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Article ; Online: An abdominal mass with thrombosis due to inferior vena cava agenesis mimicking lymphoma.

Weijmans, Maaike / Vermeulen, Rosa / Kleijwegt, Fleur S / Boiten, Henk-Jan

2021 Volume 100, Issue 11, Page(s) 2871–2872

MeSH term(s)	Abdomen/pathology ; Adult ; Humans ; Lymphoma/diagnosis ; Lymphoma/pathology ; Male ; Thrombosis/diagnosis ; Thrombosis/pathology ; Vena Cava, Inferior/pathology
Language	English
Publishing date	2021-08-02
Publishing country	Germany
Document type	Case Reports ; Letter
ZDB-ID	1064950-5
ISSN	1432-0584 ; 0939-5555 ; 0945-8077
ISSN (online)	1432-0584
ISSN	0939-5555 ; 0945-8077
DOI	10.1007/s00277-021-04626-5
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Article: Infectious tolerance as candidate therapy for type 1 diabetes: transfer of immunoregulatory properties from human regulatory T cells to other T cells and proinflammatory dendritic cells.

Kleijwegt, Fleur S / Roep, Bart O

Critical reviews in immunology

2013 Volume 33, Issue 5, Page(s) 415–434

Abstract: Type 1 diabetes is a T-cell-mediated autoimmune disease in which the insulin-producing cells in the islets of Langerhans are selectively destroyed. Although symptomatic insulin therapy is able to control glucose levels in the blood, many patients do not ... ...

Abstract	Type 1 diabetes is a T-cell-mediated autoimmune disease in which the insulin-producing cells in the islets of Langerhans are selectively destroyed. Although symptomatic insulin therapy is able to control glucose levels in the blood, many patients do not obtain the desired glycemic control, which increases the risk of diabetic complications. While many immunotherapeutic efforts to intervene in the disease process focus on systemic immune-suppressive therapies, antigen-specific immune modulation represents an attractive alternative. Dendritic cells modulated with 1.25(OH)2 vitamin D3, and dexamethasone (tolerogenic DCs) loaded with islet antigens induce Ag-specific regulatory CD4 T cells (iaTregs), offering a tissue-specific intervention therapy. iaTregs exert their function via linked suppression to diminish effector cells by modulating pro-inflammatory DCs to upregulate inhibitory receptors. In turn, these re-educated mature DCs induce IL-10-producing cells from the naïve T-cell pool. Thus, tolerogenic DCs transfer regulatory properties to pro-inflammatory DCs via iaTregs (i.e., infectious tolerance). In this review, we describe the current knowledge regarding regulatory mechanisms of these tolerogenic DCs and the Tregs that they induce, and we propose that cell therapy with human tolerogenic DCs provides new opportunities for immune intervention in patients with autoimmune diseases.
MeSH term(s)	Animals ; Dendritic Cells/immunology ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/therapy ; Humans ; Immune Tolerance ; Inflammation/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes, Regulatory/immunology
Language	English
Publishing date	2013-10-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1353116-5
ISSN	1040-8401
ISSN	1040-8401
DOI	10.1615/critrevimmunol.2013006782
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Article ; Online: Rare but Serious: Ibrutinib Induced Liver Failure.

Kleijwegt, Fleur S / Roda, Afnan Abdul / Rolvink, José / Kater, Arnon P / Kersten, Marie José / Vos, Josephine M I

HemaSphere

2019 Volume 3, Issue 6, Page(s) e307

Language	English
Publishing date	2019-10-22
Publishing country	United States
Document type	Case Reports
ISSN	2572-9241
ISSN (online)	2572-9241
DOI	10.1097/HS9.0000000000000307
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Article ; Online: Tailored anticoagulant treatment after a first venous thromboembolism: protocol of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study - cohort-based randomised controlled trial.

Burggraaf-van Delft, J Louise I / van Rein, Nienke / Bemelmans, Remy H H / van den Berg, Jan-Willem K / Bruggeman, Coty Y / Cloos-van Balen, Marissa / Coppens, Michiel / Eefting, Matthijs / Ende-Verhaar, Yvonne / van Es, Nick / van Guldener, Coen / de Jong, Wouter K / Kleijwegt, Fleur / Koster, Ted / Kroon, Cees / Kuipers, Saskia / Leentjens, Jenneke / Luijten, Dieuwke / Mairuhu, Albert T A /

Meijer, Karina / van de Ree, Marcel A / Roos, Rick / Schrover, Ilse / Swart-Heikens, Janneke / van der Velden, Annette W G / van den Akker-van Marle, Elske M / le Cessie, Saskia / Geersing, Geert-Jan / Middeldorp, Saskia / Huisman, Menno V / Klok, Frederikus A / Cannegieter, Suzanne C

BMJ open

2024 Volume 14, Issue 3, Page(s) e078676

Abstract: Introduction: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain ... ...

Abstract	Introduction: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks. Methods and analysis: The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients. Ethics and dissemination: The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences. Trial registration number: NCT06087952.
MeSH term(s)	Humans ; Anticoagulants/adverse effects ; Hemorrhage/chemically induced ; Hemorrhage/complications ; Multicenter Studies as Topic ; Quality of Life ; Randomized Controlled Trials as Topic ; Recurrence ; Thrombosis ; Venous Thromboembolism/etiology
Chemical Substances	Anticoagulants
Language	English
Publishing date	2024-03-23
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2023-078676
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Article ; Online: Tolerogenic dendritic cells impede priming of naïve CD8⁺ T cells and deplete memory CD8⁺ T cells.

Kleijwegt, Fleur S / Jansen, Diahann T S L / Teeler, Josefine / Joosten, Antoinette M / Laban, Sandra / Nikolic, Tatjana / Roep, Bart O

European journal of immunology

2013 Volume 43, Issue 1, Page(s) 85–92

Abstract: Type 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8(+) T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic cells (Combi-DCs) loaded with islet antigens inducing ... ...

Abstract	Type 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8(+) T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic cells (Combi-DCs) loaded with islet antigens inducing islet-specific regulatory CD4(+) T cells may offer a tissue-specific intervention therapy. The effect of Combi-DCs on CD8(+) T cells, however, remains unknown. To investigate the interaction of CD8(+) T cells with Combi-DCs presenting epitopes on HLA class I, naive, and memory CD8(+) T cells were co-cultured with DCs and proliferation and function of peptide-specific T cells were analyzed. Antigen-loaded Combi-DCs were unable to prime naïve CD8(+) T cells to proliferate, although a proportion of T cells converted to a memory phenotype. Moreover, expansion of CD8(+) T cells that had been primed by mature monocyte-derived DCs (moDCs) was curtailed by Combi-DCs in co-cultures. Combi-DCs expanded memory T cells once, but CD8(+) T-cell numbers collapsed by subsequent re-stimulation with Combi-DCs. Our data point that (re)activation of CD8(+) T cells by antigen-pulsed Combi-DCs does not promote, but rather deteriorates, CD8(+) T-cell immunity. Yet, Combi-DCs pulsed with CD8(+) T-cell epitopes also act as targets of cytotoxicity, which is undesirable for survival of Combi-DCs infused into patients in therapeutic immune intervention strategies.
MeSH term(s)	CD8-Positive T-Lymphocytes/immunology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Cholecalciferol/immunology ; Clonal Deletion ; Coculture Techniques ; Cytotoxicity, Immunologic ; Dendritic Cells/immunology ; Dendritic Cells/transplantation ; Dexamethasone/immunology ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/therapy ; Epitopes, T-Lymphocyte/immunology ; Epitopes, T-Lymphocyte/metabolism ; HLA Antigens/metabolism ; Humans ; Immune Tolerance ; Immunologic Memory ; Lymphocyte Activation ; Lymphocyte Depletion ; T-Lymphocyte Subsets/immunology
Chemical Substances	Epitopes, T-Lymphocyte ; HLA Antigens ; Cholecalciferol (1C6V77QF41) ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2013-01
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201242879
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Article ; Online: Differential Protein Pathways in 1,25-Dihydroxyvitamin D3 and Dexamethasone Modulated Tolerogenic Human Dendritic Cells

Ferreira, Gabriela Bomfim / Kleijwegt, Fleur S. / Waelkens, Etienne / Lage, Kasper / Nikolić, Tatjana / Hansen, Daniel Aaen / Workman, Christopher T. / Roep, Bart O. / Overbergh, Lut / Mathieu, Chantal

Journal of Proteome Research. 2012 Feb. 03, v. 11, no. 2 p.941-971

2012

Abstract: Tolerogenic dendritic cells (DC) that are maturation-resistant and locked in a semimature state are promising tools in clinical applications for tolerance induction. Different immunomodulatory agents have been shown to induce a tolerogenic DC phenotype, ... ...

Abstract	Tolerogenic dendritic cells (DC) that are maturation-resistant and locked in a semimature state are promising tools in clinical applications for tolerance induction. Different immunomodulatory agents have been shown to induce a tolerogenic DC phenotype, such as the biologically active form of vitamin D (1,25(OH)₂D₃), glucocorticoids, and a synergistic combination of both. In this study, we aimed to characterize the protein profile, function and phenotype of DCs obtained in vitro in the presence of 1,25(OH)₂D₃, dexamethasone (DEX), and a combination of both compounds (combi). Human CD14⁺ monocytes were differentiated toward mature DCs, in the presence or absence of 1,25(OH)₂D₃ and/or DEX. Cells were prefractionated into cytoplasmic and microsomal fractions and protein samples were separated in two different pH ranges (pH 3–7NL and 6–9), analyzed by 2D-DIGE and differentially expressed spots (p < 0.05) were identified after MALDI-TOF/TOF analysis. In parallel, morphological and phenotypical analyses were performed, revealing that 1,25(OH)₂D₃- and combi-mDCs are closer related to each other than DEX-mDCs. This was translated in their protein profile, indicating that 1,25(OH)₂D₃ is more potent than DEX in inducing a tolerogenic profile on human DCs. Moreover, we demonstrate that combining 1,25(OH)₂D₃ with DEX induces a unique protein expression pattern with major imprinting of the 1,25(OH)₂D₃ effect. Finally, protein interaction networks and pathway analysis suggest that 1,25(OH)₂D₃, rather than DEX treatment, has a severe impact on metabolic pathways involving lipids, glucose, and oxidative phosphorylation, which may affect the production of or the response to ROS generation. These findings provide new insights on the molecular basis of DC tolerogenicity induced by 1,25(OH)₂D₃ and/or DEX, which may lead to the discovery of new pathways involved in DC immunomodulation.
Keywords	calcitriol ; dendritic cells ; dexamethasone ; glucocorticoids ; glucose ; humans ; immunomodulation ; monocytes ; oxidative phosphorylation ; pH ; phenotype ; protein composition ; protein synthesis ; 2D-DIGE ; dendritic cell ; vitamin D ; mass spectrometry ; pathway analysis ; protein interaction networks
Language	English
Dates of publication	2012-0203
Size	p. 941-971.
Publishing place	American Chemical Society
Document type	Article ; Online
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021%2Fpr200724e
Database	NAL-Catalogue (AGRICOLA)

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Article: Induction of Treg by monocyte-derived DC modulated by vitamin D₃ or dexamethasone: Differential role for PD-L1

Unger, Wendy W.J / Laban, Sandra / Kleijwegt, Fleur S / van der Slik, Arno R / Roep, Bart O

European journal of immunology. 2009 Nov., v. 39, no. 11

2009

Abstract: Specific therapy with modulated DC may restore immunological tolerance, thereby obviating the need for chronic immunosuppression in transplantation or autoimmunity. In this study we compared the tolerizing capacity of dexamethasone (Dex)- and 1α,25- ... ...

Abstract	Specific therapy with modulated DC may restore immunological tolerance, thereby obviating the need for chronic immunosuppression in transplantation or autoimmunity. In this study we compared the tolerizing capacity of dexamethasone (Dex)- and 1α,25-dihydroxyvitamin D3 (VD3)-modulated DC. Treatment of monocytes with either VD3 or Dex resulted in DC with stable, semi-mature phenotypes compared with standard DC, with intermediate levels of co-stimulatory and MHC class II molecules, which remained unaltered after subsequent pro-inflammatory stimulation. IL-12p70 secretion was lost by VD3- and Dex-DC, whereas IL-10 secretion was unaffected. VD3-DC distinctly produced large amounts of TNF-α. Both VD3- and Dex-DC possessed the capacity to convert CD4 T cells into IL-10-secreting Treg potently suppressing the proliferation of responder T cells. However, only Treg induced by VD3-DC exhibited antigen specificity. VD3-, but not Dex-, DC expressed significant high levels of PD-L1 (programmed death-1 ligand), upon activation. Blockade of PD-L1 during priming redirected T cells to produce IFN-γ instead of IL-10 and abolished acquisition of regulatory capacity. Our findings demonstrate that both VD3- and Dex-DC possess durable but differential tolerogenic features, acting via different mechanisms. Both are potentially useful to specifically down-regulate unwanted immune responses and induce immune tolerance. These modulated DC appear suitable as adjuvant in antigen-specific clinical vaccination intervention strategies.
Language	English
Dates of publication	2009-11
Size	p. 3147-3159.
Publishing place	Wiley-VCH Verlag
Document type	Article
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.200839103
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Article ; Online: Transfer of regulatory properties from tolerogenic to proinflammatory dendritic cells via induced autoreactive regulatory T cells.

Kleijwegt, Fleur S / Laban, Sandra / Duinkerken, Gaby / Joosten, Antoinette M / Koeleman, Bobby P C / Nikolic, Tatjana / Roep, Bart O

Journal of immunology (Baltimore, Md. : 1950)

2011 Volume 187, Issue 12, Page(s) 6357–6364

Abstract: Infectious tolerance is a term generally assigned to the process through which regulatory T cells (Tregs) transfer immunoregulatory properties to other T cells. In this study, we demonstrated that a similar process applies to human dendritic cells (DCs), ...

Abstract	Infectious tolerance is a term generally assigned to the process through which regulatory T cells (Tregs) transfer immunoregulatory properties to other T cells. In this study, we demonstrated that a similar process applies to human dendritic cells (DCs), albeit through a different mechanism. We induced and cloned proinsulin-specific Tregs using tolerogenic DCs and investigated mechanisms by which induced Ag-specific regulatory T cells (iaTregs) endorse the suppressive effects. iaTregs expressed FOXP3, programmed death-1, and membrane-bound TGF-β and upregulated IL-10 and CTLA-4 after stimulation with the cognate Ag. The iaTregs suppressed effector T cells only when both encountered the cognate Ags on the same APCs (linked suppression). This occurred independently of IL-10, TGF-β, programmed death-1, or CTLA-4. Instead, iaTregs used a granzyme B-mediated mechanism to kill B cells and monocytes, whereas proinflammatory DCs that resisted being killed were induced to upregulate the inhibitory receptors B7 (family) homolog 3 and ICOS ligand. These re-educated mature monocyte-derived dendritic cells (mDCs) suppressed effector T cells and induced IL-10-producing cells from the naive T cell pool. Our data indicated that human tolerogenic DCs confer infectious tolerance by inducing Ag-specific Tregs, which, in turn, re-educate proinflammatory mature DCs into DCs with regulatory properties.
MeSH term(s)	Cell Differentiation/immunology ; Cells, Cultured ; Cholecalciferol/physiology ; Clone Cells ; Coculture Techniques ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Dendritic Cells/pathology ; Epitopes, T-Lymphocyte/immunology ; Forkhead Transcription Factors/biosynthesis ; HLA-DRB1 Chains/physiology ; Humans ; Immune Tolerance ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Inflammation Mediators/physiology ; Interleukin-2 Receptor alpha Subunit/biosynthesis ; Lymphocyte Activation/immunology ; Monocytes/cytology ; Monocytes/immunology ; Monocytes/metabolism ; Programmed Cell Death 1 Receptor/biosynthesis ; Proinsulin/biosynthesis ; Proinsulin/immunology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/pathology
Chemical Substances	Epitopes, T-Lymphocyte ; FOXP3 protein, human ; Forkhead Transcription Factors ; HLA-DRB1 Chains ; HLA-DRB1*04:01 antigen ; IL2RA protein, human ; Inflammation Mediators ; Interleukin-2 Receptor alpha Subunit ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Cholecalciferol (1C6V77QF41) ; Proinsulin (9035-68-1)
Language	English
Publishing date	2011-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1101638
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Article ; Online: Critical role for TNF in the induction of human antigen-specific regulatory T cells by tolerogenic dendritic cells.

Kleijwegt, Fleur S / Laban, Sandra / Duinkerken, Gaby / Joosten, Antoinette M / Zaldumbide, Arnaud / Nikolic, Tatjana / Roep, Bart O

Journal of immunology (Baltimore, Md. : 1950)

2010 Volume 185, Issue 3, Page(s) 1412–1418

Abstract: TNF is a pleiotropic cytokine with differential effects on immune cells and diseases. Anti-TNF therapy was shown to be effective in rheumatoid arthritis but proved inefficient or even detrimental in other autoimmune diseases. We studied the role of TNF ... ...

Abstract	TNF is a pleiotropic cytokine with differential effects on immune cells and diseases. Anti-TNF therapy was shown to be effective in rheumatoid arthritis but proved inefficient or even detrimental in other autoimmune diseases. We studied the role of TNF in the induction of Ag-specific regulatory T cells (Tregs) by tolerogenic vitamin D3-modulated human dendritic cells (VD3-DCs), which previously were shown to release high amounts of soluble TNF (sTNF) upon maturation with LPS. First, production of TNF by modulated VD3-DCs was analyzed upon maturation with LPS or CD40L with respect to both secreted (cleaved) TNF (sTNF) and expression of the membrane-bound (uncleaved) form of TNF (mTNF). Next, TNF antagonists were tested for their effect on induction of Ag-specific Tregs by modulated DCs and the subsequent functionality of these Tregs. VD3-DCs expressed greater amounts of mTNF than did control DCs (nontreated DCs), independent of the maturation protocol. Inhibition of TNF with anti-TNF Ab (blocking both sTNF and mTNF) during the priming of Tregs with VD3-DCs prevented generation of Tregs and their suppression of proliferation of CD4(+) T cells. In contrast, sTNF receptor II (sTNFRII), mainly blocking sTNF, did not change the suppressive capacity of Tregs. Blocking of TNFRII by anti-CD120b Ab during Treg induction similarly abrogated their subsequent suppressive function. These data point to a specific role for mTNF on VD3-DCs in the induction of Ag-specific Tregs. Interaction between mTNF and TNFRII instructs the induction of suppressive Tregs by VD3-DCs. Anti-TNF therapy may therefore act adversely in different patients or disease pathways.
MeSH term(s)	Cell Differentiation/immunology ; Cell Membrane/immunology ; Cell Membrane/metabolism ; Cholecalciferol/pharmacology ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Epitopes, T-Lymphocyte/immunology ; Humans ; Immune Tolerance ; Lymphocyte Activation/immunology ; Protein Binding/immunology ; Protein Isoforms/antagonists & inhibitors ; Protein Isoforms/metabolism ; Protein Isoforms/physiology ; T-Lymphocytes, Regulatory/cytology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Necrosis Factor-alpha/physiology
Chemical Substances	Epitopes, T-Lymphocyte ; Protein Isoforms ; TNF protein, human ; Tumor Necrosis Factor-alpha ; Cholecalciferol (1C6V77QF41)
Language	English
Publishing date	2010-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1000560
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Article ; Online: Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1.

Unger, Wendy W J / Laban, Sandra / Kleijwegt, Fleur S / van der Slik, Arno R / Roep, Bart O

European journal of immunology

2009 Volume 39, Issue 11, Page(s) 3147–3159

Abstract	Specific therapy with modulated DC may restore immunological tolerance, thereby obviating the need for chronic immunosuppression in transplantation or autoimmunity. In this study we compared the tolerizing capacity of dexamethasone (Dex)- and 1 alpha,25-dihydroxyvitamin D3 (VD3)-modulated DC. Treatment of monocytes with either VD3 or Dex resulted in DC with stable, semi-mature phenotypes compared with standard DC, with intermediate levels of co-stimulatory and MHC class II molecules, which remained unaltered after subsequent pro-inflammatory stimulation. IL-12p70 secretion was lost by VD3- and Dex-DC, whereas IL-10 secretion was unaffected. VD3-DC distinctly produced large amounts of TNF-alpha. Both VD3- and Dex-DC possessed the capacity to convert CD4 T cells into IL-10-secreting Treg potently suppressing the proliferation of responder T cells. However, only Treg induced by VD3-DC exhibited antigen specificity. VD3-, but not Dex-, DC expressed significant high levels of PD-L1 (programmed death-1 ligand), upon activation. Blockade of PD-L1 during priming redirected T cells to produce IFN-gamma instead of IL-10 and abolished acquisition of regulatory capacity. Our findings demonstrate that both VD3- and Dex-DC possess durable but differential tolerogenic features, acting via different mechanisms. Both are potentially useful to specifically down-regulate unwanted immune responses and induce immune tolerance. These modulated DC appear suitable as adjuvant in antigen-specific clinical vaccination intervention strategies.
MeSH term(s)	Anti-Inflammatory Agents/pharmacology ; B7-1 Antigen/immunology ; B7-H1 Antigen ; Cell Differentiation/drug effects ; Cell Differentiation/immunology ; Cell Separation ; Chemotaxis, Leukocyte/immunology ; Cholecalciferol/pharmacology ; Cytokines/biosynthesis ; Cytokines/immunology ; Dendritic Cells/cytology ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dexamethasone/pharmacology ; Flow Cytometry ; Humans ; Immune Tolerance/drug effects ; Immune Tolerance/immunology ; Immunomodulation/immunology ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Membrane Glycoproteins/immunology ; Monocytes/drug effects ; Monocytes/immunology ; Peptides/immunology ; Polymerase Chain Reaction ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Anti-Inflammatory Agents ; B7-1 Antigen ; B7-H1 Antigen ; Cd274 protein, mouse ; Cytokines ; Membrane Glycoproteins ; Peptides ; Cholecalciferol (1C6V77QF41) ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2009-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.200839103
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