scholarly journals Dextromethorphan Inhibits Activations and Functions in Dendritic Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Der-Yuan Chen ◽  
Pei-Shan Song ◽  
Jau-Shyong Hong ◽  
Ching-Liang Chu ◽  
I-Horng Pan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Monocyte ◽  
Surface Expression ◽  
Suppressive Effect ◽  
Murine Bone Marrow ◽  
Cytokines And Chemokines ◽  
And Function ◽  
The Impact

Dendritic cells (DCs) play an important role in connecting innate and adaptive immunity. Thus, DCs have been regarded as a major target for the development of immunomodulators. In this study, we examined the effect of dextromethorphan (DXM), a common cough suppressant with a high safety profile, on the activation and function of DCs. In the presence of DXM, the LPS-induced expression of the costimulatory molecules in murine bone marrow-derived dendritic cells (BMDCs) was significantly suppressed. In addition, DXM treatment reduced the production of reactive oxygen species (ROS), proinflammatory cytokines, and chemokines in maturing BMDCs that were activated by LPS. Therefore, DXM abrogated the ability of LPS-stimulated DCs to induce Ag-specific T-cell activation, as determined by their decreased proliferation and IFN-γsecretion in mixed leukocyte cultures. Moreover, the inhibition of LPS-induced MAPK activation and NF-κB translocation may contribute to the suppressive effect of DXM on BMDCs. Remarkably, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived dendritic cells (MDDCs). These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases.

Thyroglobulin-pulsed human monocyte-derived dendritic cells induce CD4+ T cell activation

2004 ◽  
Author(s):  
Mariko Morishita ◽  
Kaoru Uchimaru ◽  
Katsuaki Sato ◽  
Akira Ohtsuru ◽  
Shunichi Yamashita ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Monocyte ◽  
Cd4 T Cell

Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 758-765 ◽  
Author(s):  
Jagadeesh Bayry ◽  
Sébastien Lacroix-Desmazes ◽  
Cedric Carbonneil ◽  
Namita Misra ◽  
Vladimira Donkova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Intravenous Immunoglobulin ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Activity ◽  
Interleukin 12 ◽  
Immune Mediated ◽  
And Function

Normal immunoglobulin G for therapeutic use (intravenous immunoglobulin [IVIg]) is used in an increasing number of immune-mediated conditions, including acute and chronic/relapsing autoimmune diseases, transplantation, and systemic inflammatory disorders. Several mutually nonexclusive mechanisms of action account for the immunoregulatory effects of IVIg. Although IVIg inhibits T-cell proliferation and T-cell cytokine production, it is unclear whether these effects are directly dependent on the effects of IVIg on T cells or they are dependent through the inhibition of antigen-presenting cell activity. Here, we examined the effects of IVIg on differentiation, maturation, and function of dendritic cells (DCs). We show that IVIg inhibits the differentiation and maturation of DCs in vitro and abrogates the capacity of mature DC to secrete interleukin-12 (IL-12) on activation while enhancing IL-10 production. IVIg-induced down-regulation of costimulatory molecules associated with modulation of cytokine secretion resulted in the inhibition of autoreactive and alloreactive T-cell activation and proliferation. Modulation of DC maturation and function by IVIg is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions.

A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-γ treatment

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3499-3504 ◽  
Author(s):  
Paul J. Mosca ◽  
Amy C. Hobeika ◽  
Timothy M. Clay ◽  
Smita K. Nair ◽  
Elaine K. Thomas ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Monocyte ◽  
Cd40 Ligand ◽  
Cell Surface Expression ◽  
Interleukin 12 ◽  
Cytokine Detection

Abstract Dendritic cells (DCs) may arise from multiple lineages and progress through a series of intermediate stages until fully mature, at which time they are capable of optimal antigen presentation and T-cell activation. High cell surface expression of CD83 is presumed to correlate with full maturation of DCs, and a number of agents have been shown to increase CD83 expression on DCs. We hypothesized that interleukin 12 (IL-12) expression would be a more accurate marker of functionally mature DCs capable of activating antigen-specific T cells. We used combinations of signaling through CD40, using CD40 ligand trimer (CD40L), and interferon gamma to demonstrate that CD83 expression is necessary but not sufficient for optimal production of IL-12 by DCs. Phenotypically mature DCs could be induced to produce high levels of IL-12 p70 only when provided 2 simultaneous stimulatory signals. By intracellular cytokine detection, we determined that only a subset of cells that express high levels of CD80 and CD83 generate large amounts of IL-12. DCs matured with both signals are superior to DCs stimulated with the individual agents in activating antigen-specific T cell in vitro. These findings have important implications regarding the identification, characterization, and clinical application of functionally mature DCs.

scholarly journals Differentiation and function of human monocyte-derived dendritic cells under the influence of leflunomide

2011 ◽  
Vol 63 (2) ◽  
pp. 353-364
Author(s):  
Z. Stojic-Vukanic ◽  
M. Colic ◽  
A. Backovic ◽  
J. Antic-Stankovic ◽  
B. Bufan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Flow Cytometric Analysis ◽  
Human Monocyte ◽  
Surface Expression ◽  
Immunosuppressive Drugs ◽  
Experimental Models ◽  
Immunosuppressive Drug ◽  
Adhesive Molecules ◽  
And Function

Leflunomide is an immunosuppressive drug effective in experimental models of transplantation and autoimmune diseases and in the treatment of active rheumatoid arthritis (RA). Having in mind that it has been shown that some other immunosuppressive drugs (glucocorticoids, mycophenolate mofetil, sirolimus etc.) impair dendritic cell (DC) phenotype and function, we investigated the effect of A77 1726, an active metabolite of leflunomide, on the differentiation and function of human monocyte-derived dendritic cells (MDDC) in vitro. Immature MDDC were generated by cultivating monocytes in medium supplemented with GM-CSF and IL-4. To induce maturation, immature MDDC were cultured for 2 additional days with LPS. A77 1726 (100 ?M) was added at the beginning of cultivation. Flow cytometric analysis showed that MDDC differentiated in the presence of A77 1726 exhibited an altered phenotype, with a down-regulated surface expression of CD80, CD86, CD54 and CD40 molecules. Furthermore, the continuous presence of A77 1726 during differentiation and maturation prevented successful maturation, judging by the decreased expression of maturation marker CD83, costimulatory and adhesive molecules on A77 1726-treated mature MDDC. In addition, A77 1726-pretreated MDDC exhibited a poor stimulatory capacity of the allogeneic T cells and a low production of IL-10 and IL-18. These data suggest that leflunomide impairs the differentiation, maturation and function of human MDDC in vitro, which is an additional mechanism of its immunosuppressive effect.

Immunosuppressive Drugs up-Regulate the Immunoinhibitory Receptor Osteoactivin On Human Monocyte-Derived Dendritic Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3284-3284
Author(s):  
Sabine Braun ◽  
Michael Gutknecht ◽  
Mark-Alexander Schwarzbich ◽  
Lothar Kanz ◽  
Helmut R Salih ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cyclosporine A ◽  
Cell Activation ◽  
Immunosuppressive Drugs ◽  
Type I ◽  
Transmembrane Glycoprotein ◽  
The Impact

Abstract Abstract 3284 Introduction: Dendritic cells (DC) abundantly express the type I transmembrane glycoprotein Osteoactivin (OA) - also known as transmembrane glycoprotein NMB and DC-HIL - compared to low expression levels on monocytes. Antigen-presenting cells interact via OA with the type I transmembrane proteoglycan syndecan-4 (SD-4) on T cells which inhibits T cell activation. We previously reported on increased expression of OA upon exposure of monocyte-derived DC (moDC) to immunosuppressive drugs (e.g., Gutknecht et al ASH annual meeting 2011). Here we extended these analyses and comparatively analyzed the impact of various immunsuppressive drugs (ID) on moDC phenotype and function. Methods: The moDC were generated from blood monocytes by plastic adherence and exposure to GM-CSF and IL-4. Clinically relevant concentrations of ID were added to the culture medium every second day starting with the first day of culture (cyclosporine A: 1μg/ml, prednisolone: 3.5μg/ml, tacrolimus: 10ng/ml, mycophenolat-mofetil 0.1μM, methotrexat 230ng/ml). Cells were harvested for immunophenotyping by flow cytometry, western-blotting and real-time PCR. Cytokine release by moDC was determined on day 7 by ELISA. Functional properties were determined by mixed lymphocyte reactions (MLR) on day 7 of culture. Results: Exposure of moDC to therapeutic concentrations of prednisolone resulted in significantly reduced expression of the costimulatory molecules CD83 and CD86 and increased levels of the monocyte marker CD14, indicative of impaired differentiation. Tacrolimus significantly increased CD14 expression and reduced CD83 expression, while the other ID did not cause significant alterations. All ID altered the release of the immunomodulatory cytokines IL-10, IL-6 and TGF-ß. Notably, all ID except cyclosporine A caused a substantial upregulation of the immunoinhibitory receptor OA in moDC. The extent of OA expression increased over time of exposure to ID during differentiation and resulted in reduced capacity of the moDC to stimulate allogenic T cells which could be restored by disruption of OA/SD-4 interaction using a blocking OA antibody. Conclusion: Increased expression of OA on moDC upon exposure to ID contributes to inhibition of T-cell activation. The mechanisms underlying the differential effect of cyclosporine A are presently under study. Our results indicate that targeting OA/SD-4 interaction may hold promise for modulation of T cell responses in various pathophysiological conditions and immunotherapeutic strategies. Disclosures: No relevant conflicts of interest to declare.

Enhanced T-cell activation and T-cell-dependent IL-2 production by CD83+, CD25high, CD43high human monocyte-derived dendritic cells

2007 ◽  
Vol 44 (7) ◽  
pp. 1544-1550 ◽  
Author(s):  
Florian W. Velten ◽  
Florian Rambow ◽  
P. Metharom ◽  
Sergij Goerdt
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Monocyte

scholarly journals Alterations of Dendritic Cells in Sepsis: Featured Role in Immunoparalysis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Xia Fan ◽  
Zheng Liu ◽  
He Jin ◽  
Jun Yan ◽  
Hua-ping Liang
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Immune Disorder ◽  
And Function ◽  
Antigen Presenting

Sepsis, the leading cause of mortality in intensive care unit, is characterized by hyperinflammatory response in the early stage and followed by a period of immunosuppression. This immune disorder is believed to be the potent factor that is tightly associated with high mortality in sepsis. Dendritic cells (DCs) serve as professional antigen-presenting cells that play a vital role in immune response by activating T lymphocytes. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Therefore, a better understanding of the DCs pathology will be undoubtedly beneficial for resolving the problems occurring in sepsis. This review discusses effects of sepsis on DCs number and function, including surface molecules expression, cytokines secretion, and T cell activation, and the underlying mechanism as well as some potential therapeutic strategies.

Maturation of Monocyte-Derived Dendritic Cells Induced by Dual Targeting of Endocytosis Receptor and CD40

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4293-4293
Author(s):  
Matthias Staudinger ◽  
Inga Rebekka Catenhusen ◽  
Matthias Peipp ◽  
Christian Kellner ◽  
Roland Repp ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Specific Binding ◽  
Surface Expression ◽  
Tumor Vaccination ◽  
Dual Targeting

Abstract Abstract 4293 Dendritic cells (DC) are professional antigen presenting cells, which can induce and regulate adaptive immune responses. Hence, DC are attractive candidates for anti-tumor vaccination strategies. The aim of this study was to create recombinant bispecific Fab to target and activate DC, by using derivates of monovalent agonistic CD40 scFv and endocytosis receptors FcγRI (CD64), FcαR (CD89), DEC205 (CD205), as well as DC-SIGN (CD209), respectively. The recombinant bispecific molecules were expressed in the eukaryotic cell line Hek 293T, enriched to homogeneity by affinity chromatography and analyzed for specific binding to the targeted receptors. Functional analysis of these molecules indicated, that concurrent engagement of CD40 and endocytosis receptors expressed by immature IL-4/GM-CSF cultured monocytes-derived DC induced maturation of these DC. This was suggested by changes of DC phenotype, especially enhanced surface expression of co-stimulatory molecules like CD80 and CD86, and gain of CD83 expression as measured by flow cytometry. To particularly analyze the T cell activation properties of these DC, MACS enriched T cells of autologous donors were co-cultivated with antigen-loaded and subsequently maturated DC for seven days. After restimulation of T cells, flow cytometric detection of intracellular IFN-γ levels and surface expression of CD69 used as markers for T cell activation implies, that these DC exhibit elevated properties to activate antigen specific T cells. In contrast, a bispecific [CD64scFv × CD40scFv] Fab used as control failed to induce maturation of DC lacking CD64 expression, which may be due to abrogation of bivalent binding of this molecule and therefore CD40 cross-linking. Moreover, dual targeting with these novel immunoconstructs when linked to peptides of a tumor-associated antigen may allow direct antigen delivery to DC in combination with DC activation, and thus anti-tumor vaccination in vivo. Disclosures: No relevant conflicts of interest to declare.

scholarly journals An Immunological Approach to the Biocompatibility of Mesoporous SiO2-CaO Nanospheres

2020 ◽  
Vol 21 (21) ◽  
pp. 8291
Author(s):  
María Montes-Casado ◽  
Adrian Sanvicente ◽  
Laura Casarrubios ◽  
María José Feito ◽  
José M. Rojo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoid Cells ◽  
Phosphoinositide 3 Kinase ◽  
Antigen Presenting ◽  
The Impact

Mesoporous bioactive glass nanospheres (NanoMBGs) have high potential for clinical applications. However, the impact of these nanoparticles on the immune system needs to be addressed. In this study, the biocompatibility of SiO2-CaO NanoMBGs was evaluated on different mouse immune cells, including spleen cells subsets, bone marrow-derived dendritic cells (BMDCs), or cell lines like SR.D10 Th2 CD4+ lymphocytes and DC2.4 dendritic cells. Flow cytometry and confocal microscopy show that the nanoparticles were rapidly and efficiently taken up in vitro by T and B lymphocytes or by specialized antigen-presenting cells (APCs) like dendritic cells (DCs). Nanoparticles were not cytotoxic and had no effect on cell viability or proliferation under T-cell (anti-CD3) or B cell (LPS) stimuli. Besides, NanoMBGs did not affect the balance of spleen cell subsets, or the production of intracellular or secreted pro- and anti-inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-6, IL-10) by activated T, B, and dendritic cells (DC), as determined by flow cytometry and ELISA. T cell activation surface markers (CD25, CD69 and Induced Costimulator, ICOS) were not altered by NanoMBGs. Maturation of BMDCs or DC2.4 cells in vitro was not altered by NanoMBGs, as shown by expression of Major Histocompatibility Complex (MHC) and costimulatory molecules (CD40, CD80, CD86), or IL-6 secretion. The effect of wortmannin and chlorpromazine indicate a role for phosphoinositide 3-kinase (PI3K), actin and clathrin-dependent pathways in NanoMBG internalization. We thus demonstrate that these NanoMBGs are both non-toxic and non-inflammagenic for murine lymphoid cells and myeloid DCs despite their efficient intake by the cells.

scholarly journals Effects of Filovirus Interferon Antagonists on Responses of Human Monocyte-Derived Dendritic Cells to RNA Virus Infection

2016 ◽  
Vol 90 (10) ◽  
pp. 5108-5118 ◽  
Author(s):  
Benjamin C. Yen ◽  
Christopher F. Basler
Keyword(s):  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ebola Virus ◽  
Human Monocyte ◽  
Marburg Virus ◽  
Innate Immune ◽  
Dc Maturation

ABSTRACTDendritic cells (DCs) are major targets of filovirus infectionin vivo. Previous studies have shown that the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) suppress DC maturationin vitro. Both viruses also encode innate immune evasion functions. The EBOV VP35 (eVP35) and the MARV VP35 (mVP35) proteins each can block RIG-I-like receptor signaling and alpha/beta interferon (IFN-α/β) production. The EBOV VP24 (eVP24) and MARV VP40 (mVP40) proteins each inhibit the production of IFN-stimulated genes (ISGs) by blocking Jak-STAT signaling; however, this occurs by different mechanisms, with eVP24 blocking nuclear import of tyrosine-phosphorylated STAT1 and mVP40 blocking Jak1 function. MARV VP24 (mVP24) has been demonstrated to modulate host cell antioxidant responses. Previous studies demonstrated that eVP35 is sufficient to strongly impair primary human monocyte-derived DC (MDDC) responses upon stimulation induced through the RIG-I-like receptor pathways. We demonstrate that mVP35, like eVP35, suppresses not only IFN-α/β production but also proinflammatory responses after stimulation of MDDCs with RIG-I activators. In contrast, eVP24 and mVP40, despite suppressing ISG production upon RIG-I activation, failed to block upregulation of maturation markers or T cell activation. mVP24, although able to stimulate expression of antioxidant response genes, had no measurable impact of DC function. These data are consistent with a model where filoviral VP35 proteins are the major suppressors of DC maturation during filovirus infection, whereas the filoviral VP24 proteins and mVP40 are insufficient to prevent DC maturation.IMPORTANCEThe ability to suppress the function of dendritic cells (DCs) likely contributes to the pathogenesis of disease caused by the filoviruses Ebola virus and Marburg virus. To clarify the basis for this DC suppression, we assessed the effect of filovirus proteins known to antagonize innate immune signaling pathways, including Ebola virus VP35 and VP24 and Marburg virus VP35, VP40, and VP24, on DC maturation and function. The data demonstrate that the VP35s from Ebola virus and Marburg virus are the major suppressors of DC maturation and that the effects on DCs of the remaining innate immune inhibitors are minor.

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