Dendritic Cells Activated by Lipopolysaccharide after Dexamethasone Treatment Induce Donor-Specific Allograft Hyporesponsiveness

Emmer, P.M.; Vlag, Johan van der; Adema, Gosse J.; Hilbrands, Luuk B.

doi:10.1097/01.tp.0000208801.51222.bd

Cited by 65 publications

(67 citation statements)

References 39 publications

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“…Priming with Dex-DC leads to a decrease in the number of IFN-g-producing cells, while increasing the number of IL-10 producing cells both in vivo and in vitro, which could point to the induction of Tr1-like Treg [16,19]. In line with this, an up-regulation of FoxP3 expression marking Treg in mice was recently observed in lymph node cells upon in vivo treatment with Dex-DC [18]. However, conclusive data on functional involvement of Treg induced by Dex-DC are lacking.…”

Section: Introductionsupporting

confidence: 61%

“…In addition, Dex-DC possess durable immaturity [10] as high IL-10 and little IL-12 production was maintained up to 5 days after removal of Dex. In vivo, application of Dex-DC prior to allograft transplantation significantly prolonged the survival of the grafts in an antigendependent fashion in mice [16,18]. Priming with Dex-DC leads to a decrease in the number of IFN-g-producing cells, while increasing the number of IL-10 producing cells both in vivo and in vitro, which could point to the induction of Tr1-like Treg [16,19].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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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 1a,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-a. 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-c 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.Key words: Antigen specificity . Autoimmunity . Modulated DC . PD-L1 . Treg IntroductionRestoring immunological tolerance is the ''holy grail'' in the fields of autoimmunity and transplantation. Current applied therapies, which include immunosuppressive drugs, do not target the cause of the disease and, in addition, are associated with considerable non-specific side effects. Therefore, it is desirable to design therapies that specifically target the immunopathogenesis.DC are important modulators of T-cell activity [1]. Depending on the type of pathogen encountered and the profile of co-stimulatory and T-cell polarizing molecules, DC drive the development of either pro-inflammatory Th type 1 (Th1), type 2 (Th2) and type 17 (Th17) cells or protective Treg [2][3][4]. In conjunction with this, human monocyte-derived DC (moDC) can be differentiated into Th1-, Th2-, Th17-or Treg-promoting DC in vitro. Priming of moDC with microbial compounds or tissue-derived factors such as IFN-g, prostaglandin E2 (PGE2) or IL-23 and IL-1 results in enhanced expression of MHC class II and co-stimulatory molecules and drives the development of effector Th1, Th2 and Th17 cells [5][6][7]. It is now clear that certain immunosuppressive drugs and anti-inflammatory agents induce DC with tolerogenic properties [8][9][10][11][12][13][14][15]. For example, DC treated with either dexamethasone (Dex) or the active form of vitamin D, 1a,25-dihydroxyvitamin D 3 (VD3), arrest DC in a semimature state and prevent the up-regulation of co-stimulatory Trea...

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Section: Introductionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…BALB/c (H-2 d ) and CBA (H-2 k ) mice ages 8-10 weeks were purchased from Charles River (Maastricht, The Netherlands) and maintained under specific pathogen-free conditions and handled according to the guidelines of the local ethics committee of the Radboud University Nijmegen. Bone marrow-derived DCs were obtained by culturing bone marrow from BALB/c mice as previously described (30,31). Briefly, bone marrow was flushed from femur and tibia and cultured for 8 days in 6-well plates (1 ϫ 10 6 cells/well; Corning Costar, Badhoevedorp, The Netherlands) containing RPMI 1640 DM medium (Invitrogen Life Technologies, Breda, The Netherlands) with 10% fetal calf serum (FCS; Greiner Bio One, Alphen aan den Rijn, The Netherlands), 1% pyruvate, 1% Glutamax, 1% penicillin/streptomycin (all from Invitrogen Life Technologies), and 20 ng/ml granulocytemacrophage colony-stimulating factor (Pepro-Tech, London, (32,33) were cultured in complete RPMI 1640 DM medium supplemented with 15% WEHI-3B-conditioned medium as a source of murine IL-3 (DSMZ, Braunschweig, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Addition of 1 g/ml lipopolysaccharide (LPS) (L4391; Sigma-Aldrich) was used as a positive control for maturation of DCs. After 14 hours of incubation, cells were harvested and subjected to direct or indirect fluorescence staining of cell surface markers, essentially as described previously (31). Briefly, cells were stained with anti-CD40 (clone FGK45.5; Miltenyi Biotec, Utrecht, The Netherlands) or isotype-matched control antibodies (R35-95; BD PharMingen), followed by phycoerythrin (PE)-conjugated goat anti-F(abЈ) 2 anti-rat (Beckman Coulter, Bedfordshire, UK) and Alexa 647-conjugated anti-CD11c (N418; Serotec, Oxford, UK), or with PE-conjugated anti-CD86 (PO3.1; eBioscience, Malden, The Netherlands) and Alexa 647-conjugated anti-CD11c.…”

Section: Methodsmentioning

confidence: 99%

Mouse dendritic cells matured by ingestion of apoptotic blebs induce T cells to produce interleukin‐17

Fransen¹,

Hilbrands²,

Ruben³

et al. 2009

Arthritis & Rheumatism

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Objective. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of antinuclear autoantibodies. Increased apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE, but the underlying mechanisms remain elusive. During apoptosis apoptotic blebs are formed in which autoantigens are clustered. The cellular remnants after blebbing are referred to as apoptotic cell bodies. We undertook this study to compare the effects of apoptotic blebs and apoptotic cell bodies on maturation of dendritic cells (DCs) and their T cell stimulatory capacity in a murine setting.Methods. The uptake by DCs of apoptotic blebs and apoptotic cell bodies was analyzed by flow cytometry and confocal microscopy. DC maturation and DCinduced T cell activation were determined by measuring expression of costimulatory molecules using flow cytometry and by measuring production of cytokines using enzyme-linked immunosorbent assay.Results. DCs internalized apoptotic blebs more efficiently than apoptotic cell bodies. Incubation of DCs with apoptotic blebs resulted in increased CD40 and CD86 expression and increased interleukin-6 (IL-6) and tumor necrosis factor ␣ production, while apoptotic cell bodies had no stimulatory effects. Using chloroquine, apoptotic bleb-induced DC maturation was shown to be independent of Toll-like receptors 3, 7, and 9. Interestingly, in cocultures with allogeneic T cells, bleb-matured DCs induced production of IL-2, interferon-␥, and, in particular, IL-17, suggesting a Th1/Th17 response.Conclusion. Apoptotic blebs, in contrast to apoptotic cell bodies, induce DC maturation, thereby providing DCs with increased Th17 cell stimulatory capacity. These data imply that apoptotic bleb-induced DC maturation represents an important driving force in the autoimmune response in SLE.

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“…For instance, it was previously demonstrated that DCs treated with synthetic drugs or pathogen-derived extracts acquire immature phenotype and upon adoptive transfer suppress the severity of collagen-induced arthritis, mouse kidney grafts and experimental autoimmune encephalomyelitis (EAE). [13][14][15][16][17][18][19][20][21][22] The mechanisms of DC-induced suppression are mostly dependent on the generation of Treg cells in vivo. 17 EAE is a T-cell-dependent neuroinflammation that, in many aspects, mimics human multiple sclerosis.…”

Section: Introductionmentioning

confidence: 99%

Dendritic cells treated with crude Plasmodium berghei extracts acquire immune‐modulatory properties and suppress the development of autoimmune neuroinflammation

et al. 2014

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SummaryDendritic cells (DCs) are professional antigen-presenting cells specifically targeted during Plasmodium infection. Upon infection, DCs show impaired antigen presentation and T-cell activation abilities. In this study, we aimed to evaluate whether cellular extracts obtained from Plasmodium berghei-infected erythrocytes (PbX) modulate DCs phenotypically and functionally and the potential therapeutic usage of PbX-modulated DCs in the control of experimental autoimmune encephalomyelitis (EAE, the mouse model for human multiple sclerosis). We found that PbX-treated DCs have impaired maturation and stimulated the generation of regulatory T cells when cultured with naive T lymphocytes in vitro. When adoptively transferred to C57BL/6 mice the EAE severity was reduced. Disease amelioration correlated with a diminished infiltration of cytokine-producing T cells in the central nervous system as well as the suppression of encephalitogenic T cells. Our study shows that extracts obtained from P. berghei-infected erythrocytes modulate DCs towards an immunosuppressive phenotype. In addition, the adoptive transfer of PbX-modulated DCs was able to ameliorate EAE development through the suppression of specific cellular immune responses towards neuro-antigens. To our knowledge, this is the first study to present evidence that DCs treated with P. berghei extracts are able to control autoimmune neuroinflammation.

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Dendritic Cells Activated by Lipopolysaccharide after Dexamethasone Treatment Induce Donor-Specific Allograft Hyporesponsiveness

Abstract: Alternatively activated DC are more efficacious than the classical imDC in the regulation of the alloimmune response, which may be related to a distinct cytokine profile characterized by an increased IL-10/IL12 ratio.

Cited by 65 publications

References 39 publications

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

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

Mouse dendritic cells matured by ingestion of apoptotic blebs induce T cells to produce interleukin‐17

Dendritic cells treated with crude Plasmodium berghei extracts acquire immune‐modulatory properties and suppress the development of autoimmune neuroinflammation

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Dendritic Cells Activated by Lipopolysaccharide after Dexamethasone Treatment Induce Donor-Specific Allograft Hyporesponsiveness

Abstract: Alternatively activated DC are more efficacious than the classical imDC in the regulation of the alloimmune response, which may be related to a distinct cytokine profile characterized by an increased IL-10/IL12 ratio.

Cited by 65 publications

References 39 publications

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

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

Mouse dendritic cells matured by ingestion of apoptotic blebs induce T cells to produce interleukin‐17

Dendritic cells treated with crude Plasmodium berghei extracts acquire immune‐modulatory properties and suppress the development of autoimmune neuroinflammation

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

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