scholarly journals Stroke-Induced Modulation of Myeloid-Derived Suppressor Cells (MDSCs) and IL-10-Producing Regulatory Monocytes

2020 ◽  
Vol 11 ◽  
Author(s):  
Lennart Achmus ◽  
Johanna Ruhnau ◽  
Sascha Grothe ◽  
Bettina von Sarnowski ◽  
Barbara M. Bröker ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Geometric Mean ◽  
Suppressor Cells ◽  
Interleukin 10 ◽  
Experimental Stroke ◽  
Myeloid Derived Suppressor Cells ◽  
Stroke Patients ◽  
Post Stroke ◽  
Arginase 1 ◽  
Hla Dr

Background: Stroke patients are at risk of acquiring secondary infections due to stroke-induced immune suppression (SIIS). Immunosuppressive cells comprise myeloid-derived suppressor cells (MDSCs) and immunosuppressive interleukin 10 (IL-10)-producing monocytes. MDSCs represent a small but heterogeneous population of monocytic, polymorphonuclear (or granulocytic), and early progenitor cells (“early” MDSC), which can expand extensively in pathophysiological conditions. MDSCs have been shown to exert strong immune-suppressive effects. The role of IL-10-producing immunosuppressive monocytes after stroke has not been investigated, but monocytes are impaired in oxidative burst and downregulate human leukocyte antigen—DR isotype (HLA-DR) on the cell surface.Objectives: The objective of this work was to investigate the regulation and function of MDSCs as well as the immunosuppressive IL-10-producing monocytes in experimental and human stroke.Methods: This longitudinal, monocentric, non-interventional prospective explorative study used multicolor flow cytometry to identify MDSC subpopulations and IL-10 expression in monocytes in the peripheral blood of 19 healthy controls and 27 patients on days 1, 3, and 5 post-stroke. Quantification of intracellular STAT3p and Arginase-1 by geometric mean fluorescence intensity was used to assess the functionality of MDSCs. In experimental stroke induced by electrocoagulation in middle-aged mice, monocytic (CD11b+Ly6G−Ly6Chigh) and polymorphonuclear (CD11b+Ly6G+Ly6Clow) MDSCs in the spleen were analyzed by flow cytometry.Results: Compared to the controls, stroke patients showed a relative increase in monocytic MDSCs (percentage of CD11b+ cells) in whole blood without evidence for an altered function. The other MDSC subgroups did not differ from the control. Also, in experimental stroke, monocytic, and in addition, polymorphonuclear MDSCs were increased. The numbers of IL-10-positive monocytes did not differ between the patients and controls. However, we provide a new insight into monocytic function post-stroke since we can report that a differential regulation of HLA-DR and PD-L1 was found depending on the IL-10 production of monocytes. IL-10-positive monocytes are more activated post-stroke, as indicated by their increased HLA-DR expression.Conclusions: MDSC and IL-10+ monocytes can induce immunosuppression within days after stroke.

scholarly journals Myeloid-derived suppressor cells in the blood of Iranian COVID-19 patients

2021 ◽  
Author(s):  
Esmaeil Mortaz ◽  
mehrnaz movassaghi ◽  
Ali Bassir ◽  
Neda K Dezfuli ◽  
Neda D Roofchayee ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Healthy Subjects ◽  
Cell Function ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cytokine Storm ◽  
Hla Dr ◽  
Significant Difference ◽  
Biochemical Features ◽  
Ventilated Patients

Abstract Background: A cytokine storm and lymphopenia are reported in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection associated with coronavirus disease 2019 (COVID-19). Myeloid-derived suppressive cells (MDSCs) exist in two different forms, granulocyte (G-MDSCs) and monocytic (M-MDSCs) that both suppress T-cell function. Serum IL-6 and IL-8 levels seem to correlate with the number of blood MDSCs. Objective: To determine the frequency of MDSCs in severe COVID-19 patients from Iran and their correlations with serum IL-8 levels. Methods: 37 severe (8 on ventilation, 29 without ventilation) and 13 moderate COVID-19 patients together with 8 healthy subjects were enrolled at the Masih Daneshvari Hospital, Tehran-Iran between 10th April 2020- 9th March 2021. Clinical and biochemical features, serum and whole blood were obtained. CD14, CD15, CD11b and HLA-DR expression on MDSCs was measured by flow cytometry. Results: M-MDSCs (P≤0.0001) and G-MDSCs (P≤0.0001) frequency were higher in Iranian COVID-19 patients compared to healthy subjects. M-MDSC frequency was higher in non-ventilated compared to moderate COVID-19 subjects (P=0.004). Serum IL-8 levels were higher in patients with COVID-19 than in normal healthy subjects (P=0.03). IL8 level was significant difference in ventilated, non-ventilated and moderate patients (P=0.005). The frequency of G-MDSCs correlated negatively with INR (r=-0.39, P=0.02). Conclusion: Serum IL-8 levels did not correlate with the number of systemic MDSCs in COVID-19 patients. The highest levels of M-MDSCs were seen in the blood of severe non-ventilated patients. MDSC frequency in blood in the current study did not predict the survival and severity of COVID-19 patients. Keywords: MDSC, IL-8, COVID-19, peripheral blood

Myeloid-Derived Suppressor Cells in Patients with Hodgkin Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3662-3662
Author(s):  
Nunziatina Parrinello ◽  
Piera La Cava ◽  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Orazio Di Bartolo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Hodgkin Lymphoma ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Suppressor Cells ◽  
Cell Number ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr

Abstract Abstract 3662 Poster Board III-598 Background Immune suppression and angiogenesis are mechanisms key to tumour growth and progression. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells of myeloid origin and include immature macrophages, dendritic cells (DC) and other myeloid cells. In mice are phenotypically characterized as CD11b+Gr-1+ cells, while in human they have an immature phenotype, including lineage negative (Lin-), CD14-, HLA-DR-, CD15+, CD34+, CD11b+, CD33+, and CD13+ cells. MDSC reduce activated T-cell number and inhibit their function through different mechanisms including: L-arginine metabolism, nitric oxide (NO), up-regulation of reactive oxygen species (ROS), and secretion of immunosuppressive cytokines. MDSC also promote tumor-dependent angiogenesis as well as tumor metastasis. Their accumulation has been described in patients affected by some solid tumors but information on haematological neoplasms are lacking. Our study investigated by flow cytometry the presence of MSDC in the peripheral blood of patients affected by Hodgkin Lymphoma (HL). Methods We studied 14 patients with HL at diagnosis and 10 age-matched healthy controls (HC). Peripheral blood mononuclear cells were stained with the following monoclonal antibodies:CD11b, CD13, CD14, CD34, CD45, for 20 minutes at room temperature. After lysing red cells, cells were analyzed by flow cytometry. Results we observed a increased number of MDSC (CD11b+,CD13+,CD34+,CD14-, CD45+) in the peripheral blood of patients with HL compared to HC (13,37 ± 17,77 ×109/l vs 1,45± 0,98 ×109/l, p=0,0007). We also found that patients with advanced-stage Hodgkin disease (III and IV) have higher number of MDSC, compared to patients stage I and II (p= 0,04). Conclusion These data suggest a role for myeloid-derived suppressor cells in promoting tumor cell proliferation in hodgkin lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expansion of Myeloid-Derived Suppressor Cells in Patients with Acute Coronary Syndrome

2015 ◽  
Vol 35 (1) ◽  
pp. 292-304 ◽  
Author(s):  
Yan-ge Wang ◽  
Xin Xiong ◽  
Zhu-yue Chen ◽  
Kan-ling Liu ◽  
Jin-hua Yang ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Plasma Levels ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Suppressive Function ◽  
Coronary Syndrome ◽  
Arginase 1 ◽  
Hla Dr ◽  
Tnf Α ◽  
And Function

Aim: The aim of this study was to explore whether the circulating frequency and function of myeloid-derived suppressor cells (MDSCs) are altered in patients with acute coronary syndrome (ACS). Methods: The frequency of MDSCs in peripheral blood was determined by flow cytometry, and mRNA expression in purified MDSCs was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR). The suppressive function of MDSCs isolated from different groups was also determined. The plasma levels of certain cytokines were determined using Bio-Plex Pro™ Human Cytokine Assays. Results: The frequency of circulating CD14+HLA-DR-/low MDSCs; arginase-1 (Arg-1) expression; and plasma levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-33 were markedly increased in ACS patients compared to stable angina (SA) or control patients. Furthermore, MDSCs from ACS patients were more potent suppressors of T-cell proliferation and IFN-γ production than those from the SA or control groups at ratios of 1:4 and 1:2; this effect was partially mediated by Arg-1. In addition, the frequency of MDSCs was positively correlated with plasma levels of IL-6, IL-33, and TNF-α. Conclusions: We observed an increased frequency and suppressive function of MDSCs in ACS patients, a result that may provide insights into the mechanisms involved in ACS.

scholarly journals Increased Levels of Granulocytic Myeloid-Derived Suppressor Cells in Peripheral Blood and Tumour Tissue of Pancreatic Cancer Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Yazan S. Khaled ◽  
Basil J. Ammori ◽  
Eyad Elkord
Keyword(s):  
Pancreatic Cancer ◽  
Suppressor Cells ◽  
Blood Levels ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase 1 ◽  
Hla Dr ◽  
Healthy Donors ◽  
And Function ◽  
Immunosuppressive Cells

Pancreatic cancer (PC) often presents late with poor survival. While role of immunosuppressive cells in preclinical studies provided help to develop immunotherapeutic agents, these cells remain under investigation in PC. The aim of this study was to characterise the different subsets of myeloid-derived suppressor cells (MDSCs) and evaluate their level and function in the circulation and tissue of PC patients. Significant increases in circulating and tumour-infiltrating granulocytic (Lin-HLA-DR-CD33+CD11b+CD15+), but not monocytic (Lin-HLA-DR-CD14+), MDSCs were detected in PC patients when compared with healthy donors and patients with chronic pancreatitis. The circulating MDSCs from PC patients expressed arginase 1, which represents their functional state. Blood levels of MDSCs showed no association with PC stage or preoperative levels of tumour markers. These findings provide a first characterisation of the phenotype of different subsets of peripheral and local MDSCs in PC patients and suggest that the frequency and contribution of these cells are predominantly granulocytic. This information demonstrates that MDSCs play a role in pancreatic cancer and future large validation studies may help in the development of new immunotherapeutic strategies to inhibit or eliminate MDSC function.

Dendritic Cell Vaccination in Acute Leukemia Patients Induces Reduction of Myeloid-Derived Suppressor Cells : Immunological Analysis of a Pilot Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1113-1113 ◽  
Author(s):  
Masahiro Ogasawara ◽  
Shuichi Ota
Keyword(s):  
T Cells ◽  
Acute Leukemia ◽  
Suppressor Cells ◽  
Absolute Number ◽  
The Other ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase 1 ◽  
Hla Dr ◽  
Healthy Donors ◽  
Before And After

Abstract Background and Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population that have an immunesuppresive function and play an important role in tumor immunology and self tolerance. Elevated levels of MDSCs in peripheral blood (PB) are reported in various cancers and hematological malignancies such as MDS, NHL and MM. We reported that vaccination with Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cells (DC) in NHL patients induced not only WT1 specific immune responses but also innate immunity which correlated with clinical efficacy (ASH 2013). In the present study, we focused on MDSCs and investigated the effects of DC vaccination on the alteration of MDSCs which have negative influence on disease progression. Patients and Methods: 8 patients with acute leukemia (6 AML and 2ALL patients; aged 16-77) who were treated with WT1 peptide-loaded DC vaccination were enrolled in the present study. MDSCs were analyzed by FACS. Linage negative, CD11b+CD33+HLA-DR- cells were defined as MDSC. Monocytic and granulocytic MDSC were defined as CD14+HLA-DRlow/- and CD15+CD11b+CD33+HLA-DR-, respectively. For proliferation assay, CD14+DR- cells and CD3+ T cells were isolated by magnetic beads method. CFSE-labeled CD3+ T cells were stimulated with anti-CD3 and anti-CD28 moAb together with IL-2 in the presence or absence of CD14+DR-cells for 4 days and cell division was analyzed by FACS. Cytoplasmic staining of indoleamine 2,3-deoxygenase (IDO) and arginase 1 were performed by permeabilization using saponin followed by moAb staining. Arginase 1 protein levels in plasma was assessed using a commercially available ELISA kit. Results: 3 patients were in complete remission (responder) and 5 others were in disease progression (non-responder) following one course of vaccination. WT1 specific T cell responses evaluated by a HLA-tetramer assay and a delayed type hypersensitivity (DTH) test were observed in all the responders and 2 non-responders. Mean percentage of MDSCs, monocytic and granulocytic MDSCs in PB was higher in acute leukemia patients than in healthy donors (1.60±0.72%, 16.56±6.07%, 1.34±0.69%, respectively in patients; 0.60±0.31%, 13.1±4.1%, 0.37±0.1%, respectively in healthy donors). Absolute number of circulating monocytic and granulocytic MDSCs before and after vaccination in responders was 359.4±117.8/μl and 35.2±14.8/μl, 282.8±119.2 /μl and 14.4±12.0/μl, respectively. On the other hand, those in non-responders were 126.3±60.2/μl and 36.3±21.7/μl, 181.3±124.0/μl and 65.1±12.0/μl, respectively. While DC vaccination resulted in reduction of both monocytic and granulocytic MDSCs by 21.3% and 59.1%, respectively in responders, it induced augmentation of these MDSCs by 43.5% and 79.3%, respectively in non-responders. A portion of MDSCs expressed IDO and arginase 1 in cytoplasm. While the percentage of IDO positive cells in monocytic MDSCs increased by 2.2 and 2.3 times in responders and non-responders, respectively following vaccination, the positivity of arginase 1 decreased by 59% in responders. On the other hand, the positivity of IDO and arginase 1 in granulocytic MDSCs decreased at the same level in both responders and non-responders following vaccination. CD14+DR-cells inhibited the proliferation of CD3+ T cells in a dose dependent manner, indicating that these cells share characteristics of MDSCs. The inhibition of the proliferation of CD3+T cells was partially restored by the addition of 1-methyl-DL-tryptophan (IDO inhibitor) and Nω-hydroxy-nor-arginine (arginase 1 inhibitor), suggesting that the inhibition was mediated at least in part by IDO and arginase 1. Amount of arginase 1 in the plasma before and after vaccination decreased by 25% in responders, not in non-responders. Conclusions: These results demonstrated that DC vaccination resulted in the reduction of the absolute number of MDSCs which seems to be correlated with clinical efficacy. DC vaccination may have inhibitory effects on several functions of MDSCs that can suppress immune surveillance against leukemia, which is favorable for regression of leukemia cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals T-Cell Defect in Diffuse Large B-Cell Lymphomas Involves Expansion of Myeloid Derived Suppressor Cells Expressing IL-10, PD-L1, and S100A12

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1478-1478 ◽  
Author(s):  
Imane Azzaoui ◽  
Fabrice Uhel ◽  
Delphine Rossille ◽  
Céline Pangault ◽  
Joelle Dulong ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Proliferation ◽  
T Cell ◽  
B Cell ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase 1 ◽  
Culture Supernatants ◽  
Large B Cell

Abstract Introduction: In diffuse large B-cell lymphoma (DLBCL), the number of circulating monocytes and neutrophils represents an independent prognostic factor. These cells include monocytic and granulocytic myeloid derived suppressor cells (M- and G-MDSCs) defined by their ability to suppress T-cell responses. MDSCs are a heterogeneous population described in inflammatory or infectious diseases as well as in numerous tumors including multiple myeloma, chronic lymphocytic leukemia and DLBCL. However, their mechanisms of action in DLBCL remain unclear. The aim of the study was to investigate the presence and mechanisms of suppression of MDSC subsets in DLBCL. Methods: Whole blood from 56 DLBCL at diagnosis and 45 healthy donors (HD) were analyzed by flow cytometry. Quantitative Real Time PCR were analyzed on Taqman@ array microfluidic cards. Cytokine levels in plasma and culture supernatants were measured by Luminex and Elisa. T-cell proliferation after monocyte depletion or treatment with inhibitors, was analyzed by CFSE assay. Results: By flow cytometry, we identified an expansion of G-MDSC (Linneg HLA-DRneg CD33pos CD11bpos) and M-MDSC (CD14pos HLA-DRlow) in DLBCL compared to HD (p<0.001). Interestingly, only M-MDSC number was correlated with the International Prognostic Index (IPI), the event-free survival (EFS), and the number of circulating Treg. Furthermore, T-cell proliferation was restored after monocyte depletion. To identify the mechanism of suppression involved, we evaluated the gene expression of key enzymes (ARG1, IDO1, NOS2, HO-1 and PTGS2) or immunomodulatory molecules (IL10, TGF β1, CD274/PD-L1, S100A8, S100A9, S100A12) involved in MDSC biology. ARG1, IDO1, IL10, CD274/PD-L1 and S100A12 were significantly up-regulated in DLBCL (p<0.05). At the protein level arginase 1, IL-10 and S100A12 were increased in DLBCL plasma, whereas PD-L1 expression on monocyte was increased in DLBCL compared to HD (p=0.03). Arginase 1 and IDO activities where increased in DLBCL patients. In DLBCL, IL-10 and S100A12 were detected in culture supernatants from stimulated PBMC and these molecules were decreased after CD14pos depletion (p<0.05). Finally, we defined 2 groups of DLBCL depending on M-MDSC content and analyzed the percentage of proliferating T cells after CD3/CD28 stimulation in the presence of various inhibitors or blocking antibodies (L-1MT, nor-NOHA, anti-IL-10, anti-PD-1 and anti-S100A12). In the group of patients with circulating MDSC, neutralizing IL-10, PDL-1 and S100A12 resulted in an increase of CD4 and/or CD8 T-cell proliferation. Conclusion: In summary, we identified MDSC subsets expanded in DLBCL as well as new mechanisms of immunosuppression in DLBCL. Myeloid-dependent T-cell suppression is attributed to a release of IL-10 and S100A12 and an increase of PD-L1 expression. Disclosures Cartron: Roche: Consultancy, Honoraria; GSK: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Gilead: Honoraria.

scholarly journals Myeloid-derived Suppressor Cells in the Blood of Iranian COVID-19 Patients

2021 ◽  
Author(s):  
Esmaeil Mortaz ◽  
Mehrnaz Movasaghi ◽  
Ali Bassir ◽  
Neda K.Dezfuli ◽  
Neda Dalil Roofchayee ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Healthy Subjects ◽  
Cell Function ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cytokine Storm ◽  
Hla Dr ◽  
Significant Difference ◽  
Biochemical Features ◽  
Ventilated Patients

Abstract Background: A cytokine storm and lymphopenia are reported in coronavirus disease 2019 (COVID-19). Myeloid-derived suppressive cells (MDSCs) exist in two different forms, granulocyte (G-MDSCs) and monocytic (M-MDSCs) that both suppress T-cell function. Serum IL-6 and IL-8 levels seem to correlate with the number of blood MDSCs.Objective: In the current study we aimed to find MDSCs frequency in severe COVID-19 patients from Iran and their correlations with serum IL-8 levels. Methods: 37 severe (8 on ventilation, 29 without ventilation) and 13 moderate COVID-19 patients together with 8 healthy subjects were enrolled at the Masih Daneshvari Hospital, Tehran-Iran between 10th April 2020- 9th March 2021. Clinical and biochemical features, serum and whole blood were obtained. CD14, CD15, CD11b and HLA-DR expression on MDSCs was measured by flow cytometry. Results: M-MDSCs (P≤0.0001) and G-MDSCs (P≤0.0001) frequency were higher in Iranian COVID-19 patients compared to healthy subjects. M-MDSC frequency was higher in non-ventilated compared to moderate COVID-19 subjects (P=0.004). IL-8 levels were higher in patients serum with COVID-19 than in normal healthy subjects (P=0.03). IL8 level was significant difference in ventilated, non-ventilated and moderate patients (P=0.005). The frequency of G-MDSCs correlated negatively with INR (r=-0.39, P=0.02).Conclusion: Serum IL-8 levels did not correlate with the number of systemic MDSCs in COVID-19 patients. The highest levels of M-MDSCs were seen in the blood of severe non-ventilated patients. MDSC frequency in blood in the current study did not predict the survival and severity of COVID-19 patients.

scholarly journals Myeloid phenotypes in severe COVID-19 predict secondary infection and mortality: a pilot study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Clémence Marais ◽  
Caroline Claude ◽  
Nada Semaan ◽  
Ramy Charbel ◽  
Simon Barreault ◽  
...  
Keyword(s):  
Critically Ill ◽  
Host Response ◽  
Secondary Infection ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Human Leukocyte ◽  
Myeloid Derived Suppressor Cells ◽  
Phenotypic Characteristics ◽  
Leukocyte Antigen ◽  
Hla Dr

Abstract Background De-regulated host response to severe coronavirus disease 2019 (COVID-19), directly referring to the concept of sepsis-associated immunological dysregulation, seems to be a strong signature of severe COVID-19. Myeloid cells phenotyping is well recognized to diagnose critical illness-induced immunodepression in sepsis and has not been well characterized in COVID-19. The aim of this study is to review phenotypic characteristics of myeloid cells and evaluate their relations with the occurrence of secondary infection and mortality in patients with COVID-19 admitted in an intensive care unit. Methods Retrospective analysis of the circulating myeloid cells phenotypes of adult COVID-19 critically ill patients. Phenotyping circulating immune cells was performed by flow cytometry daily for routine analysis and twice weekly for lymphocytes and monocytes subpopulations analysis, as well as monocyte human leukocyte antigen (mHLA)-DR expression. Results Out of the 29 critically ill adult patients with severe COVID-19 analyzed, 12 (41.4%) developed secondary infection and six patients died during their stay. Monocyte HLA-DR kinetics was significantly different between patients developing secondary infection and those without, respectively, at day 5–7 and 8–10 following admission. The monocytes myeloid-derived suppressor cells to total monocytes ratio was associated with 28- and 60-day mortality. Those myeloid characteristics suggest three phenotypes: hyperactivated monocyte/macrophage is significantly associated with mortality, whereas persistent immunodepression is associated with secondary infection occurrence compared to transient immunodepression. Conclusions Myeloid phenotypes of critically ill COVID-19 patients may be associated with development of secondary infection, 28- and 60-day mortality.

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