Integrase-defective lentiviral vectors encoding cytokines induce differentiation of human dendritic cells and stimulate multivalent immune responses in vitro and in vivo

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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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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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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Dendritic Cell Responses to Early Murine Cytomegalovirus Infection

Journal of Experimental Medicine ◽

10.1084/jem.20021522 ◽

2003 ◽

Vol 197 (7) ◽

pp. 885-898 ◽

Cited By ~ 272

Author(s):

Marc Dalod ◽

Tanya Hamilton ◽

Rachelle Salomon ◽

Thais P. Salazar-Mather ◽

Stanley C. Henry ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Lymphocyte Activation ◽

Murine Cytomegalovirus ◽

Cell Responses ◽

Dc Maturation

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.

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Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines

Frontiers in Immunology ◽

10.3389/fimmu.2021.786144 ◽

2022 ◽

Vol 12 ◽

Author(s):

Valentina Ceglia ◽

Sandra Zurawski ◽

Monica Montes ◽

Mitchell Kroll ◽

Aurélie Bouteau ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Class I ◽

Agonist Activity ◽

Cell Immunity ◽

Hiv 1

CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses in vitro and in vivo. In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8+ T cells versus CD4+ T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4+ T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were in vitro skewing responses towards CD8+ T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4+ T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.

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Sorafenib but not sunitinib affects the induction of immune responses

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3504 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3504-3504 ◽

Cited By ~ 4

Author(s):

M. M. Hipp ◽

N. Hilf ◽

S. Walter ◽

D. Werth ◽

L. Kanz ◽

...

Keyword(s):

Immune Responses ◽

Map Kinases ◽

Kinase Inhibitors ◽

Cell Cancer ◽

Inhibitory Effects ◽

Discontinuation Of Treatment ◽

Interesting Compound ◽

Human Dendritic Cells

3504 Background: The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are approved for the treatment of patients with metastatic renal cell cancer. To analyze the possible use of these compounds in combination with immunotherapeutic approaches we investigated the effects of both TKIs on function of human dendritic cells (DCs) and induction of primary immune responses in vitro and in vivo. Methods: Human monocytes-derived DCs were treated with DMSO, sorafenib or sunitinib. Functional and phenotypic analyses as well as the possible impact on signal transduction pathways were performed. Furthermore, induction of immune responses in vivo was analyzed in animals treated with both compounds. Results: Sorafenib but not sunitinib inhibits function of DCs. Exposure of DCs to sorafenib reduces expression of CD1a, MHC and costimulatory molecules in response to stimuli via TLR ligands. Sorafenib reduces cytokine production by DCs as well as their ability to migrate and stimulate T cell (TC) responses. We found that these inhibitory effects of sorafenib are mediated via inhibition of PI3K, MAP kinases and NFκB signaling. The TKIs have no influence on phenotype and proliferation of TCs. To analyze the effects of TKIs on the generation of immune responses in vivo, induction of TC responses was assessed by peptide vaccination with the model antigen OVA-001 in C57BL/6 mice. When mice were pretreated with both TKIs which were also given during vaccination, it was observed that sorafenib, but not sunitinib significantly reduces the generation of vaccine-specific CD8+ TCs. Numbers of CD4+ CD25+ regulatory TCs are reduced in sunitinib-treated mice, but not in sorafenib-treated animals. All effects of the TKIs are reversible, and the immune responses go back to normal levels if mice are immunized after discontinuation of treatment. Conclusions: In summary, sunitinib represents an interesting compound to be used in combination with immunotherapeutic approaches to treat cancer patients. No significant financial relationships to disclose.

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MHC Class I+/II− Dendritic Cells Induce Hapten-Specific Immune Responses In Vitro and In Vivo

Journal of Investigative Dermatology ◽

10.1111/1523-1747.ep12337508 ◽

1997 ◽

Vol 109 (4) ◽

pp. 580-585 ◽

Cited By ~ 21

Author(s):

Andrea Kolesaric ◽

Georg Stingl ◽

Adelheid Elbe-Bürger

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Mhc Class I ◽

Class I

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