Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Sébastien Fleury is active.

Publication


Featured researches published by Sébastien Fleury.


Nature Medicine | 2008

Breast milk–mediated transfer of an antigen induces tolerance and protection from allergic asthma

Valérie Verhasselt; Valérie Milcent; Julie Cazareth; Akira Kanda; Sébastien Fleury; David Dombrowicz; Nicolas Glaichenhaus; Valérie Julia

Allergic asthma is a chronic disease characterized by airway obstruction in response to allergen exposure. It results from an inappropriate T helper type 2 response to environmental airborne antigens and affects 300 million individuals. Its prevalence has increased markedly in recent decades, most probably as a result of changes in environmental factors. Exposure to environmental antigens during infancy is crucial to the development of asthma. Epidemiological studies on the relationship between breastfeeding and allergic diseases have reached conflicting results. Here, we have investigated whether the exposure of lactating mice to an airborne allergen affects asthma development in progeny. We found that airborne antigens were efficiently transferred from the mother to the neonate through milk and that tolerance induction did not require the transfer of immunoglobulins. Breastfeeding-induced tolerance relied on the presence of transforming growth factor (TGF)-β during lactation, was mediated by regulatory CD4+ T lymphocytes and depended on TGF-β signaling in T cells. In conclusion, breast milk–mediated transfer of an antigen to the neonate resulted in oral tolerance induction leading to antigen-specific protection from allergic airway disease. This study may pave the way for the design of new strategies to prevent the development of allergic diseases.


Mucosal Immunology | 2010

Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development.

E Mosconi; A Rekima; B Seitz-Polski; Akira Kanda; Sébastien Fleury; E Tissandie; R Monteiro; David Dombrowicz; Valérie Julia; Nicolas Glaichenhaus; Valérie Verhasselt

Allergic asthma is a chronic lung disease resulting from an inappropriate T helper (Th)-2 response to environmental antigens. Early tolerance induction is an attractive approach for primary prevention of asthma. Here, we found that breastfeeding by antigen-sensitized mothers exposed to antigen aerosols during lactation induced a robust and long-lasting antigen-specific protection from asthma. Protection was more profound and persistent than the one induced by antigen-exposed non-sensitized mothers. Milk from antigen-exposed sensitized mothers contained antigen-immunoglobulin (Ig) G immune complexes that were transferred to the newborn through the neonatal Fc receptor resulting in the induction of antigen-specific FoxP3+ CD25+ regulatory T cells. The induction of oral tolerance by milk immune complexes did not require the presence of transforming growth factor-β in milk in contrast to tolerance induced by milk-borne free antigen. Furthermore, neither the presence of IgA in milk nor the expression of the inhibitory FcγRIIb in the newborn was required for tolerance induction. This study provides new insights on the mechanisms of tolerance induction in neonates and highlights that IgG immune complexes found in breast milk are potent inducers of oral tolerance. These observations may pave the way for the identification of key factors for primary prevention of immune-mediated diseases such as asthma.


Mucosal Immunology | 2011

The oral administration of bacterial extracts prevents asthma via the recruitment of regulatory T cells to the airways

Severine Navarro; G Cossalter; C Chiavaroli; Akira Kanda; Sébastien Fleury; A Lazzari; Julie Cazareth; Tim Sparwasser; David Dombrowicz; Nicolas Glaichenhaus; Valérie Julia

The prevalence of asthma has steadily increased during the last decade, probably as the result of changes in the environment, including reduced microbial exposure during infancy. Accordingly, experimental studies have shown that deliberate infections with live pathogens prevent the development of allergic airway diseases in mice. Bacterial extracts are currently used in children suffering from repeated upper respiratory tract infections. In the present study, we have investigated whether bacterial extracts, commercially available as Broncho-Vaxom (BV), could prevent allergic airway disease in mice. Oral treatment with BV suppressed airway inflammation through interleukin-10 (IL-10)-dependent and MyD88 (myeloid differentiation primary response gene (88))-dependent mechanisms and induced the conversion of FoxP3 (forkhead box P3)− T cells into FoxP3+ regulatory T cells. Furthermore, CD4+ T cells purified from the trachea of BV-treated mice conferred protection against airway inflammation when adoptively transferred into sensitized mice. Therefore, treatment with BV could possibly be a safe and efficient strategy to prevent the development of allergic diseases in children.


The Journal of Allergy and Clinical Immunology | 2008

Peroxisome proliferator-activated receptor α regulates skin inflammation and humoral response in atopic dermatitis

Delphine Staumont-Sallé; Georges Abboud; Céline Brénuchon; Akira Kanda; Thomas Roumier; Céline Lavogiez; Sébastien Fleury; Patrick Rémy; Jean-Paul Papin; Justine Bertrand-Michel; François Tercé; Bart Staels; E. Delaporte; Monique Capron; David Dombrowicz

BACKGROUND The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma are ligand-activated transcription factors belonging to the nuclear receptor superfamily. In addition to their regulatory role on lipid and glucose metabolism, they exert anti-inflammatory properties. In skin both PPAR-alpha and PPAR-beta/delta regulate keratinocyte proliferation/differentiation and contribute to wound healing. The 3 PPAR isoforms are expressed by several cell types recruited into the dermis during inflammation. OBJECTIVE We have investigated the role of PPAR-alpha in the regulation of atopic dermatitis (AD), a common skin inflammatory disease. METHODS We chose a mouse model of inflammatory dermatosis with immunologic features of AD and used epicutaneous sensitization with ovalbumin in the absence of adjuvant, which mimics the human pathology. RESULTS On antigen sensitization, PPAR-alpha-deficient mice display increased epidermal thickening, dermal recruitment of inflammatory cells, lung inflammation, airway hyperresponsiveness, and IgE and IgG2a production compared with their wild-type counterparts. Increased inflammation was correlated to an enhancement of TH2 and, to a greater extent, TH1 responses and to increased skin expression of nuclear factor kappaB. Interestingly, PPAR-alpha expression was decreased in eczematous skin from patients with AD compared with skin from nonatopic donors, suggesting that defective PPAR-alpha expression might contribute to the pathology. Topical application of WY14643, a specific PPAR-alpha agonist, significantly decreased antigen-induced skin inflammation in the AD model. CONCLUSION PPAR-alpha acts as a negative regulator of skin inflammation in AD.


The Journal of Allergy and Clinical Immunology | 2009

Eosinophil-derived IFN-γ induces airway hyperresponsiveness and lung inflammation in the absence of lymphocytes

Akira Kanda; Virginie Driss; Nicolas Hornez; Marwan Abdallah; Thomas Roumier; Georges Abboud; Fanny Legrand; Delphine Staumont-Sallé; Severine Quéant; Julie Bertout; Sébastien Fleury; Patrick Rémy; Jean-Paul Papin; Valérie Julia; Monique Capron; David Dombrowicz

BACKGROUND Eosinophils are key players in T(H)2-driven pathologies, such as allergic lung inflammation. After IL-5- and eotaxin-mediated tissue recruitment, they release several cytotoxic and inflammatory mediators. However, their exact contribution to asthma remains controversial. Indeed, in human subjects anti-IL-5 treatment inhibits eosinophilia but not antigen-induced airway hyperresponsiveness (AHR). Likewise, lung fibrosis is abrogated in 2 strains of eosinophil-deficient mice, whereas AHR is inhibited in only one of them. Finally, eosinophils have been shown to attract T(H)2 lymphocytes at the inflammatory site. OBJECTIVE The ability of eosinophils to promote AHR and lung inflammation independently of lymphocytes was investigated. METHODS Adoptive transfers of resting or activated eosinophils from IL-5 transgenic mice were performed into naive BALB/c mice, mice with severe combined immunodeficiency, and IFN-gamma-deficient BALB/c recipients. RESULTS Adoptively transferred eosinophils induced lung inflammation, fibrosis, collagen deposition, and AHR not only in BALB/c mice but also in recipient mice with severe combined immunodeficiency. Surprisingly, IFN-gamma expression was increased in lungs from eosinophil-transferred animals. Furthermore, IFN-gamma neutralization in recipients partially inhibited eosinophil-induced AHR. Moreover, IFN-gamma-deficient eosinophils or eosinophils treated with a blocking anti-IFN-gamma receptor antibody failed to induce AHR in IFN-gamma-deficient recipients. Finally, in vitro and at low concentrations, IFN-gamma increased eosinophil peroxidase release, potentiated chemotaxis, and prolonged survival, suggesting the existence of an autocrine mechanism. CONCLUSIONS These results support the important and previously unsuspected contribution of eosinophils to lung inflammation independently of lymphocytes through production of IFN-gamma, the prototypical T(H)1 cytokine.


Blood | 2011

p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages.

Céline Cudejko; Kristiaan Wouters; Lucía Fuentes; Sarah Anissa Hannou; Charlotte Paquet; Kadiombo Bantubungi; Emmanuel Bouchaert; Jonathan Vanhoutte; Sébastien Fleury; Patrick Rémy; Anne Tailleux; Giulia Chinetti; David Dombrowicz; Bart Staels; Réjane Paumelle

The CDKN2A locus, which contains the tumor suppressor gene p16(INK4a), is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMϕ) or alternatively (AAMϕ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16(INK4a) deficiency (p16(-/-)) modulates the macrophage phenotype. Transcriptome analysis revealed that p16(-/-) BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4-induced macrophage polarization. In line with this observation, p16(-/-) BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16(-/-) BM displayed higher hepatic AAMϕ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMϕ phenotype skewing. Surprisingly, p16(-/-) BMDMs did not display increased IL-4-induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)-induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16(INK4a) as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.


The Journal of Allergy and Clinical Immunology | 2008

A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally

Elsa Mazuc; Bruno O. Villoutreix; Odile Malbec; Thomas Roumier; Sébastien Fleury; Jean-Paul Leonetti; David Dombrowicz; Marc Daëron; Pierre Martineau; Piona Dariavach

BACKGROUND The spleen tyrosine kinase (Syk) is recognized as a potential pharmaceutical target for the treatment of type I hypersensitivity reactions including allergic rhinitis, urticaria, asthma, and anaphylaxis because of its critical position upstream of immunoreceptor signaling complexes that regulate inflammatory responses in leukocytes. OBJECTIVE Our aim was to improve the selectivity of anti-Syk therapies by impeding the interaction of Syk with its cellular partners, instead of targeting its catalytic site. METHODS We have previously studied the inhibitory effects of the anti-Syk intracellular antibody G4G11 on Fc epsilonRI-induced release of allergic mediators. A compound collection was screened by using an antibody displacement assay to identify functional mimics of G4G11 that act as potential inhibitors of the allergic response. The effects of the selected druglike compounds on mast cell activation were evaluated in vitro and in vivo. RESULTS We discovered compound 13, a small molecule that inhibits Fc epsilonRI-induced mast cell degranulation in vitro and anaphylactic shock in vivo. Importantly, compound 13 was efficient when administered orally to mice. Structural analysis, docking, and site-directed mutagenesis allowed us to identify the binding cavity of this compound, located at the interface between the 2 Src homology 2 domains and the interdomain A of Syk. CONCLUSION We have isolated a new class of druglike compounds that modulate the interaction of Syk with some of its macromolecular substrates implicated in the degranulation pathway in mast cells.


Journal of Immunology | 2010

Regulation of Th2 Responses and Allergic Inflammation through Bystander Activation of CD8+ T Lymphocytes in Early Life

Nathalie Deruytter; Brigitte Adams; Akira Kanda; Sébastien Fleury; David Torres; Angelique Francois; Michel Petein; Michel Goldman; David Dombrowicz; Véronique Flamand

Th2-biased immune responses characterizing neonates may influence the later onset of allergic disease. The contribution of regulatory T cell populations in the prevention of Th2-driven pathologies in early life is poorly documented. We investigated the potential of CD8+ T cells stimulated at birth with alloantigens to modulate the development of allergic airway inflammation. Newborn mice were immunized with semiallogeneic splenocytes or dendritic cells (DCs) and exposed at the adult stage to OVA aeroallergens. DC-immunized animals displayed a strong Th1 and Tc1/Tc2 alloantigen-specific response and were protected against the development of the allergic reaction with reduced airway hyperresponsiveness, mucus production, eosinophilia, allergen-specific IgE and IgG1, and reduction of lung IL-4, IL-5, IL-10, and IL-13 mRNA levels. By contrast, splenocyte-immunized mice displayed a Th2 and a weak Tc2 alloantigen-specific response and were more sensitive to the development of the allergen-specific inflammation compared with mice unexposed at birth to alloantigens. DC-immunized animals displayed an important increase in the percentage of IFN-γ–producing CD8+CD44high, CD8+CD62Lhigh, and CD8+CD25+ subsets. Adoptive transfers of CD8+ T cells from semiallogeneic DC-immunized animals to adult β2m-deficient animals prevented the development of allergic response, in particular IgE, IL-4, and IL-13 mRNA production in an IFN-γ–dependent manner, whereas transfers of CD8+ T cells from semiallogeneic splenocyte-immunized mice intensified the lung IL-4 and IL-10 mRNA level and the allergen-specific IgE. These findings demonstrated that neonatal induction of regulatory CD8+ T cells was able to modulate key parameters of later allergic sensitization in a bystander manner, without recognition of MHC class I molecules.


The Journal of Allergy and Clinical Immunology | 2016

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity

Laetitia Everaere; Saliha Ait-Yahia; Olivier Molendi-Coste; Han Vorng; Sandrine Quemener; Pauline LeVu; Sébastien Fleury; Emmanuel Bouchaert; Ying Fan; Catherine Duez; Patricia de Nadai; Bart Staels; David Dombrowicz; Anne Tsicopoulos

BACKGROUND Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). OBJECTIVE We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. METHODS Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. RESULTS HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and TH2 and TH17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1β levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including TH2 and TH17 infiltration. CONCLUSION These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s.


Journal of Immunology | 2009

FcεRI and FcγRIII/CD16 Differentially Regulate Atopic Dermatitis in Mice

Georges Abboud; Delphine Staumont-Sallé; Akira Kanda; Thomas Roumier; Nathalie Deruytter; Céline Lavogiez; Sébastien Fleury; Patrick Rémy; Jean-Paul Papin; Monique Capron; David Dombrowicz

The high-affinity IgE receptor FcεRI and, in some models, the low-affinity IgG receptor FcγRIII/CD16 play an essential role in allergic diseases. In human skin, they are present on APCs and effector cells recruited into the inflamed dermis. FcRγ is a subunit shared, among other FcRs, by FcεRI and CD16 and is essential to their assembly and signal transduction. Using an experimental model reproducing some features of human atopic dermatitis and specific FcR-deficient mice, we have herein delineated the respective contribution of FcεRI and FcγRIII/CD16 to the pathology. We demonstrate that symptoms of atopic dermatitis are completely absent in FcRγ-deficient animals but only partially inhibited in either FcεRI- or FcγRIII/CD16-deficient animals. Absence or attenuation of the pathology is correlated to increased skin expression of regulatory IL-10 and Foxp3. While FcεRI controls both Th1 and Th2 skin response, mast cell recruitment into draining lymph nodes and IgE production, CD16 regulates only Th2 skin response, as well as T cell proliferation and IgG1 production. This isotype-specific regulation by the cognate FcR is associated to a differential regulation of IL-4 and IL-21 expression in the draining lymph nodes. FcεRI and CD16 thus contribute to atopic dermatitis but differentially regulate immune responses associated with the disease. Targeting both IgE/FcεRI and IgG/CD16 interactions might represent an efficient therapeutic strategy for allergic diseases.

Collaboration


Dive into the Sébastien Fleury's collaboration.

Top Co-Authors

Avatar

David Dombrowicz

French Institute of Health and Medical Research

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge