Induction of specific immune responses against the Plasmodium vivax liver-stage via in vitro activation by dendritic cells

TGF-β-induced regulatory T cells (iTregs) retain Foxp3 expression and immune-suppressive activity in collagen-induced arthritis (CIA). However, the mechanisms whereby transferred iTregs suppress immune responses, particularly the interplay between iTregs and dendritic cells (DCs)in vivo, remain incompletely understood. In this study, we found that after treatment with iTregs, splenic CD11c+DCs, termed “DCiTreg,” expressed tolerogenic phenotypes, secreted high levels of IL-10, TGF-β, and IDO, and showed potent immunosuppressive activityin vitro. After reinfusion with DCiTreg, marked antiarthritic activity improved clinical scores and histological end-points were observed. The serological levels of inflammatory cytokines and anti-CII antibodies were low and TGF-βproduction was high in the DCiTreg-treated group. DCiTregalso induced new iTregsin vivo. Moreover, the inhibitory activity of DCiTregon CIA was lost following pretreatment with the inhibitor of indoleamine 2,3-dioxygenase (IDO). Collectively, these findings suggest that transferred iTregs could induce tolerogenic characteristics in splenic DCs and these cells could effectively dampen CIA in an IDO-dependent manner. Thus, the potential therapeutic effects of iTregs in CIA are likely maintained through the generation of tolerogenic DCsin vivo.

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Bisphenol A Does Not Mimic Estrogen in the Promotion of the In Vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands

Mediators of Inflammation ◽

10.1155/2017/2034348 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Marita Chakhtoura ◽

Uma Sriram ◽

Michelle Heayn ◽

Joshua Wonsidler ◽

Christopher Doyle ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Bisphenol A ◽

Endocrine Disrupting Chemicals ◽

Receptor Ligands ◽

Gm Csf ◽

Estrogen Receptor Modulators ◽

Tlr9 Ligand ◽

In Vitro Response

Sex hormones affect immune responses and might promote autoimmunity. Endocrine disrupting chemicals such as bisphenol A (BPA) may mimic their immune effects. Conventional dendritic cells (cDCs) are pivotal initiators of immune responses upon activation by danger signals coming from pathogens or distressed tissues through triggering of the Toll-like receptors (TLRs). We generated in vitro murine cDCs in the absence of estrogens and measured the effects of exogenously added estrogen or BPA on their differentiation and activation by the TLR ligands LPS and CpG. Estrogen enhanced the differentiation of GM-CSF-dependent cDCs from bone marrow precursors in vitro, and the selective estrogen receptor modulators (SERMs) tamoxifen and fulvestrant blocked these effects. Moreover, estrogen augmented the upregulation of costimulatory molecules and proinflammatory cytokines (IL-12p70 and TNFα) upon stimulation by TLR9 ligand CpG, while the response to LPS was less estrogen-dependent. These effects are partially explained by an estrogen-dependent regulation of TLR9 expression. BPA did not promote cDC differentiation nor activation upon TLR stimulation. Our results suggest that estrogen promotes immune responses by increasing DC activation, with a preferential effect on TLR9 over TLR4 stimulation, and highlight the influence of estrogens in DC cultures, while BPA does not mimic estrogen in the DC functions that we tested.

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IN LABORATORY GENERATION AND MATURATION OF HUMAN MONOCYTE-DERIVED DENDRITIC CELLS FOR CANCER IMMUNOTHERAPY

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2020.v12s4.40104 ◽

2020 ◽

pp. 46-52

Author(s):

KANCHAN K. MISHRA ◽

SUMIT BHARADVA ◽

MEGHNAD G. JOSHI ◽

ARVIND GULBAKE

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Gradient Centrifugation ◽

Critical Role ◽

Human Monocyte ◽

Blood Monocytes ◽

Adaptive Immune ◽

Immunodeficiency Virus ◽

Adaptive Immune Systems

Dendritic cells (DCs) play a critical role in the regulation of adaptive immune responses, furthermore they act as a bridge between the innate and the adaptive immune systems they have been ideal candidates for cell-based immunotherapy of cancers and infections in humans. The first reported trial using DCs in 1995, since they have been used in trials all over the world for several of indications, including cancer and human immunodeficiency virus infection. Generally, for in vitro experiments or for DCs vaccination monocyte-derived dendritic cells (moDCs) were generated from purified monocytes that isolated from peripheral blood by density gradient centrifugation. A variety of methods can be used for enrichment of monocytes for generation of clinical-grade DCs. Herein we summarized up to date understanding of systems and inputs used in procedures to differentiate DCs from blood monocytes in vitro.

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Downregulation of L-arginine metabolism in dendritic cells induces tolerance to exogenous antigen

International Journal of Immunopathology and Pharmacology ◽

10.1177/0394632016678873 ◽

2017 ◽

Vol 30 (1) ◽

pp. 44-57 ◽

Cited By ~ 10

Author(s):

Patricia U Simioni ◽

Luis GR Fernandes ◽

Wirla MSC Tamashiro

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Immune Responses ◽

Adoptive Transfer ◽

Arginine Metabolism ◽

Exogenous Antigen ◽

Microbial Products ◽

Oxide Synthase ◽

Important Therapeutic Target

Dendritic cells (DC) are potential tools for therapeutic applications and several strategies to generate tolerogenic DCs are under investigation. When activated by cytokines and microbial products, DCs express mediators that modulate immune responses. In this regard, the metabolites generated by the activities of inducible nitric oxide synthase (iNOS) and arginase in DCs seem to play important roles. Here, we evaluated the effects of adoptive transfer of DCs generated in vitro from bone marrow precursors (BMDC) modulated with L-NAME (Nω-nitro-L-arginine methyl ester) and NOHA (NG-Hydroxy-L-arginine), inhibitors of iNOS and arginase, respectively, upon the immune response of the wild type (BALB/c) and OVA-TCR transgenic (DO11.10) mice. The modulation with L-NAME increased CD86 expression in BMDC, whereas treatment with NOHA increased both CD80 and CD86 expression. Adoptive transfer of either L-NAME- or NOHA-modulated BMDCs to BALB/c mice reduced the plasma levels of ovalbumin-specific antibody as well as proliferation and cytokine secretion in cultures of spleen cells in comparison adoptive transfer of non-modulated DCs. Conversely, transfer of both modulated and non-modulated BMDCs had no effect on immune response of DO11.10 mice. Together, these results show that the treatment with iNOS and Arg inhibitors leads to increased expression of co-stimulatory molecules in DCs, and provides evidences that L-arginine metabolism may be an important therapeutic target for modulating immune responses in inflammatory disorders.

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Influence of Epinastine Hydrochloride, an -Receptor Antagonist, on the Function of Mite Allergen-Pulsed Murine Bone Marrow-Derived Dendritic Cells In Vitro and In Vivo

Mediators of Inflammation ◽

10.1155/2009/738038 ◽

2009 ◽

Vol 2009 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Ken-Zaburo Oshima ◽

Kazuhito Asano ◽

Ken-Ichi Kanai ◽

Miyuki Suzuki ◽

Harumi Suzaki

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Immune Responses ◽

Clinical Status ◽

Mouse Bone Marrow ◽

Dc Functions ◽

Receptor Antagonists ◽

Murine Bone Marrow

There is established concept that dendritic cells (DCs) play essential roles in the development of allergic immune responses. However, the influence of receptor antagonists on DC functions is not well defined. The aim of the present study was to examine the effect of epinastine hydrochloride (EP), the most notable histamine receptor antagonists in Japan, onDermatophagoides farinae (Der f)-pulsed mouse bone marrow-derived DCs in vitro and in vivo. EP at more than 25 ng/mL could significantly inhibit the production of IL-6, TNF- and IL-10 fromDer f-pulsed DCs, which was increased byDer fchallenge in vitro. On the other hand, EP increased the ability ofDer f-pulsed DCs to produce IL-12. Intranasal instillation ofDer f-pulsed DCs resulted in nasal eosinophilia associated with a significant increase in IL-5 levels in nasal lavage fluids.Der f-pulsed and EP-treated DCs significantly inhibited nasal eosinophila and reduced IL-5. These results indicate that EP inhibits the development of Th2 immune responses through the modulation of DC functions and results in favorable modification of clinical status of allergic diseases.

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CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

Journal of Experimental Medicine ◽

10.1084/jem.20030654 ◽

2003 ◽

Vol 198 (2) ◽

pp. 259-266 ◽

Cited By ~ 169

Author(s):

Guillaume Oldenhove ◽

Magali de Heusch ◽

Georgette Urbain-Vansanten ◽

Jacques Urbain ◽

Charlie Maliszewski ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Peripheral Tolerance ◽

T Helper Cell ◽

Helper Cell ◽

T Helper

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

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Chronic and Acute Alcohol Exposure Prevents Monocyte-Derived Dendritic Cells from Differentiating and Maturing

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463200802100417 ◽

2008 ◽

Vol 21 (4) ◽

pp. 929-939 ◽

Cited By ~ 10

Author(s):

B. Buttari ◽

E. Profumo ◽

R. Mancinelli ◽

U. Cesta Incani ◽

M.E. Tosti ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Healthy Subjects ◽

Alcohol Exposure ◽

Hla Dr ◽

Maturation In Vitro ◽

Tnf Α ◽

Human Dendritic Cells ◽

And Control

Increasing evidence suggests that alcohol abuse may be linked to adverse immunomodulatory effects on immune responses. Our study was undertaken to clarify the immunological consequences of chronic and acute alcohol exposure on differentiation and maturation of human dendritic cells (DCs). Using immunochemical and cytofluorimetric analysis we determined the phenotype and functions of monocyte-derived DCs from alcoholics and healthy subjects and analyzed their ability to respond to lipopolysaccharide (LPS) in the presence or absence of ethanol (EtOH) exposure. Our results showed that alcoholics' monocytes differentiated to immature DCs with altered phenotype and functions (alc-iDCs). Alc-iDCs showed fewer CD1a+ cells, weaker CD86 expression and higher HLA-DR expression associated with lower endocytosis and allostimulatory functions than iDCs from healthy subjects (control-iDCs). Despite these impairments, alc-iDCs produced TNF-α and IL-6 in large amounts. LPS stimulation failed to induce full phenotypical and functional alc-iDC maturation. In vitro acute EtOH exposure also prevented alc-iDCs and control-iDCs from maturing in response to LPS. T-cell priming experiments showed that EtOH treatment prevented LPS-stimulated control-iDCs from priming and polarizing naïve allogeneic T cells into Th1 cells, thus favouring a predominant Th2 environment. Collectively, our results provide evidence that chronic and acute alcohol exposure prevents DCs from differentiating and maturing in response to a microbial stimulus.

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Malaria Blood Stage Suppression of Liver Stage Immunity by Dendritic Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021072 ◽

2003 ◽

Vol 197 (2) ◽

pp. 143-151 ◽

Cited By ~ 168

Author(s):

Carlos Ocaña-Morgner ◽

Maria M. Mota ◽

Ana Rodriguez

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Cd8 T Cell ◽

Blood Stage ◽

Liver Stage ◽

Cell Responses ◽

Blood Stage Infection ◽

Stage Infection

Malaria starts with Plasmodium sporozoites infection of the host's liver, where development into blood stage parasites occurs. It is not clear why natural infections do not induce protection against the initial liver stage and generate low CD8+ T cell responses. Using a rodent malaria model, we show that Plasmodium blood stage infection suppresses CD8+ T cell immune responses that were induced against the initial liver stage. Blood stage Plasmodium affects dendritic cell (DC) functions, inhibiting maturation and the capacity to initiate immune responses and inverting the interleukin (IL)-12/IL-10 secretion pattern. The interaction of blood stage parasites with DCs induces the secretion of soluble factors that inhibit the activation of CD8+ T cells in vitro and the suppression of protective CD8+ T cell responses against the liver stage in vivo. We propose that blood stage infection induces DCs to suppress CD8+ T cell responses in natural malaria infections. This evasion mechanism leaves the host unprotected against reinfection by inhibiting the immune response against the initial liver stage of the disease.

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Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity

Journal of Immunology Research ◽

10.1155/2016/5134329 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Sandra Winning ◽

Joachim Fandrey

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Adaptive Immune Response ◽

Mature Dendritic Cell ◽

Innate And Adaptive Immunity ◽

Cell Functions ◽

Adaptive Immune ◽

Oxygen Shortage

Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to linkin vitroresults to actualin vivostudies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity.

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Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ–resident dendritic cells

Journal of Experimental Medicine ◽

10.1084/jem.20121103 ◽

2013 ◽

Vol 210 (5) ◽

pp. 1035-1047 ◽

Cited By ~ 163

Author(s):

Elodie Segura ◽

Mélanie Durand ◽

Sebastian Amigorena

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Lymphoid Organ ◽

Lymphoid Organs ◽

Endocytic Pathway ◽

Soluble Antigen ◽

Cross Presentation ◽

Antigen Presenting ◽

Secondary Lymphoid Organs

Dendritic cells (DCs) represent a heterogeneous population of antigen-presenting cells that initiate and orient immune responses in secondary lymphoid organs. In mice, lymphoid organ–resident CD8+ DCs are specialized at cross-presentation and have developed specific adaptations of their endocytic pathway (high pH, low degradation, and high export to the cytosol). In humans, blood BDCA3+ DCs were recently shown to be the homologues of mouse CD8+ DCs. They were also proposed to cross-present antigens more efficiently than other blood DC subsets after in vitro activation, suggesting that in humans cross-presentation is restricted to certain DC subsets. The DCs that cross-present antigen physiologically, however, are the ones present in lymphoid organs. Here, we show that freshly isolated tonsil-resident BDCA1+ DCs, BDCA3+ DCs, and pDCs all cross-present soluble antigen efficiently, as compared to macrophages, in the absence of activation. In addition, BDCA1+ and BDCA3+ DCs display similar phagosomal pH and similar production of reactive oxygen species in their phagosomes. All three DC subsets, in contrast to macrophages, also efficiently export internalized proteins to the cytosol. We conclude that all freshly isolated lymphoid organ–resident human DCs, but not macrophages, display high intrinsic cross-presentation capacity.

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