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See detailEffect of a CpG-ODN on the innate immune system of the horse: an in-vivo trial
Tosi, Irène ULg; Pirottin, Dimitri ULg; Fievez, Laurence ULg et al

Poster (2015, October 16)

Oligodeoxynucleotides containing cytosine-phosphate-guanosine motifs (CpG-ODN) represent a class of agonists of Toll-like Receptor 9 (TLR9). TLR9 activation induces the secretion of cytokines and the ... [more ▼]

Oligodeoxynucleotides containing cytosine-phosphate-guanosine motifs (CpG-ODN) represent a class of agonists of Toll-like Receptor 9 (TLR9). TLR9 activation induces the secretion of cytokines and the maturation of immune cells, thus initiating both innate and adaptive immune responses. Therefore, CpG-ODN has been investigated in different species as a potential immune-modulator targeting infectious, allergic and neoplastic diseases. It has been administered by nebulisation to RAO-affected horses with promising results. Nonetheless, there is no in-vivo study on the effect of CpG administered systemically to the horse. Therefore, we tested the effect of CpG, given by intramuscular injection, on the equine immune response. Eight horses were used for this study. Five mg/horse were injected to 4 horses at D0 and D7; the other horses received a placebo (PBS). Blood was collected 2 days prior to each injection, then regularly up to D21. A clinical exam was realised daily. Laboratory analyses included haematology, ELISA tests for IFN-alpha, IFN-gamma, TNF-alpha and IL-10 and cytometry analyses for MCHII and CD86 expressions on B-lymphocytes. A cross-over of the 2 groups was realised after 2 months of washout. CpG was well tolerated. Significant transient eosinopenia, monocytosis and leukopenia were observed after CpG injection, while ELISA and cytometry analyses did not reveal any significant modification. This trial represents the first in-vivo study where CpG is administered systemically to healthy horses. Further studies are needed to adjust the dose, the formulation and the sampling schedule and to fully investigate this molecule as potentiel modulator of the equine immune system. [less ▲]

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See detailGeneration of a soluble recombinant trimeric form of bovine CD40L and its potential use as a vaccine adjuvant in cows
Pujol, Julien ULg; Bouillenne, Fabrice ULg; Farnir, Frédéric ULg et al

in Veterinary immunology and immunopathology (2015), 168(1), 1-13

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See detailAntigen presenting cell-derived IL-6 restricts Th2-cell differentiation.
Mayer, Alice; Debuisson, Delphine; Denanglaire, Sebastien et al

in European Journal of Immunology (2014), 44(11), 3252-62

The identification of DC-derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific ... [more ▼]

The identification of DC-derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen-loaded, IL-6-deficient DCs to naive mice induced an exacerbated Th2 response, characterized by the differentiation of GATA-3-expressing T lymphocytes secreting high levels of IL-4, IL-5, and IL-13. Coinjection of wild type and IL-6-deficient bone marrow-derived dendritic cells (BMDCs) confirmed that IL-6 exerted a dominant, negative influence on Th2-cell development. This finding was confirmed in vitro, where exogenously added IL-6 was found to limit IL-4-induced Th2-cell differentiation. iNKT cells were required for optimal Th2-cell differentiation in vivo although their activation occurred independently of IL-6 secretion by the BMDCs. Collectively, these observations identify IL-6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity. [less ▲]

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See detailCytokine and transcription factor expression by Aspergillus fumigatus-stimulated peripheral blood mononuclear cells in dogs with sino-nasal aspergillosis
Vanherberghen, Morgane; Bureau, Fabrice ULg; Peters, I.R. et al

in Veterinary Immunology and Immunopathology (2013), 154(3-4), 111-20

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See detailMyeloid Hif1alpha counteracts allergic airway sensitization in mice through macrophage-mediated immunoregulation
Toussaint, Marie ULg; Fievez, Laurence ULg; Drion, Pierre ULg et al

in Abstract book of Keystone Symposium "Myeloid Cells: Regulation and Inflammation" (2013)

Hypoxia Inducible Factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid ... [more ▼]

Hypoxia Inducible Factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. In contrast, we observed that mice conditionally deficient for Hif1alpha in myeloid cells display enhanced sensitivity to the development of airway allergy to the experimental allergen ovalbumin as well as to house dust mite antigens. Following allergen exposure, these mice indeed developed enhanced allergen-specific T cell responses due to augmented activation of lung dendritic cells. Further analyses supported the idea that upon allergen exposure, MyD88-dependent upregulation of Hif1alpha boosts the expression of the immunosuppressive cytokine Interleukin (IL)-10 by lung interstitial macrophages. Interstitial macrophage-derived IL-10 in turn counteracts allergen-induced lung dendritic cell activation, consequently preventing the development of allergen-specific T cell responses. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1alpha possesses immunoregulatory functions implicated in the prevention of airway allergy. [less ▲]

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See detailMyeloid hypoxia-inducible factor 1alpha prevents airway allergy in mice through macrophage-mediated immunoregulation
Toussaint, Marie ULg; Fievez, Laurence ULg; Drion, Pierre ULg et al

in Mucosal Immunology (2013), 6(3), 485-97

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid ... [more ▼]

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. By contrast, we report here that mice conditionally deficient for Hif1alpha in myeloid cells display enhanced sensitivity to the development of airway allergy to experimental allergens and house-dust mite antigens. We support that upon allergen exposure, MyD88-dependent upregulation of Hif1alpha boosts the expression of the immunosuppressive cytokine interleukin (IL)-10 by lung interstitial macrophages (IMs). Hif1alpha-dependent IL-10 secretion is required for IMs to block allergen-induced dendritic cell activation and consequently for preventing the development of allergen-specific T-helper cell responses upon allergen exposure. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1alpha possesses immunoregulatory functions implicated in the prevention of airway allergy. [less ▲]

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See detailSirtuin inhibition attenuates the production of inflammatory cytokines in lipopolysaccharide-stimulated macrophages.
Fernandes, Claudia A.; Fievez, Laurence ULg; Neyrinck, Audrey M. et al

in Biochemical and Biophysical Research Communications (2012), 420(4), 857-861

In several inflammatory conditions such as rheumatoid arthritis or sepsis, the regulatory mechanisms of inflammation are inefficient and the excessive inflammatory response leads to damage to the host ... [more ▼]

In several inflammatory conditions such as rheumatoid arthritis or sepsis, the regulatory mechanisms of inflammation are inefficient and the excessive inflammatory response leads to damage to the host. Sirtuins are class III histone deacetylases that modulate the activity of several transcription factors that are implicated in immune responses. In this study, we evaluated the impact of sirtuin inhibition on the activation of lipopolysaccharide (LPS)-stimulated J774 macrophages by assessing the production of inflammatory cytokines. The pharmacologic inhibition of sirtuins decreased the production of tumour necrosis factor-alpha (TNF-alpha) interleukin 6 (IL-6) and Rantes. The reduction of cytokine production was associated with decreased nuclear factor kappa B (NF-kappaB) activity and inhibitor kappa B alpha (IkappaBalpha) phosphorylation while no impact was observed on the phosphorylation status of p38 mitogen-activated kinase (p38 MAPK). This work shows that sirtuin pharmacologic inhibitors are a promising tool for the treatment of inflammatory conditions. [less ▲]

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See detailIncreased hypoxia-inducible factor 1alpha expression in lung cells of horses with recurrent airway obstruction.
Toussaint, Marie ULg; Fievez, Laurence ULg; Desmet, Christophe ULg et al

in BMC Veterinary Research (2012), 8(1), 64

ABSTRACT: BACKGROUND: Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological ... [more ▼]

ABSTRACT: BACKGROUND: Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-alpha in myeloid cells in horse with recurrent airway obstruction. RESULTS: In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-alpha mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-alpha mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction. CONCLUSION: Taken together, our results suggest an important role for Hif1-alpha in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO. [less ▲]

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See detailMyeloid HIF-1alpha prevents airway allergy in mice by promoting macrophage-mediated immunosuppression
Toussaint, Marie ULg; Fievez, Laurence ULg; Lekeux, Pierre ULg et al

in Proceedings of the 1st Scientific Meeting of the Faculty of Veterinary Medicine (2011, December 09)

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See detailSirtuin 1 Promotes Th2 Responses and Airway Allergy by Repressing Peroxisome Proliferator-Activated Receptor-γ Activity in Dendritic Cells
Legutko, Agnieszka; Marichal, Thomas ULg; Fievez, Laurence ULg et al

in Journal of Immunology (2011), 187(9), 4517-4529

Sirtuins are a unique class of NAD+-dependent deacetylases that regulate diverse biological functions such as aging, metabolism, and stress resistance. Recently, it has been shown that sirtuins may have ... [more ▼]

Sirtuins are a unique class of NAD+-dependent deacetylases that regulate diverse biological functions such as aging, metabolism, and stress resistance. Recently, it has been shown that sirtuins may have anti-inflammatory activities by inhibiting proinflammatory transcription factors such as NF-κB. In contrast, we report in this study that pharmacological inhibition of sirtuins dampens adaptive Th2 responses and subsequent allergic inflammation by interfering with lung dendritic cell (DC) function in a mouse model of airway allergy. Using genetic engineering, we demonstrate that sirtuin 1 represses the activity of the nuclear receptor peroxisome proliferator-activated receptor-γ in DCs, thereby favoring their maturation toward a pro-Th2 phenotype. This study reveals a previously unappreciated function of sirtuin 1 in the regulation of DC function and Th2 responses, thus shedding new light on our current knowledge on the regulation of inflammatory processes by sirtuins. [less ▲]

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See detailNicotinamide enhances apoptosis of G(M)-CSF-treated neutrophils and attenuates endotoxin-induced airway inflammation in mice.
Fernandes, Claudia A.; Fievez, Laurence ULg; Ucakar, Bernard et al

in American journal of physiology. Lung cellular and molecular physiology (2011), 300(3), 354-61

Neutrophils constitute the first line of host defense against invading microorganisms. Yet their removal from the inflammatory environment is fundamental for injury restraint and resolution of ... [more ▼]

Neutrophils constitute the first line of host defense against invading microorganisms. Yet their removal from the inflammatory environment is fundamental for injury restraint and resolution of inflammation. Nicotinamide, a component of vitamin B(3), is known to modulate cell survival. In this study, we assessed the influence of nicotinamide on neutrophil apoptosis, both in vitro and in vivo in a mouse model of endotoxin-induced lung inflammation. In vitro, nicotinamide promoted apoptosis of human blood neutrophils in a dose-dependent manner in the presence of the apoptosis inhibitors granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor. The highest concentration of nicotinamide completely neutralized the pro-survival effect of granulocyte (macrophage) colony-stimulating factor. Nicotinamide proapoptotic effect was associated with enhanced caspase-3 activity. In addition, nicotinamide slightly reduced neutrophil chemotaxis in vitro. In vivo, pulmonary nicotinamide delivery decreased the levels of cellular and biochemical inflammation markers and increased the percentage of apoptotic neutrophils in bronchoalveolar lavages. Our findings suggest that nicotinamide is an apoptotic stimulus for neutrophils, thereby contributing to the resolution of neutrophilic inflammation in the lungs. [less ▲]

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See detailEffects of formoterol and ipratropium bromide on repeated cadmium inhalation -induced pulmonary inflammation and emphysema in rats
Zhang, Whenhui; Fievez, Laurence ULg; Zhang, F. et al

in European Journal of Pharmacology (2010), 25(647), 178-187

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See detailCharacterization of pentraxin 3 in the horse and its expression in airways.
Ramery, Eve ULg; Fievez, Laurence ULg; Fraipont, Audrey ULg et al

in Veterinary Research (2010), 41(2), 18

The long pentraxin 3 (PTX3) plays an important role in host defence and its over-expression may contribute to airway injury. The aim of the present study was therefore to characterize in more detail PTX3 ... [more ▼]

The long pentraxin 3 (PTX3) plays an important role in host defence and its over-expression may contribute to airway injury. The aim of the present study was therefore to characterize in more detail PTX3 and its expression in the horses airway. Six healthy horses and six horses affected by recurrent airway obstruction (R.A.O.) were submitted to a dusty environment challenge. PTX3 DNA and cDNA were cloned and sequenced. PTX3 expression was evaluated by RT-qPCR, western blotting and immuno-histochemistry in bronchoalveolar lavage fluid (BALF) cells, BALF supernatant and bronchial epithelial cells. An alternative splicing of the second exon of PTX3 occurred, resulting in two forms of the protein: spliced (32 kDa) and full length (42 kDa). PTX3 was detected in BALF macrophages, neutrophils and bronchial epithelial cells. It was over-expressed in the BALF supernatant from R.A.O.-affected horses in crisis. However, dust was unable to induce PTX3 in BALF cells ex vivo, indicating that dust is an indirect inducer of PTX3. Dust exposure in-vivo induced PTX3 in BALF macrophages but there was no significant difference between healthy and R.A.O.-affected horses. Conversely, PTX3 was over-expressed in the bronchial epithelial cells from R.A.O-affected horses in crisis. These data indicate a differential regulatory mechanism in inflammatory and bronchial epithelial cells and offer therapeutically interesting perspectives. [less ▲]

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See detailSirtuin inhibition modulates endotoxin-induced lung inflammation
Fernandez, C. A.; Fievez, Laurence ULg; Bureau, Fabrice ULg et al

in Shortbook: Annual Congress of the European Respiratory Society (ERS) (2010)

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See detailEffects of ipratropium bromide on repeated cadmium inhalation-induced lune inflammation and airspace enlargement in rats
Zhang, W. H.; Fievez, Laurence ULg; Cheu, Esteban ULg et al

in Fundamental & Clinical Pharmacology (2010), 10

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