, specifically recognizing MDSCs. The present study was aimed at examination of this suggestion using both in vitro and in vivo approaches. MDSCs, obtained from the spleen of Ehrlich carcinoma bearing mice, selectively bound AFP labeled with fluorescein isothiocyanate. AFP conjugated to daunorubicin (AFP-DR) and DR alone showed similar in vitro cytotoxicity against the granulocytic MDSC subpopulation. The monocytic MDSC subpopulation was resistant to treatment with DR, whereas it was completely depleted in the presence of AFP-DR. Treatment of mice bearing Ehrlich carcinoma with AFP-DR resulted in reduced numbers of splenic MDSCs, normalization of NK cell levels, and inhibition of tumor growth. The obtained results demonstrate that cytotoxic conjugates based on AFP are promising anticancer drugs, which, in addition to the direct effect on tumor cells expressing receptors to AFP, may contribute to elimination of MDSCs.

Mechanisms of chronic inflammation significantly differ from mechanisms of acute inflammation, which is morphologically characterized by the presence of mast cells, neutrophils and macrophages. In the case of unresolved acute inflammation, by reasons not fully elucidated, a chronic inflammation develops, which is characterized by the presence of T-lymphocytes, macrophages and fibroblasts. Taken together, these cells support prolonged chronic inflammation, a characteristic feature of which is the phenomenon of the simultaneous presence of proinflammatory and anti-inflammatory cytokines. We hypothesized that the key role in this process belongs to so-called myeloid derived suppressor cells (MDSC), which represent a heterogeneous population of early hematopoietic progenitors of myelomonocytic branch (neutrophils and monocytes), and are identified in mice by expression of CD11b and Gr-1 markers and the ability to inhibit NK and cytotoxic T cell activity. We suggested that MDSC phenomenon is not a prerogative of cancer process but most probably is linked to pathogenesis of chronic inflammation, which precedes and to a certain extent induces carcinogenesis.The aim of the study was a flow cytometric analysis of different MDSC subpopulations (G-MDSC and M-MDSC) in mice with adjuvant arthritis, a classic experimental model of chronic inflammation. Flow cytometry was used as the main method, the applicability of which to the phenotypic evaluation of MDSC was confirmed earlier by Ehrlich carcinoma subcutaneous model in CBA mice. As it turned out, tumor growth correlated with an increase in splenic CD11b+Gr-1+ MDSCs. According to our data, development of local chronic inflammation also resulted in an elevated level of circulating MDSCs. By the end of two weeks after administration of complete Freund's adjuvant (CFA) in the hind limb of CD-1 mice, we showed a more than two-fold increase of total MDSC in the spleen, in both monocyte (M-MDSC) and granulocyte (G-MDSC) MDSC fractions. The increase in MDSCs persisted until forth week. Also, we found a significantly increased level of CD11b+Gr-1+ cells expressing CD184 (CXCR4). In addition, by the end of the fourth week of the chronic inflammation, we observed an increase in MDSCs expressing CD195+ (CCR5+), and an increased proportion of CD62+ MDSC by the second week.Thus, the processes, associated with the development of local chronic inflammation lead to an increase in the spleen levels of MDSCs and their ability to migrate into the inflammatory sites by increasing the expression of receptors to SDF-1α and RANTES chemoattractants.

Human natural killer (NK) cells are not only professional cytotoxic cells integrated into effector branch of innate immunity, but they are also regulatory cells, managing different immune processes. Immunoregulatory NK cells, expressing HLA-G and IL-10, have been generated in vitro from human hematopoietic progenitors and found in vivo among decidual NK cells of pregnant women. Human peripheral blood NK cells have been shown to acquire suppressive properties after HLA-G uptake during trogocytosis. Moreover, it has been shown that circulating NK cells contain a trace amount of cells producing TGF-β and IL-10, which exert a suppressive influence upon innate and adaptive immunity. In this study, we report on a minor subset of peripheral blood HLA-G(+) NK cells possessing suppressive activity toward effector functions of NK cells. Further we demonstrate an increased number of circulating HLA-G(+), IL-10(+), and TGF-β(+) NK cells in breast cancer patients which might impair efficiency of anti-tumor immunity.

Беляев, Н. Н. Моделирование разрушения подпорных стен при взаимодействии с агрессивными подземными водами / Н. Н. Беляев, Е. Ю. Гунько // Мости та тунелі: теорія, дослідження, практика. — 2014. — Вип. 5. — С. 4—8. — Бібліогр. в кінці ст.

Н. Беляев: ORCID 0000-0002-1531-7882, А. Берлов: ORCID 0000-0002-7442-0548, П. Машихина:ORCID 0000-0003-3057-9204

According to a new paradigm of carcinogenesis, a tumor arises not from transformed cell, but only from tumor initiating cells called cancer stem cells (CSCs), which can originate from tissue stem cells. CSC are resistant to conventional therapy and after treatment form new tumors and give rise to metastases. Only natural killer (NK) cells are capable of lysing CSCs, but within different tumor types these cells experience a condition known as "split anergy", whereby the NK cells lose the ability to kill CSCs and being to produce cytokines. As a result, uncontrolled tumor growth arises and tumor stroma accumulates anergic NK cells. We hypothesize that anergic tumor infiltrating NK (TINK) cells transmit their property to naïve NK cells by infecting" them with a state of "split anergy" in a similar manner as T conventional cells are transformed into T regulatory cells during the process of "infectious tolerance". Anergic TINK cells egress from the tumor stroma via the lymphatic system, where they reach regional lymph nodes and transmit their properties to naïve NK cells, which in turn become anergic toward CSCs and lose immunosurveillance functions. The mechanisms proposed for this hypothesis and the methodological approaches for confirming the idea are presented in this issue.