Dendritic Cells as a Novel Target for Erythropoietin: Studies in a Human System.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 316-316
Author(s):  
Sari Prutchi Sagiv ◽  
Lilach Lifshitz ◽  
Ruth Orkin ◽  
Drorit Newmann ◽  
Moshe Mittelman
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Ex Vivo ◽  
The Novel ◽  
Antigen Uptake ◽  
Hla Dr ◽  
Novel Target ◽  
And Function ◽  
Antigen Presenting

Abstract The immunomodulatory effects of erythropoietin (EPO) on the cellular and humoral compartments of the immune system have been described for some time; however, the mechanism of action by which EPO affects lymphocyte number and function has yet to be elucidated. Our search for possible mechanisms by which EPO affects these parameters led us to the novel discovery that EPO receptors (EPO-R) are expressed in dendritic cells (DCs), the most potent antigen presenting cells and most efficient T cell primers. Furthermore, we show that EPO has direct effects on the phenotype and function of human DCs. When added in vitro, EPO increased the percentage of peripheral blood originated DCs that express the co-stimulatory molecules CD80, CD86 and CD40. We also show that EPO up-regulates the level of expression of these molecules, as well as that of HLA-DR in monocyte-derived DCs. When added to immature DCs, EPO alone can induce their maturation. Furthermore, we demonstrate that EPO enhances DC function, as revealed by increased antigen uptake, secretion of interleukin (IL)-12 and stimulatory function in allogeneic mononuclear cell proliferation. We propose that DCs may represent a missing link which might explain previously observed immunomodulatory actions of EPO. Hence, our findings are of crucial importance and may open new clinical avenues for EPO in the optimization of ex-vivo DC-based vaccines, or when administered to patients in order to enhance immune system responses.

Antibody Response after Vaccination with Antigen-Pulsed Dendritic Cells

2004 ◽  
Vol 19 (3) ◽  
pp. 213-220
Author(s):  
F. Battaini ◽  
D. Besusso ◽  
L. Sfondrini ◽  
A. Rossini ◽  
D. Morelli ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Immune Responses ◽  
Antibody Response ◽  
Cancer Patients ◽  
Antibody Production ◽  
Tumor Antigens ◽  
Antigen Uptake ◽  
Antigen Presenting

Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system capable of initiating immune responses to antigens. It is also well documented that cancer patients often experience anergy against tumor antigens. In this study we selected the best protocol for inducing the production of antibodies against the HER2 oncoprotein using DCs to overcome anergy. Murine DCs were pulsed in vitro, using different protocols, with recombinant HER2 fused to a human Fc (in order to improve DC antigen uptake) and were used to vaccinate mice. The obtained results indicate that antigen-pulsed DCs can induce an antibody response and that adding CpG after antigen pulsing greatly increases anti-HER2 antibody production.

scholarly journals Inhibition of O-GlcNAc Transferase Alters the Differentiation and Maturation Process of Human Monocyte Derived Dendritic Cells

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3312
Author(s):  
Matjaž Weiss ◽  
Marko Anderluh ◽  
Martina Gobec
Keyword(s):  
Dendritic Cells ◽  
Posttranslational Modification ◽  
Human Monocyte ◽  
T Cell Differentiation ◽  
Maturation Process ◽  
Hla Dr ◽  
Glcnac Transferase ◽  
And Function

The O-GlcNAcylation is a posttranslational modification of proteins regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase. These enzymes regulate the development, proliferation and function of cells, including the immune cells. Herein, we focused on the role of O-GlcNAcylation in human monocyte derived dendritic cells (moDCs). Our study suggests that inhibition of OGT modulates AKT and MEK/ERK pathways in moDCs. Changes were also observed in the expression levels of relevant surface markers, where reduced expression of CD80 and DC-SIGN, and increased expression of CD14, CD86 and HLA-DR occurred. We also noticed decreased IL-10 and increased IL-6 production, along with diminished endocytotic capacity of the cells, indicating that inhibition of O-GlcNAcylation hampers the transition of monocytes into immature DCs. Furthermore, the inhibition of OGT altered the maturation process of immature moDCs, since a CD14medDC-SIGNlowHLA-DRmedCD80lowCD86high profile was noticed when OGT inhibitor, OSMI-1, was present. To evaluate DCs ability to influence T cell differentiation and polarization, we co-cultured these cells. Surprisingly, the observed phenotypic changes of mature moDCs generated in the presence of OSMI-1 led to an increased proliferation of allogeneic T cells, while their polarization was not affected. Taken together, we confirm that shifting the O-GlcNAcylation status due to OGT inhibition alters the differentiation and function of moDCs in in vitro conditions.

scholarly journals In-VitroDifferentiation of Mature Dendritic Cells From Human Blood Monocytes

1998 ◽  
Vol 6 (1-2) ◽  
pp. 25-39 ◽  
Author(s):  
Robert Gieseler ◽  
Dirk Heise ◽  
Afsaneh Soruri ◽  
Peter Schwartz ◽  
J. Hinrich Peters
Keyword(s):  
Dendritic Cells ◽  
Human Blood ◽  
T Cell Response ◽  
Blood Monocytes ◽  
Gm Csf ◽  
Hla Dr ◽  
Hla Dq ◽  
Specific Stimulation ◽  
Antigen Presenting

Representing the most potent antigen-presenting cells, dendritic cells (DC) can now be generated from human blood monocytes. We recently presented a novel protocol employing GM-CSF, IL-4, and IFN-γto differentiate monocyte-derived DCin vitro. Here, such cells are characterized in detail. Cells in culture exhibited both dendritic and veiled morphologies, the former being adherent and the latter suspended. Phenotypically, they were CD1a-/dim, CD11a+, CD11b++, CD11c+, CD14dim/-, CD16a-/dim, CD18+, CD32dim/-, CD33+, CD40+, CD45R0+, CD50+, CD54+, CD64-/dim, CD68+, CD71+, CD80dim, CD86+/++, MHC class I++/+++HLA-DR++/+++HLA-DP+, and HLA-DQ+. The DC stimulated a strong allogeneic T-cell response, and further evidence for their autologous antigen-specific stimulation is discussed. Although resembling a mature CD 11c+CD45R0+blood DC subset identified earlier, their differentiation in the presence of the Thl and Th2 cytokines IFN-γand IL-4 indicates that these DC may conform to mature mucosal DC.

Isolation of Human Blood Dendritic Cells Using the CMRF-44 Monoclonal Antibody: Implications for Studies on Antigen-Presenting Cell Function and Immunotherapy

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3708-3716 ◽  
Author(s):  
D.B. Fearnley ◽  
A.D. McLellan ◽  
S.I. Mannering ◽  
B.D. Hock ◽  
D.N.J. Hart
Keyword(s):  
Monoclonal Antibody ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Function ◽  
Cell Clone ◽  
Antigen Uptake ◽  
T Cell Clone ◽  
Antigen Presenting ◽  
Dc Maturation

Abstract Dendritic cells (DC) are potent antigen-presenting cells (APC) with the capacity to stimulate a primary T lymphocyte immune response and are therefore of interest for potential immunotherapeutic applications. Freshly isolated DC or DC precursors may be preferable for studies of antigen uptake and the potential control of APC costimulator activity. In this report, we report that the monoclonal antibody CMRF-44 can be used to detect early DC differentiation. The majority of DC circulating in blood do not express any known DC lineage specific markers, but can be identified by CMRF-44 labeling after a brief period of in vitro culture. The sequential acquisition of DC activation antigens allows the identification of two stages of DC maturation/activation. Cytokines, especially granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor (TNF )α, enhance both phases of this process, whereas CD40-ligand trimer preferentially enhances the final DC maturation to a fully mature, activated phenotype. DC positively selected using CMRF-44 possess potent allostimulatory activity and are efficient at the uptake, processing, and presentation of soluble antigens for both primary and secondary immune responses. CMRF-44+ DC are also more potent than other APC types at restimulation of a chronic myeloid leukemia peptide specific T-cell clone. The use of a purified population of freshly isolated DC may be advantageous in attempts to initiate, maintain, and direct immune responses for immunotherapeutic applications.

scholarly journals Hantavirus Infection of Dendritic Cells

2002 ◽  
Vol 76 (21) ◽  
pp. 10724-10733 ◽  
Author(s):  
Martin J. Raftery ◽  
Annette A. Kraus ◽  
Rainer Ulrich ◽  
Detlev H. Krüger ◽  
Günther Schönrich
Keyword(s):  
Dendritic Cells ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Hantavirus Infection ◽  
Necrosis Factor Alpha ◽  
Antigen Uptake ◽  
Antiviral Immune Response ◽  
Factor Alpha ◽  
Antigen Presenting

ABSTRACT Dendritic cells (DCs) play a pivotal role as antigen-presenting cells in the antiviral immune response. Here we show that Hantaan virus (HTNV), which belongs to the Bunyaviridae family (genus Hantavirus) and causes hemorrhagic fever with renal syndrome, productively infects human DCs in vitro. In the course of HTNV infection, DCs did not show any cytopathic effect and viral replication did not induce cell lysis or apoptosis. Furthermore, HTNV did not affect apoptosis-inducing signals that are important for the homeostatic control of mature DCs. In contrast to immunosuppressive viruses, e.g., human cytomegalovirus, HTNV activated immature DCs, resulting in upregulation of major histocompatibility complex (MHC), costimulatory, and adhesion molecules. Intriguingly, strong upregulation of MHC class I molecules and an increased intercellular cell adhesion molecule type 1 expression was also detected on HTNV-infected endothelial cells. In addition, antigen uptake by HTNV-infected DCs was reduced, another characteristic feature of DC maturation. Consistent with these findings, we observed that HTNV-infected DCs stimulated T cells as efficiently as did mature DCs. Finally, infection of DCs with HTNV induced the release of the proinflammatory cytokines tumor necrosis factor alpha and alpha interferon. Taken together, our findings indicate that hantavirus-infected DCs may significantly contribute to hantavirus-associated pathogenesis.

The role of dendritic cells in shaping the immune response

2004 ◽  
Vol 5 (2) ◽  
pp. 191-195 ◽  
Author(s):  
C. J. Howard ◽  
B. Charleston ◽  
S. A. Stephens ◽  
P. Sopp ◽  
J. C. Hope
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune System ◽  
Innate Immune System ◽  
Adaptive Response ◽  
Ex Vivo ◽  
T Cell Response ◽  
Innate Immune ◽  
Myeloid Dendritic Cells

AbstractDendritic cells are central to the initiation of primary immune responses. They are the only antigen-presenting cell capable of stimulating naive T cells, and hence they are pivotal in the generation of adaptive immunity. Dendritic cells also interact with and influence the response of cells of the innate immune system. The manner in which dendritic cells influence the responses in cells of both the innate and adaptive immune systems has consequences for the bias of the adaptive response that mediates immunity to infection after vaccination or infection. It also provides an opportunity to intervene and to influence the response, allowing ways of developing appropriate vaccination strategies. Mouse and human studies have identified myeloid, lymphoid and plasmacytoid dendritic cells. Studies in domesticated animals with agents of specific infectious diseases have confirmed the applicability of certain of the generic models developed from mice or from in vitro studies on human cells. In vivo and ex vivo studies in cattle have demonstrated the existence of a number of subpopulations of myeloid dendritic cells. These cells differ in their ability to stimulate T cells and in the cytokines that they produce, observations clearly having important implications for the bias of the T-cell response. Dendritic cells also interact with the innate immune system, inducing responses that potentially bias the subsequent adaptive response.

scholarly journals Isolation of Human Blood Dendritic Cells Using the CMRF-44 Monoclonal Antibody: Implications for Studies on Antigen-Presenting Cell Function and Immunotherapy

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3708-3716 ◽  
Author(s):  
D.B. Fearnley ◽  
A.D. McLellan ◽  
S.I. Mannering ◽  
B.D. Hock ◽  
D.N.J. Hart
Keyword(s):  
Monoclonal Antibody ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Function ◽  
Cell Clone ◽  
Antigen Uptake ◽  
T Cell Clone ◽  
Antigen Presenting ◽  
Dc Maturation

Dendritic cells (DC) are potent antigen-presenting cells (APC) with the capacity to stimulate a primary T lymphocyte immune response and are therefore of interest for potential immunotherapeutic applications. Freshly isolated DC or DC precursors may be preferable for studies of antigen uptake and the potential control of APC costimulator activity. In this report, we report that the monoclonal antibody CMRF-44 can be used to detect early DC differentiation. The majority of DC circulating in blood do not express any known DC lineage specific markers, but can be identified by CMRF-44 labeling after a brief period of in vitro culture. The sequential acquisition of DC activation antigens allows the identification of two stages of DC maturation/activation. Cytokines, especially granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor (TNF )α, enhance both phases of this process, whereas CD40-ligand trimer preferentially enhances the final DC maturation to a fully mature, activated phenotype. DC positively selected using CMRF-44 possess potent allostimulatory activity and are efficient at the uptake, processing, and presentation of soluble antigens for both primary and secondary immune responses. CMRF-44+ DC are also more potent than other APC types at restimulation of a chronic myeloid leukemia peptide specific T-cell clone. The use of a purified population of freshly isolated DC may be advantageous in attempts to initiate, maintain, and direct immune responses for immunotherapeutic applications.

scholarly journals Fascinating Dendritic Cells—Sentinel Cells of the Immune System a Review

2021 ◽  
Vol 65 (4) ◽  
pp. 12-19
Author(s):  
Z. Kiššová ◽  
Ľ. Tkáčiková
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Experimental Models ◽  
The Body ◽  
Main Role ◽  
Tumour Immunity ◽  
System A ◽  
Antigen Presenting

Abstract Dendritic cells (DC) are specialized antigen presenting cells which have the unique ability to activate naive T-lymphocytes. Their role in the immune system is much more sophisticated than it seems, as they do not kill the pathogens directly, but provide a long-lasting antigen specific immune response thanks to that sufficiently bridging the innate and the adaptive immunity. In recent years, there has been a growing interest in studies of their role in immune regulation, autoimmune reactions, as well as in immune responses against pathogens and tumours. Processing and presentation capabilities of a highly specific and unique tumour antigen makes them an interesting tool for stimulating effective anti-tumour immunity. In vitro generations of DC represent a preferred model for more detailed studies of DC biology in other fields. The aim of this review was to discuss the main role of dendritic cells in the body as well as their current use as experimental models for further scientific studies.

scholarly journals Sepsis Inflammation Impairs the Generation of Functional Dendritic Cells by Targeting Their Progenitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Lu ◽  
Kun Sun ◽  
Huiping Yang ◽  
Dan Fan ◽  
He Huang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Tnf Α ◽  
Ifn Γ ◽  
And Function ◽  
Antigen Presenting ◽  
The Impact

BackgroundSepsis is a complex systemic immune dysfunction syndrome induced by infection. Sepsis has a high mortality rate, with most patients dying due to systemic organ failure or secondary infection. Dendritic cells (DCs) are professional antigen-presenting cells. Upon infection with microbes, DCs are activated to induce adaptive immune responses for controlling infection. DC generation and function are impaired during sepsis; however, the underlying mechanisms remain largely unknown.MethodsPeripheral blood samples from sepsis patients were collected to examine DC subsets, DC progenitors, and apoptosis of DCs by flow cytometer. In vitro induction of DCs from hematopoietic stem/progenitor cells were established and a variety of sepsis-associated inflammatory mediators [e.g., interferon-gamma (IFN-γ), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF)] and Lipopolysaccharide (LPS) were determined for the impact on DC generation and function in vitro.ResultsOur results demonstrate that sepsis-induced systemic inflammation impairs the capacity of hematopoietic stem and progenitor cells (HSPCs) to produce DCs, including conventional DCs (cDCs) and plasmacytoid DCs (pDCs). We investigated peripheral blood (PB) samples from 34 pediatric patients on days 1 to 7 following diagnosis. Compared to healthy donors (n = 18), the sepsis patients exhibited a significantly fewer percentage and number of pDCs and cDCs, and a lower expression of antigen presenting molecule HLD-DR and co-stimulatory molecules (e.g., CD86) on the surface of DCs. This sepsis-induced DC impairment was associated with significantly increased apoptotic death of DCs and marked decreases of progenitor cells that give rise to DCs. Furthermore, we observed that among the tested sepsis-associated cytokines (e.g., IFN-γ, IL-1β, TNF-α, and G-CSF), G-CSF and IFN-γ impaired DC development from cultured HSPCs. G-CSF also markedly decreased the expression of HLA-DR on HSPC-derived DCs and their cytokine production, including IL-12 and IFN-β.ConclusionsCollectively, these findings indicate that sepsis impairs the survival of functional DCs and their development from HSPCs. Strategies for improving DC reconstitution following sepsis may restore DC progenitors and their associated function.

Hsp90 Is Critical for the Regulation of Phenotype and Functionality of Human Dendritic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2401-2401
Author(s):  
Jooeun Bae ◽  
Constantine Mitsiades ◽  
Tai Yu-Tzu ◽  
Jeff Martinson ◽  
Ramesh Babu Batchu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
T Lymphocytes ◽  
Clinical Data ◽  
Antigen Presenting Cells ◽  
Hsp90 Inhibitor ◽  
Antigen Uptake ◽  
Dc Function ◽  
Antigen Presenting ◽  
Inhibitor Treatment

Abstract Hsp90, a molecular chaperone, plays a critical role in protein folding and transport, and thereby it modulates cellular activity. Pre-clinical data shows over-expression of Hsp90 in multiple myeloma (MM) and efficacy of Hsp90 inhibitor in myeloma has been determined in vitro. Based on these results, phase I/II trial evaluating clinical efficacy of the Hsp90 inhibitor is underway in MM. Although Hsp90 inhibitor shows significant effects on tumor cells, there is limited information concerning its effects on the immune system. The objective of this study was to evaluate the effects of Geldanamycin on activity of antigen-presenting cells. Immature and mature monocyte derived dendritic cells (DC) from normal human donors were used as the source of antigen-presenting cells in this study. Geldanamycin treatment of DC for 24 hours had no effect on cell viability (>90%), however, it led to a significant down-regulation of surface antigens associated with activation (CD86, CD80), maturation (CD83) and antigen presentation (HLA-ABC, HLA-DPQR). This decline was associated with changes in gene expression levels of these antigens, however the protein expression analyzed by % positive cells was not down-regulated with the treatment. Exposure to Hsp90 inhibitor was associated with significant decreases in IL-12 secretion (untrt vs. trt = 135 vs. 21 pg/ml), antigen uptake (MFI untrt 798 vs. MFI trt 449, Dextran-FITC), and antigen processing. These changes were associated with decline in DC function, which were demonstrated by significant decrease in Hsp90-treated DC compared to untreated DC in presentation of Tetanus Toxoid to autologous T lymphocytes (untrt vs. trt = 73 % vs. 47 %, CFSE proliferation), allogeneic T lymphocytes stimulation (untrt vs. trt = 232795 cpm vs. 116876 cpm, 3H-thymidine incorporation), and induction of IFN-g secretion from allogenic T lymphocytes (untrt vs. trt = 500 vs. 30 pg/ml). Taken together, these results show significant decline in DC function following Hsp90 inhibitor treatment. Further studies are underway using MM patient samples pre- and post-Hsp90 inhibitor treatment to understand in vivo effects on the immune system. Our pre-clinical data suggests the need to consider proper sequence of various therapeutic modalities, including immunotherapy, to optimize and improve clinical outcome.

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