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Dendritic Cells—Conductors and Activators of the Immunological Orchestra

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 21426

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Prof. Dr. Helga Maria Schmetzer

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Med III, Department for Hematopoetic Transplantations, Klinikum Grosshadern, Ludwig-Maximilian-University of Munich, Marchioninistrße 15, 81377 Munich, Germany
Interests: dendritic cells; leukemia derived DC; AML; immunotherapy
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Dear Colleagues,

Dendritic Cells (DCs), professional antigen-presenting cells that are present in all tissues including tumors, connect the innate and adaptive immune systems. Immature DCs phagocyte and process infectious/tumor-antigens. They mature after inflammatory “danger-signaling” and migrate to organs/tissues where they express “DC-/MHC-antigens” and attract and regulate immune functions.

Different “activating” and “inhibiting/tolerogenic” DC-subsets (e.g., conventional, monocyte, Langerhans, plasmacytoid, and tolerogenic-CD85K DCs) mediate and reactivate antigen-specific immune reactions against infections and tumors. They can also be used against inflammation, autoimmune diseases, allergies, in transplant medicine (TolDC), or against malignant cells. The use of DCs generated from precursor cells or monocytes and pulsed/loaded with tumor antigens as vaccinations showed promising results in patients with leukemia or tumors in terms of tolerability, safety, induction of antitumor/tumor specific reactions, and installation of immunological memory.

“Leukemia-derived DC” (DCleu) presenting leukemic antigens can be generated or quantified ex vivo from myeloid leukemic cells. They can reactivate the humoral, innate, or adaptive anti-leukemic immune-system, along with clonally-restricted T-cells. Predictive correlations of the frequencies and quality of DC/T-cell subsets have been performed after culture with induced anti-leukemic T-cell responses ex-vivo and in-vivo.

Ex vivo DC/DCleu production is time-consuming, requires good manufactural practice (GMP) and contamination-free conditions and yields limited cell products.

The combination of two approved drugs (“kits”) was shown to generate DCleu from leukemic whole-blood containing patients’ soluble/cellular factors and (re)activate antileukemic cells.

The initiation of antitumor reactions by designed DCs (loaded with tumor antigens) or DCleu induced in-vivo by “kits” with antigen presentation and migration capability could be promising treatment options for the initiation of anti-tumor or anti-leukemic reactions and the installation of immunological memory in-vivo independent of patient age, MHC, mutation, or transplantation status.

Prof. Dr. Helga Maria Schmetzer
Guest Editor

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Keywords

dendritic cells
leukemia derived DCs
leukemia
tumor immunotherapy
immune modulation

Published Papers (6 papers)

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Research

20 pages, 3150 KiB

Open AccessArticle

The Monocytic Cell Line THP-1 as a Validated and Robust Surrogate Model for Human Dendritic Cells

by Johanna Maria Hölken and Nicole Teusch

Int. J. Mol. Sci. 2023, 24(2), 1452; https://doi.org/10.3390/ijms24021452 - 11 Jan 2023

Cited by 4 | Viewed by 6134

Abstract

We have implemented an improved, cost-effective, and highly reproducible protocol for a simple and rapid differentiation of the human leukemia monocytic cell line THP-1 into surrogates for immature dendritic cells (iDCs) or mature dendritic cells (mDCs). The successful differentiation of THP-1 cells into iDCs was determined by high numbers of cells expressing the DC activation markers CD54 (88%) and CD86 (61%), and the absence of the maturation marker CD83. The THP-1-derived mDCs are characterized by high numbers of cells expressing CD54 (99%), CD86 (73%), and the phagocytosis marker CD11b (49%) and, in contrast to THP-1-derived iDCs, CD83 (35%) and the migration marker CXCR4 (70%). Treatment of iDCs with sensitizers, such as NiSO₄ and DNCB, led to high expression of CD54 (97%/98%; GMFI, 3.0/3.2-fold induction) and CD86 (64%/96%; GMFI, 4.3/3.2-fold induction) compared to undifferentiated sensitizer-treated THP-1 (CD54, 98%/98%; CD86, 55%/96%). Thus, our iDCs are highly suitable for toxicological studies identifying potential sensitizing or inflammatory compounds. Furthermore, the expression of CD11b, CD83, and CXCR4 on our iDC and mDC surrogates could allow studies investigating the molecular mechanisms of dendritic cell maturation, phagocytosis, migration, and their use as therapeutic targets in various disorders, such as sensitization, inflammation, and cancer. Full article

(This article belongs to the Special Issue Dendritic Cells—Conductors and Activators of the Immunological Orchestra)

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24 pages, 3806 KiB

Open AccessArticle

Generation of Leukaemia-Derived Dendritic Cells (DC_leu) to Improve Anti-Leukaemic Activity in AML: Selection of the Most Efficient Response Modifier Combinations

by Christoph Schwepcke, Lara Kristina Klauer, Diana Deen, Daniel Christoph Amberger, Zuzana Fischer, Fatemeh Doraneh-Gard, Carina Gunsilius, Annika Hirn-Lopez, Tanja Kroell, Johanna Tischer, Melanie Weinmann, Jan-Ole Werner, Andreas Rank, Christoph Schmid and Helga Maria Schmetzer

Int. J. Mol. Sci. 2022, 23(15), 8333; https://doi.org/10.3390/ijms23158333 - 28 Jul 2022

Cited by 4 | Viewed by 1637

Abstract

Dendritic cells (DC) and leukaemia derived DC (DC_leu) are potent stimulators of anti-leukaemic activity in acute myeloid leukaemia (AML) and can be generated from mononuclear cells in vitro following standard DC/DC_leu-generating protocols. With respect to future clinical applications though, DC/DC_leu-generating protocols specifically designed for application in a whole-blood-(WB)-environment must be established. Therefore, we developed ten new DC/DC_leu-generating protocols (kits; Kit-A/-C/-D/-E/-F/-G/-H/-I/-K/-M) for the generation of DC/DC_leu from leukaemic WB, containing calcium-ionophore, granulocyte-macrophage-colony-stimulating-factor (GM-CSF), tumour-necrosis-factor-alpha, prostaglandin-E₁ (PGE₁), prostaglandin-E₂ (PGE₂) and/or picibanil (OK-432). All protocols were evaluated regarding their performance in generating DC/DC_leu using refined classification and/or ranking systems; DC/DC_leu were evaluated regarding their performance in stimulating anti-leukaemic activity using a cytotoxicity fluorolysis assay. Overall, we found the new kits capable to generate (mature) DC/DC_leu from leukaemic WB. Through refined classification and ranking systems, we were able to select Kit-I (GM-CSF + OK-432), -K (GM-CSF + PGE₂) and -M (GM-CSF + PGE₁) as the most efficient kits in generating (mature) DC/DC_leu, which are further competent to stimulate immunoreactive cells to show an improved anti-leukaemic cytotoxicity as well. This great performance of Kit-I, -K and -M in mediating DC/DC_leu-based anti-leukaemic immunity in a WB-environment in vitro constitutes an important and directive step for translating DC/DC_leu-based immunotherapy of AML into clinical application. Full article

(This article belongs to the Special Issue Dendritic Cells—Conductors and Activators of the Immunological Orchestra)

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11 pages, 1168 KiB

Open AccessArticle

Potency Assessment of Dendritic Cell Anticancer Vaccine: Validation of the Co-Flow DC Assay

by Silvia Carloni, Claudia Piccinini, Elena Pancisi, Valentina Soldati, Monica Stefanelli, Anna Maria Granato, Toni Ibrahim and Massimiliano Petrini

Int. J. Mol. Sci. 2021, 22(11), 5824; https://doi.org/10.3390/ijms22115824 - 29 May 2021

Cited by 3 | Viewed by 2253

Abstract

For many years, oncological clinical trials have taken advantage of dendritic cells (DC) for the design of DC-based cellular therapies. This has required the design of suitable quality control assays to evaluate the potency of these products. The purpose of our work was to develop and validate a novel bioassay that uses flow cytometry as a read-out measurement. In this method, CD3+ cells are labeled with a fluorescent dye and the DC costimulatory activity is measured by the degree of T cell proliferation caused by the DC–T cell interaction. The validation of the method was achieved by the evaluation of essential analytical parameters defined by international guidelines. Our results demonstrated that the method could be considered specific, selective, and robust. The comparison between measured values and estimated true values confirmed a high level of accuracy and a lack of systematic error. Repeated experiments have shown the reproducibility of the assay and the proportionality between the potency and the DC amount has proven its linearity. Our results suggest that the method is compliant with the guidelines and could be adopted as a quality control assay or batch-release testing within GMP facilities. Full article

(This article belongs to the Special Issue Dendritic Cells—Conductors and Activators of the Immunological Orchestra)

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16 pages, 3011 KiB

Open AccessArticle

Elucidating the Role of Ezh2 in Tolerogenic Function of NOD Bone Marrow-Derived Dendritic Cells Expressing Constitutively Active Stat5b

by Echarki Zerif, Farhan Ullah Khan, Ahmed Aziz Raki, Véronique Lullier, Denis Gris, Gilles Dupuis and Abdelaziz Amrani

Int. J. Mol. Sci. 2020, 21(18), 6453; https://doi.org/10.3390/ijms21186453 - 4 Sep 2020

Cited by 6 | Viewed by 3283

Abstract

Tolerogenic dendritic cells (toDCs) are crucial to controlling the development of autoreactive T cell responses and the prevention of autoimmunity. We have reported that NOD.CD11c^Stat5b-CA transgenic mice expressing a constitutively active (CA) form of Stat5b under the control of a CD11c promoter are protected from diabetes and that Stat5b-CA-expressing DCs are tolerogenic and halt ongoing diabetes in NOD mice. However, the molecular mechanisms by which Stat5b-CA modulates DC tolerogenic function are not fully understood. Here, we used bone marrow-derived DCs (BMDCs) from NOD.CD11c^Stat5b-CA transgenic mice (Stat5b-CA.BMDCs) and found that Stat5b-CA.BMDCs displayed high levels of MHC class II, CD80, CD86, PD-L1, and PD-L2 and produced elevated amounts of TGFβ but low amounts of TNFα and IL-23. Stat5b-CA.BMDCs upregulated Irf4 and downregulated Irf8 genes and protein expression and promoted CD11c⁺CD11b⁺ DC2 subset differentiation. Interestingly, we found that the histone methyltransferase Ezh2 and Stat5b-CA bound gamma-interferon activated site (GAS) sequences in the Irf8 enhancer IRF8 transcription, whereas Stat5b but not Ezh2 bound GAS sequences in the Irf4 promoter to enhance IRF4 transcription. Injection of Stat5b-CA.BMDCs into prediabetic NOD mice halted progression of islet inflammation and protected against diabetes. Importantly, inhibition of Ezh2 in tolerogenic Stat5b-CA.BMDCs reduced their ability to prevent diabetes development in NOD recipient mice. Taken together, our data suggest that the active form of Stat5b induces tolerogenic DC function by modulating IRF4 and IRF8 expression through recruitment of Ezh2 and highlight the fundamental role of Ezh2 in Stat5b-mediated induction of tolerogenic DC function. Full article

(This article belongs to the Special Issue Dendritic Cells—Conductors and Activators of the Immunological Orchestra)

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11 pages, 1124 KiB

Open AccessCommunication

TLR2, TLR4 and TLR10 Shape the Cytokine and Chemokine Release of H. pylori-Infected Human DCs

by Theresa Neuper, Tobias Frauenlob, Muamera Sarajlic, Gernot Posselt, Silja Wessler and Jutta Horejs-Hoeck

Int. J. Mol. Sci. 2020, 21(11), 3897; https://doi.org/10.3390/ijms21113897 - 29 May 2020

Cited by 24 | Viewed by 3656

Abstract

Helicobacter pylori (H. pylori) is a stomach pathogen that persistently colonizes the gastric mucosa, often leading to chronic inflammation and gastric pathologies. Although infection with H. pylori is the primary risk factor for gastric cancer, the underlying mechanisms of pathogen persistence and consequential chronic inflammation are still not well understood. Conventional dendritic cells (cDCs), which are among the first immune cells to encounter H. pylori in the gastric lining, and the cytokines and chemokines they secrete, contribute to both acute and chronic inflammation. Therefore, this study aimed to unravel the contributions of specific signaling pathways within human CD1c⁺ cDCs (cDC2s) to the composition of secreted cytokines and chemokines in H. pylori infection. Here, we show that the type IV secretion system (T4SS) plays only a minor role in H. pylori-induced activation of cDC2s. In contrast, Toll-like receptor 4 (TLR4) signaling drives the secretion of inflammatory mediators, including IL-12 and IL-18, while signaling via TLR10 attenuates the release of IL-1β and other inflammatory cytokines upon H. pylori infection. The TLR2 pathway significantly blocks the release of CXCL1 and CXCL8, while it promotes the secretion of TNFα and GM-CSF. Taken together, these results highlight how specific TLR-signaling pathways in human cDC2s shape the H. pylori-induced cytokine and chemokine milieu, which plays a pivotal role in the onset of an effective immune response. Full article

(This article belongs to the Special Issue Dendritic Cells—Conductors and Activators of the Immunological Orchestra)

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25 pages, 1623 KiB

Open AccessArticle

PGE₁-Containing Protocols Generate Mature (Leukemia-Derived) Dendritic Cells Directly from Leukemic Whole Blood

by Daniel Christoph Amberger, Fatemeh Doraneh-Gard, Carina Gunsilius, Melanie Weinmann, Sabine Möbius, Christoph Kugler, Nicole Rogers, Corinna Böck, Uwe Ködel, Jan-Ole Werner, Doris Krämer, Britta Eiz-Vesper, Andreas Rank, Christoph Schmid and Helga Maria Schmetzer

Int. J. Mol. Sci. 2019, 20(18), 4590; https://doi.org/10.3390/ijms20184590 - 17 Sep 2019

Cited by 16 | Viewed by 3536

Abstract

Dendritic cells (DCs) and leukemia-derived DC (DC_leu) are potent stimulators of various immunoreactive cells and they play a pivotal role in the (re-) activation of the immune system. As a potential treatment tool for patients with acute myeloid leukemia, we developed and analyzed two new PGE₁-containing protocols (Pici-_PGE1, Kit M) to generate DC/DC_leu ex vivo from leukemic peripheral blood mononuclear cells (PBMCs) or directly from leukemic whole blood (WB) to simulate physiological conditions. Pici-_PGE1 generated significantly higher amounts of DCs from leukemic and healthy PBMCs when compared to control and comparable amounts as the already established protocol Pici-_PGE2. The proportions of sufficient DC-generation were even higher after DC/DC_leu-generation with Pici-_PGE1. With Kits, it was possible to generate DCs and DC_leu directly from leukemic and healthy WB without induction of blast proliferation. The average amounts of generated DCs and DC_leu-subgroups were comparable with all Kits. The PGE₁ containing Kit M generated significantly higher amounts of mature DCs when compared to the PGE₂-containing Kit K and increased the anti-leukemic-activity. In summary PGE₁-containing protocols were suitable for generating DC/DC_leu from PBMCs as well as from WB, which reliably (re-) activated immunoreactive cells, improved the overall ex vivo anti-leukemic activity, and influenced cytokine-release-profiles. Full article

(This article belongs to the Special Issue Dendritic Cells—Conductors and Activators of the Immunological Orchestra)

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