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.

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 Induction of antigen-specific regulatory T lymphocytes by human dendritic cells expressing the glucocorticoid-induced leucine zipper

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 211-219 ◽  
Author(s):  
Haifa Hamdi ◽  
Véronique Godot ◽  
Marie-Christine Maillot ◽  
Maria Victoria Prejean ◽  
Nicolas Cohen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocytes ◽  
Antigen Presentation ◽  
Leucine Zipper ◽  
Ex Vivo ◽  
Antigen Presenting Cells ◽  
Interleukin 10 ◽  
Therapeutic Effects ◽  
Regulatory T Lymphocytes ◽  
Antigen Presenting

Dendritic cells (DCs) determine whether antigen presentation leads to immune activation or to tolerance. Tolerance-inducing DCs (also called regulatory DCs) act partly by generating regulatory T lymphocytes (Tregs). The mechanism used by DCs to switch toward regulatory DCs during their differentiation is unclear. We show here that human DCs treated in vitro with glucocorticoids produce the glucocorticoid-induced leucine zipper (GILZ). Antigen presentation by GILZ-expressing DCs generates CD25highFOXP3+CTLA-4/CD152+ and interleukin-10–producing Tregs inhibiting the response of CD4+ and CD8+ T lymphocytes. This inhibition is specific to the antigen presented, and only proliferating CD4+ T lymphocytes express the Treg markers. Interleukin-10 is required for Treg induction by GILZ-expressing DCs. It is also needed for the suppressive function of Tregs. Antigen-presenting cells from patients treated with glucocorticoids generate interleukin-10–secreting Tregs ex vivo. These antigen-presenting cells produce GILZ, which is needed for Treg induction. Therefore, GILZ is critical for commitment of DCs to differentiate into regulatory DCs and to the generation of antigen-specific Tregs. This mechanism may contribute to the therapeutic effects of glucocorticoids.

CD11c+ dendritic cells and plasmacytoid DCs are activated by human cytomegalovirus and retain efficient T cell-stimulatory capability upon infection

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 2022-2029 ◽  
Author(s):  
Espen Ø. Kvale ◽  
Jakob Dalgaard ◽  
Fridtjof Lund-Johansen ◽  
Halvor Rollag ◽  
Lorant Farkas ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Human Cytomegalovirus ◽  
Immunosuppressive Treatment ◽  
Antigen Presenting Cells ◽  
Renal Transplant Recipients ◽  
Low Frequencies ◽  
Plasmacytoid Dcs ◽  
Antigen Presenting

It has been suggested that human cytomegalovirus (HCMV) evades the immune system by infecting and paralyzing antigen-presenting cells. This view is based mainly on studies of dendritic cells (DCs) obtained after culture of monocytes (moDCs). It is contradicted by the asymptomatic course of HCMV infection in healthy persons, indicating that other key antigen-presenting cells induce an efficient immune response. Here we show that HCMV activates CD11c+ DCs and plasmacytoid DCs (PDCs). In contrast to moDCs, CD11c+ DCs and PDCs produced interferon (IFN) type 1 when exposed to HCMV. Autocrine IFN type 1 partially protected CD11c+ DCs against infection, whereas PDCs were resistant to HCMV even when IFN type 1 activity was inhibited. HCMV exposure induced the maturation of CD11c+ DCs by IFN type 1-dependent and -independent mechanisms. Importantly, CD11c+ DCs infected by inhibiting IFN type 1 activity retained full capacity to stimulate T cells. Renal transplant recipients receiving immunosuppressive treatment had lower frequencies of CD11c+ DCs and PDCs in blood than did healthy controls. The results show that HCMV activates the immune system by interacting with CD11c+ DCs and PDCs and that recipients of renal transplants have low frequencies of these cell types in blood.

scholarly journals Properties of immature and mature dendritic cells: phenotype, morphology, phagocytosis, and migration

RSC Advances ◽  
2019 ◽  
Vol 9 (20) ◽  
pp. 11230-11238 ◽  
Author(s):  
Min Kyung Kim ◽  
Jaeyun Kim
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Adaptive Immunity ◽  
Antigen Presenting Cells ◽  
Innate And Adaptive Immunity ◽  
System P ◽  
And Migration ◽  
Antigen Presenting

Dendritic cells (DCs) are antigen-presenting cells that play an important role in connecting the innate and adaptive immunity of the immune system.

scholarly journals Distinctive localization of antigen-presenting cells in human lymph nodes

Blood ◽  
2009 ◽  
Vol 113 (6) ◽  
pp. 1257-1267 ◽  
Author(s):  
Catherine E. Angel ◽  
Chun-Jen J. Chen ◽  
Oliver C. Horlacher ◽  
Sintia Winkler ◽  
Thomas John ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Lymphocytes ◽  
Lymph Nodes ◽  
T Lymphocyte ◽  
Close Contact ◽  
Antigen Presenting Cells ◽  
Lymphocyte Responses ◽  
Antigen Presenting ◽  
Medullary Cords

Abstract Professional antigen-presenting cells (APCs) are sentinel cells of the immune system that present antigen to T lymphocytes and mediate an appropriate immune response. It is therefore surprising that knowledge of the professional APCs in human lymph nodes is limited. Using 3-color immunohistochemistry, we have identified APCs in human lymph nodes, excluding plasmacytoid APCs, that fall into 2 nonoverlapping classes: (1) CD209+ APCs, coexpressing combinations of CD206, CD14, and CD68, that occupied the medullary cords, lined the capsule and trabeculae and were also scattered throughout the diffuse T-lymphocyte areas of the paracortex; and (2) APCs expressing combinations of CD1a, CD207, and CD208, that were always restricted to the paracortex. Surprisingly, this second class of APCs was almost entirely absent from many lymph nodes. Our data suggest that most CD208+ cells, often referred to as “interdigitating cells,” derive from migratory APCs, and that the major APC subset consistently resident in the paracortex of human lymph nodes is the CD209+ subset. All APC subsets were demonstrated to be in close contact with the fibroreticular network. The identification of 2 distinct APC populations in the paracortex of human lymph nodes has important implications for understanding T-lymphocyte responses and optimizing vaccine design.

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.

scholarly journals O-Linked glycans control glycoprotein processing by antigen-presenting cells: a biochemical approach to the molecular aspects of MUC1 processing by dendritic cells

2003 ◽  
Vol 33 (12) ◽  
pp. 3242-3254 ◽  
Author(s):  
Franz-Georg Hanisch ◽  
Tilo Schwientek ◽  
Michael S. Von Bergwelt-Baildon ◽  
Joachim L. Schultze ◽  
Olivera Finn
Keyword(s):  
Dendritic Cells ◽  
Antigen Presenting Cells ◽  
Glycoprotein Processing ◽  
Biochemical Approach ◽  
Molecular Aspects ◽  
Antigen Presenting

Cell-Penetrating Peptide-Mediated Nanovaccine Delivery

2021 ◽  
Vol 22 ◽  
Author(s):  
Jizong Jiang
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Cell Penetrating Peptide ◽  
Antigen Delivery ◽  
Efficient Manner ◽  
Antigen Uptake ◽  
Cell Penetrating ◽  
The Stability ◽  
Antigen Presenting

Abstract: Vaccination with small antigens, such as proteins, peptides, or nucleic acids, is used to activate the immune system and trigger the protective immune responses against a pathogen. Currently, nanovaccines are undergoing development instead of conventional vaccines. The size of nanovaccines is in the range of 10–500 nm, which enables them to be readily taken up by cells and exhibit improved safety profiles. However, low-level immune responses, as the removal of redundant pathogens, trigger counter-effective activation of the immune system invalidly and present a challenging obstacle to antigen recognition and its uptake via antigen-presenting cells (APCs). In addition, toxicity can be substantial. To overcome these problems, a variety of cell-penetrating peptide (CPP)-mediated vaccine delivery systems based on nanotechnology have been proposed, most of which are designed to improve the stability of antigens in vivo and their delivery into immune cells. CPPs are particularly attractive components of antigen delivery. Thus, the unique translocation property of CPPs ensures that they remain an attractive carrier with the capacity to deliver cargo in an efficient manner for the application of drugs, gene transfer, protein, and DNA/RNA vaccination delivery. CPP-mediated nanovaccines can enhance antigen uptake, processing, and presentation by APCs, which are the fundamental steps in initiating an immune response. This review describes the different types of CPP-based nanovaccines delivery strategies.

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