CCL18 et réponse régulatrice, de la situation physiologique à l'atopie

Chemokines are a key component of homeostatic cell traffic and involved in pathological situations. In addition to this chemotactic function, specific to these molecules, they have been recently assigned an involvement in specific adaptive response polarization, by acting directly on T cells (T Lc) or indirectly through dendritic cells (DC). CCL18 is a chemokine preferentially expressed in lung and lymph nodes, able to attract DCs and T Lc, induced by Th2 cytokines such as IL-4, IL-13 but also by the immunomodulatory cytokine IL-10, and its receptor is still unknown. In our laboratory it was shown an involvement of CCL18 in allergic asthma (de Nadai, JI, 2006), and this chemokine has also been associated with various pathologies without areal clear described role. The purpose of this work was to evaluate the immune effect of CCL18 at baseline and in atopic situation. The direct effect of CCL18 was evaluated on T cell polarization. Pretreatment of memory T cells CD4+CD25-, from non allergic subjects, with CCL18 led to their switch to regulatory CD4+CD25+ Foxp3+ cells, able to produce IL-10 and TGF-b and inhibit effectors T cell proliferation, by a contact and cytokine dependent mechanism. However, this regulatory effect of CCL18 was lost when T cells were derived from allergic subjects (Chang Y et al., FASEB J, 2010). The indirect effect of CCL18 has been assessed on the immune response through DC. Monocyte, from healthy subjects, differentiated in DC with GM-CFS and CCL18 led to development of semi-mature DC, that expressed CCR7 and produced IL10 and the enzyme indoleamine 2,3-inducing dioxigenase. These cells primed regulatory Tr1 cells able to produce IL-10 and to suppress LcT effectors proliferation by a cytokine dependent mechanism. Surprisingly, when monocytes were derived from allergic patients, the tolerogenic effect of CCL18 was lost, in association with a decreased binding of CCL18 to its putative receptor (Azzaoui I and al., in revision Blood) Moreover, we have shown that CCL18 may also play a role in the resolution of the allergic reaction with a chemotactic effect, by recruitment of a subpopulation of regulatory T cells CD4+CD25highCD127lowLAP+ (Chenivesse C et al., in revision JI). The effect of corticosteroids on CCL18 expression was analyzed. These results showed that the secretion of CCL18 induced by cytokines IL-4 and IL-10 is potentiated by dexamethasone (Chabrol J et al., in preparation) which confirms the anti inflammatory role of CCL18. The last study was an approach in a murine model of allergic asthma induced by ovalbumin in mice Balb/cByJ. Intratracheal administration of recombinant CCL18 to sensitized animals, inhibits asthmatic reaction development, by decreasing pulmonary inflammation (reduced eosinophil infiltration, and inhibition of local production of Th2 cytokine) and protects them against the deterioration of their respiratory function (protection against bronchial hyperresponsiveness, and inhibition of mucus hypersecretion). However, the cellular mechanisms behind this protection appear independent of major regulatory pathways of the reaction (J Gilet et al., in preparation). All these studies show, for the first time, that a chemokine is able to induce a tolerogenic response. However, this feature is absent in allergic donors who exhibit a defect in the binding of CCL18 to its putative receptor. This may participate to the lack of tolerance response observed in allergic diseases. This data suggest that CCL18 and its putative receptor may represent therapeutic targets.Les chimiokines sont un élément essentiel du trafic cellulaire aussi bien homéostatique que dans des situations pathologiques. Outre cette fonction chimiotactique spécifique à ce type de molécules, on leur a récemment attribué une implication dans le profil de polarisation de la réponse adaptative spécifique, en agissant directement sur les lymphocytes T (Lc T) ou indirectement par le biais des cellules dendritiques (DC). CCL18 est une chimiokine exprimé préférentiellement au niveau pulmonaire et de façon moindre au niveau ganglionnaire, capable d’attirer les DC et les Lc T, elle est induite par les cytokines de type Th2 telle que l'IL-4, l'IL-13, mais aussi par la cytokine immunomodulatrice l'IL-10, son récepteur est inconnu à ce jour. Au laboratoire il a été montré une implication du CCL18 dans l’asthme allergique (de Nadai, JI, 2006), et cette chimiokine a été associée à différentes pathologies à tropisme pulmonaire ou non avec un rôle pas toujours très clair. L'objectif de ce travail a été d’étudier l’effet immunitaire de cette chimiokine, en base et en situation atopique. L'effet direct du CCL18 a été évalué sur la polarisation de la réponse T. Le prétraitement des Lc T mémoire CD4+ CD25-, de sujets non allergiques, avec le CCL18 conduit à leur transformation en Lc T régulateurs CD4+ CD25+ Foxp3+ produisant de l’IL-10 et du TGF-b capables d'inhiber la prolifération des Lc T effecteurs, à la fois par un mécanisme cytokine et contact dépendant. Cependant, cet effet de régulation de CCL18 est perdu lorsque les cellules T proviennent de sujets allergiques (Chang Y et al., FASEB J, 2010). L’effet indirect du CCL18 a été évalué sur la réponse immune via les DC. La différenciation de monocytes de sujets sains en présence de GM-SCF et CCL18 conduit au développement de DC de phénotype semi-mature, expriment le CCR7, produisant de l’IL10 et l’enzyme 2,3-indoleamine dioxigenase et induisant le développent de Lc T régulateurs de type Tr1 produisant de l’IL-10 capables d’inhiber la prolifération de Lc T effecteurs, par un mécanisme cytokine dépendant. Étonnamment, lorsque les monocytes proviennent de patients allergiques, l'effet tolérogène de CCL18 est perdu en liaison avec la diminution de la fixation de CCL18 à son récepteur putatif (Azzaoui I et al., en révision Blood). Par ailleurs, CCL18 pourrait également jouer un rôle dans la résolution de la réaction allergique par un effet chimiotactique vis-à-vis d’une sous population de LcT régulateurs CD4+CD25highCD127lowLAP+ (Chenivesse C et al., en révision JI). L'effet de corticoïdes sur l'expression de CCL18 a ensuite été analysé. Il a été montré que la sécrétion de CCL18 induite par les cytokines IL-4 et IL-10 est potentialisée par la dexaméthasone, ce qui confirme que CCL18 est plutôt une chimiokine à activité anti inflammatoire (Chabrol J et al., en préparation). La dernière étude concerne une approche dans un modèle murin d'asthme allergique, induit par l'ovalbumine chez la souris Balb/cBYJ. D'un point de vue fonctionnel, l'administration de CCL18 recombinant par voie intratrachéale à des animaux sensibilises permet d'inhiber le développement de la réaction asthmatique, en diminuant l'inflammation pulmonaire (réduction de l'infiltration éosinophilique, inhibition de la production locale de cytokines Th2) et protège ces derniers contre l'altération de leur fonction respiratoire (protection contre l'hyperréactivité bronchique, avec inhibition de l'hypersécrétion de mucus). Toutefois, les mécanismes cellulaires à l'origine de cette protection semblent indépendants de grandes voies de régulation de la réaction (Gilet J et al., en préparation). L'ensemble de ces études montre, et pour la première, qu’une chimiokine est capable d’induire le développement d’une réponse tolérogénique

CCL18 and regulatory responses from steady state to atopy

Les chimiokines sont un élément essentiel du trafic cellulaire aussi bien homéostatique que dans des situations pathologiques. Outre cette fonction chimiotactique spécifique à ce type de molécules, on leur a récemment attribué une implication dans le profil de polarisation de la réponse adaptative spécifique, en agissant directement sur les lymphocytes T (Lc T) ou indirectement par le biais des cellules dendritiques (DC). CCL18 est une chimiokine exprimé préférentiellement au niveau pulmonaire et de façon moindre au niveau ganglionnaire, capable d’attirer les DC et les Lc T, elle est induite par les cytokines de type Th2 telle que l'IL-4, l'IL-13, mais aussi par la cytokine immunomodulatrice l'IL-10, son récepteur est inconnu à ce jour. Au laboratoire il a été montré une implication du CCL18 dans l’asthme allergique (de Nadai, JI, 2006), et cette chimiokine a été associée à différentes pathologies à tropisme pulmonaire ou non avec un rôle pas toujours très clair. L'objectif de ce travail a été d’étudier l’effet immunitaire de cette chimiokine, en base et en situation atopique. L'effet direct du CCL18 a été évalué sur la polarisation de la réponse T. Le prétraitement des Lc T mémoire CD4+ CD25-, de sujets non allergiques, avec le CCL18 conduit à leur transformation en Lc T régulateurs CD4+ CD25+ Foxp3+ produisant de l’IL-10 et du TGF-b capables d'inhiber la prolifération des Lc T effecteurs, à la fois par un mécanisme cytokine et contact dépendant. Cependant, cet effet de régulation de CCL18 est perdu lorsque les cellules T proviennent de sujets allergiques (Chang Y et al., FASEB J, 2010). L’effet indirect du CCL18 a été évalué sur la réponse immune via les DC. La différenciation de monocytes de sujets sains en présence de GM-SCF et CCL18 conduit au développement de DC de phénotype semi-mature, expriment le CCR7, produisant de l’IL10 et l’enzyme 2,3-indoleamine dioxigenase et induisant le développent de Lc T régulateurs de type Tr1 produisant de l’IL-10 capables d’inhiber la prolifération de Lc T effecteurs, par un mécanisme cytokine dépendant. Étonnamment, lorsque les monocytes proviennent de patients allergiques, l'effet tolérogène de CCL18 est perdu en liaison avec la diminution de la fixation de CCL18 à son récepteur putatif (Azzaoui I et al., en révision Blood). Par ailleurs, CCL18 pourrait également jouer un rôle dans la résolution de la réaction allergique par un effet chimiotactique vis-à-vis d’une sous population de LcT régulateurs CD4+CD25highCD127lowLAP+ (Chenivesse C et al., en révision JI). L'effet de corticoïdes sur l'expression de CCL18 a ensuite été analysé. Il a été montré que la sécrétion de CCL18 induite par les cytokines IL-4 et IL-10 est potentialisée par la dexaméthasone, ce qui confirme que CCL18 est plutôt une chimiokine à activité anti inflammatoire (Chabrol J et al., en préparation). La dernière étude concerne une approche dans un modèle murin d'asthme allergique, induit par l'ovalbumine chez la souris Balb/cBYJ. D'un point de vue fonctionnel, l'administration de CCL18 recombinant par voie intratrachéale à des animaux sensibilises permet d'inhiber le développement de la réaction asthmatique, en diminuant l'inflammation pulmonaire (réduction de l'infiltration éosinophilique, inhibition de la production locale de cytokines Th2) et protège ces derniers contre l'altération de leur fonction respiratoire (protection contre l'hyperréactivité bronchique, avec inhibition de l'hypersécrétion de mucus). Toutefois, les mécanismes cellulaires à l'origine de cette protection semblent indépendants de grandes voies de régulation de la réaction (Gilet J et al., en préparation). L'ensemble de ces études montre, et pour la première, qu’une chimiokine est capable d’induire le développement d’une réponse tolérogénique.Chemokines are a key component of homeostatic cell traffic and involved in pathological situations. In addition to this chemotactic function, specific to these molecules, they have been recently assigned an involvement in specific adaptive response polarization, by acting directly on T cells (T Lc) or indirectly through dendritic cells (DC). CCL18 is a chemokine preferentially expressed in lung and lymph nodes, able to attract DCs and T Lc, induced by Th2 cytokines such as IL-4, IL-13 but also by the immunomodulatory cytokine IL-10, and its receptor is still unknown. In our laboratory it was shown an involvement of CCL18 in allergic asthma (de Nadai, JI, 2006), and this chemokine has also been associated with various pathologies without areal clear described role. The purpose of this work was to evaluate the immune effect of CCL18 at baseline and in atopic situation. The direct effect of CCL18 was evaluated on T cell polarization. Pretreatment of memory T cells CD4+CD25-, from non allergic subjects, with CCL18 led to their switch to regulatory CD4+CD25+ Foxp3+ cells, able to produce IL-10 and TGF-b and inhibit effectors T cell proliferation, by a contact and cytokine dependent mechanism. However, this regulatory effect of CCL18 was lost when T cells were derived from allergic subjects (Chang Y et al., FASEB J, 2010). The indirect effect of CCL18 has been assessed on the immune response through DC. Monocyte, from healthy subjects, differentiated in DC with GM-CFS and CCL18 led to development of semi-mature DC, that expressed CCR7 and produced IL10 and the enzyme indoleamine 2,3-inducing dioxigenase. These cells primed regulatory Tr1 cells able to produce IL-10 and to suppress LcT effectors proliferation by a cytokine dependent mechanism. Surprisingly, when monocytes were derived from allergic patients, the tolerogenic effect of CCL18 was lost, in association with a decreased binding of CCL18 to its putative receptor (Azzaoui I and al., in revision Blood) Moreover, we have shown that CCL18 may also play a role in the resolution of the allergic reaction with a chemotactic effect, by recruitment of a subpopulation of regulatory T cells CD4+CD25highCD127lowLAP+ (Chenivesse C et al., in revision JI). The effect of corticosteroids on CCL18 expression was analyzed. These results showed that the secretion of CCL18 induced by cytokines IL-4 and IL-10 is potentiated by dexamethasone (Chabrol J et al., in preparation) which confirms the anti inflammatory role of CCL18. The last study was an approach in a murine model of allergic asthma induced by ovalbumin in mice Balb/cByJ. Intratracheal administration of recombinant CCL18 to sensitized animals, inhibits asthmatic reaction development, by decreasing pulmonary inflammation (reduced eosinophil infiltration, and inhibition of local production of Th2 cytokine) and protects them against the deterioration of their respiratory function (protection against bronchial hyperresponsiveness, and inhibition of mucus hypersecretion). However, the cellular mechanisms behind this protection appear independent of major regulatory pathways of the reaction (J Gilet et al., in preparation). All these studies show, for the first time, that a chemokine is able to induce a tolerogenic response. However, this feature is absent in allergic donors who exhibit a defect in the binding of CCL18 to its putative receptor. This may participate to the lack of tolerance response observed in allergic diseases. This data suggest that CCL18 and its putative receptor may represent therapeutic targets

CCL18 and regulatory responses from steady state to atopy

Les chimiokines sont un élément essentiel du trafic cellulaire aussi bien homéostatique que dans des situations pathologiques. Outre cette fonction chimiotactique spécifique à ce type de molécules, on leur a récemment attribué une implication dans le profil de polarisation de la réponse adaptative spécifique, en agissant directement sur les lymphocytes T (Lc T) ou indirectement par le biais des cellules dendritiques (DC). CCL18 est une chimiokine exprimé préférentiellement au niveau pulmonaire et de façon moindre au niveau ganglionnaire, capable d’attirer les DC et les Lc T, elle est induite par les cytokines de type Th2 telle que l'IL-4, l'IL-13, mais aussi par la cytokine immunomodulatrice l'IL-10, son récepteur est inconnu à ce jour. Au laboratoire il a été montré une implication du CCL18 dans l’asthme allergique (de Nadai, JI, 2006), et cette chimiokine a été associée à différentes pathologies à tropisme pulmonaire ou non avec un rôle pas toujours très clair. L'objectif de ce travail a été d’étudier l’effet immunitaire de cette chimiokine, en base et en situation atopique. L'effet direct du CCL18 a été évalué sur la polarisation de la réponse T. Le prétraitement des Lc T mémoire CD4+ CD25-, de sujets non allergiques, avec le CCL18 conduit à leur transformation en Lc T régulateurs CD4+ CD25+ Foxp3+ produisant de l’IL-10 et du TGF-b capables d'inhiber la prolifération des Lc T effecteurs, à la fois par un mécanisme cytokine et contact dépendant. Cependant, cet effet de régulation de CCL18 est perdu lorsque les cellules T proviennent de sujets allergiques (Chang Y et al., FASEB J, 2010). L’effet indirect du CCL18 a été évalué sur la réponse immune via les DC. La différenciation de monocytes de sujets sains en présence de GM-SCF et CCL18 conduit au développement de DC de phénotype semi-mature, expriment le CCR7, produisant de l’IL10 et l’enzyme 2,3-indoleamine dioxigenase et induisant le développent de Lc T régulateurs de type Tr1 produisant de l’IL-10 capables d’inhiber la prolifération de Lc T effecteurs, par un mécanisme cytokine dépendant. Étonnamment, lorsque les monocytes proviennent de patients allergiques, l'effet tolérogène de CCL18 est perdu en liaison avec la diminution de la fixation de CCL18 à son récepteur putatif (Azzaoui I et al., en révision Blood). Par ailleurs, CCL18 pourrait également jouer un rôle dans la résolution de la réaction allergique par un effet chimiotactique vis-à-vis d’une sous population de LcT régulateurs CD4+CD25highCD127lowLAP+ (Chenivesse C et al., en révision JI). L'effet de corticoïdes sur l'expression de CCL18 a ensuite été analysé. Il a été montré que la sécrétion de CCL18 induite par les cytokines IL-4 et IL-10 est potentialisée par la dexaméthasone, ce qui confirme que CCL18 est plutôt une chimiokine à activité anti inflammatoire (Chabrol J et al., en préparation). La dernière étude concerne une approche dans un modèle murin d'asthme allergique, induit par l'ovalbumine chez la souris Balb/cBYJ. D'un point de vue fonctionnel, l'administration de CCL18 recombinant par voie intratrachéale à des animaux sensibilises permet d'inhiber le développement de la réaction asthmatique, en diminuant l'inflammation pulmonaire (réduction de l'infiltration éosinophilique, inhibition de la production locale de cytokines Th2) et protège ces derniers contre l'altération de leur fonction respiratoire (protection contre l'hyperréactivité bronchique, avec inhibition de l'hypersécrétion de mucus). Toutefois, les mécanismes cellulaires à l'origine de cette protection semblent indépendants de grandes voies de régulation de la réaction (Gilet J et al., en préparation). L'ensemble de ces études montre, et pour la première, qu’une chimiokine est capable d’induire le développement d’une réponse tolérogénique.Chemokines are a key component of homeostatic cell traffic and involved in pathological situations. In addition to this chemotactic function, specific to these molecules, they have been recently assigned an involvement in specific adaptive response polarization, by acting directly on T cells (T Lc) or indirectly through dendritic cells (DC). CCL18 is a chemokine preferentially expressed in lung and lymph nodes, able to attract DCs and T Lc, induced by Th2 cytokines such as IL-4, IL-13 but also by the immunomodulatory cytokine IL-10, and its receptor is still unknown. In our laboratory it was shown an involvement of CCL18 in allergic asthma (de Nadai, JI, 2006), and this chemokine has also been associated with various pathologies without areal clear described role. The purpose of this work was to evaluate the immune effect of CCL18 at baseline and in atopic situation. The direct effect of CCL18 was evaluated on T cell polarization. Pretreatment of memory T cells CD4+CD25-, from non allergic subjects, with CCL18 led to their switch to regulatory CD4+CD25+ Foxp3+ cells, able to produce IL-10 and TGF-b and inhibit effectors T cell proliferation, by a contact and cytokine dependent mechanism. However, this regulatory effect of CCL18 was lost when T cells were derived from allergic subjects (Chang Y et al., FASEB J, 2010). The indirect effect of CCL18 has been assessed on the immune response through DC. Monocyte, from healthy subjects, differentiated in DC with GM-CFS and CCL18 led to development of semi-mature DC, that expressed CCR7 and produced IL10 and the enzyme indoleamine 2,3-inducing dioxigenase. These cells primed regulatory Tr1 cells able to produce IL-10 and to suppress LcT effectors proliferation by a cytokine dependent mechanism. Surprisingly, when monocytes were derived from allergic patients, the tolerogenic effect of CCL18 was lost, in association with a decreased binding of CCL18 to its putative receptor (Azzaoui I and al., in revision Blood) Moreover, we have shown that CCL18 may also play a role in the resolution of the allergic reaction with a chemotactic effect, by recruitment of a subpopulation of regulatory T cells CD4+CD25highCD127lowLAP+ (Chenivesse C et al., in revision JI). The effect of corticosteroids on CCL18 expression was analyzed. These results showed that the secretion of CCL18 induced by cytokines IL-4 and IL-10 is potentiated by dexamethasone (Chabrol J et al., in preparation) which confirms the anti inflammatory role of CCL18. The last study was an approach in a murine model of allergic asthma induced by ovalbumin in mice Balb/cByJ. Intratracheal administration of recombinant CCL18 to sensitized animals, inhibits asthmatic reaction development, by decreasing pulmonary inflammation (reduced eosinophil infiltration, and inhibition of local production of Th2 cytokine) and protects them against the deterioration of their respiratory function (protection against bronchial hyperresponsiveness, and inhibition of mucus hypersecretion). However, the cellular mechanisms behind this protection appear independent of major regulatory pathways of the reaction (J Gilet et al., in preparation). All these studies show, for the first time, that a chemokine is able to induce a tolerogenic response. However, this feature is absent in allergic donors who exhibit a defect in the binding of CCL18 to its putative receptor. This may participate to the lack of tolerance response observed in allergic diseases. This data suggest that CCL18 and its putative receptor may represent therapeutic targets

Early-stage myeloid-derived suppressor cell count: Basophil exclusion matters

International audienc

The chemokine CCL18 generates adaptive regulatory T cells from memory CD4+ T cells of healthy but not allergic subjects.

The purpose of this study was to assess the direct effect of CCL18, a chemokine elevated in allergic diseases and induced by Th2 cytokines, on the polarization of human CD4(+) T cells. Purified human T cells from healthy subjects were pretreated or not with CCL18, and evaluated for cytokine production. CCL18-pretreated memory but not naive CD4(+) T cells exhibited an increased production of IL-10 (12.3 ± 2.6 vs. 5.6 ± 0.9 ng/ml for medium) and TGF-β1 but not IL-4, IFN-γ, and IL-17 compared with control cells. Pretreatment of highly purified CD4(+)CD25(-) memory T cells with CCL18 led to their conversion to CD4(+)CD25(+)Foxp3(+) regulatory T cells able to inhibit the proliferation of CD4(+)CD25(-) effector T cells by both cytokine and cell contact-dependent mechanisms. However, this regulatory effect of CCL18 was lost when T cells originated from allergic subjects in relation with a decreased binding of CCL18 to these cells [0.7 ± 0.3 mean fluorescence intensity (MFI)] as compared to those from healthy subjects (6.0 ± 1.7 MFI). This study is the first to define a chemokine that generates adaptive regulatory T cells from CD4(+)CD25(-) memory T cells. This mechanism appears defective in allergic patients and may underlie the decreased tolerance observed in allergic diseases.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in septic patients

International audienceRationale - Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression, but their clinical impact remains poorly defined.Objectives - To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in patients with sepsis.Methods - Peripheral blood transcriptomic analysis was performed on 29 patients with sepsis and 15 healthy donors. A second cohort of 94 consecutive patients with sepsis, 11 severity-matched intensive care patients, and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments.Measurements and main results - Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8, and ARG1, were up-regulated in the peripheral blood of patients with sepsis. CD14HLA-DR monocytic (M)-MDSCs were expanded in intensive care unit patients with and without sepsis and CD14CD15 low-density granulocytes/granulocytic (G)-MDSCs were more specifically expanded in patients with sepsis (P Conclusions - M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in patients with sepsis. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and seem to be major actors of sepsis-induced immune suppression.<br

Polycyclic Aromatic Hydrocarbons Reciprocally Regulate IL-22 and IL-17 Cytokines in Peripheral Blood Mononuclear Cells from Both Healthy and Asthmatic Subjects

<div><p>Pollution, including polycyclic aromatic hydrocarbons (PAH), may contribute to increased prevalence of asthma. PAH can bind to the Aryl hydrocarbon Receptor (AhR), a transcription factor involved in Th17/Th22 type polarization. These cells produce IL17A and IL-22, which allow neutrophil recruitment, airway smooth muscle proliferation and tissue repair and remodeling. Increased IL-17 and IL-22 productions have been associated with asthma. We hypothesized that PAH might affect, through their effects on AhR, IL-17 and IL-22 production in allergic asthmatics. Activated peripheral blood mononuclear cells (PBMCs) from 16 nonallergic nonasthmatic (NA) and 16 intermittent allergic asthmatic (AA) subjects were incubated with PAH, and IL-17 and IL-22 productions were assessed. At baseline, activated PBMCs from AA exhibited an increased IL-17/IL-22 profile compared with NA subjects. Diesel exhaust particle (DEP)-PAH and Benzo[a]Pyrene (B[a]P) stimulation further increased IL-22 but decreased IL-17A production in both groups. The PAH-induced IL-22 levels in asthmatic patients were significantly higher than in healthy subjects. Among PBMCs, PAH-induced IL-22 expression originated principally from single IL-22- but not from IL-17- expressing CD4 T cells. The Th17 transcription factors <i>RORA</i> and <i>RORC</i> were down regulated, whereas AhR target gene <i>CYP1A1</i> was upregulated. IL-22 induction by DEP-PAH was mainly dependent upon AhR whereas IL-22 induction by B[a]P was dependent upon activation of PI3K and JNK. Altogether, these data suggest that DEP-PAH and B[a]P may contribute to increased IL22 production in both healthy and asthmatic subjects through mechanisms involving both AhR -dependent and -independent pathways.</p></div

Efficacy, safety and immunological profile of combining rituximab with belimumab for adults with persistent or chronic immune thrombocytopenia: results from a prospective phase 2b trial

International audienceB-cell activating factor may be involved in the failure of B-cell depleting therapy with rituximab in immune thrombocytopenia (ITP) by promoting the emergence of splenic long-lived plasma cells. From results obtained in mouse models, we hypothesized that combining rituximab with sequential injections of belimumab could increase the rate of response at one year in patients with persistent or chronic ITP by preventing the emergence of these long-lived plasma cells. The study was a single-center, single arm, prospective phase 2b trial (RITUX-PLUS, NCT03154385) investigating the safety and efficacy of rituximab given at a fixed dose of 1,000 mg, two weeks apart, combined with five infusions of belimumab, 10 mg/kg at week 0 (W0)+2 days, W2+2 days, W4, W8 and W12 for adults with primary persistent or chronic ITP. The primary endpoint was the total number of patients achieving an overall response (complete response + response) at W52 according to a standard definition. In total, 15 non-splenectomized adults, nine (60%) with persistent IPT and six (40%) with chronic ITP, were included. No severe adverse event, infection, or severe hypogammaglobulinemia was observed. Thirteen patients achieved an initial overall response. At W52, 12 (80%) patients achieved an overall response, including ten (66.7%) with complete response. When compared with a cohort of patients receiving rituximab alone, the kinetics of B-cell repopulation appeared similar, but the number of circulating T follicular helper cells was significantly decreased with belimumab combination therapy. Combining rituximab and belimumab seems a promising strategy in ITP, with high efficacy and acceptable safety

T-cell defect in Diffuse Large B-cell Lymphomas involves expansion of myeloid derived suppressor cells expressing IL-10, PD-L1 and S100A12

International audienceIn diffuse large B-cell lymphoma (DLBCL), the number of circulating monocytes and neutrophils represents an independent prognostic factor. These cell subsets include monocytic and granulocytic myeloid-derived suppressor cells (M- and G-MDSCs) defined by their ability to suppress T-cell responses. MDSCs are a heterogeneous population described in inflammatory and infectious diseases and in numerous tumors including multiple myeloma, chronic lymphocytic leukemia, and DLBCL. However, their mechanisms of action remain unclear. We broadly assessed the presence and mechanisms of suppression of MDSC subsets in DLBCL. First, a myeloid suppressive signature was identified by gene expression profiling in DLBCL peripheral blood. Accordingly, we identified, in a cohort of 66 DLBCL patients, an increase in circulating G-MDSC (LinnegHLA-DRnegCD33posCD11bpos) and M-MDSC (CD14posHLA-DRlow) counts. Interestingly, only M-MDSC number was correlated with the International Prognostic Index, event-free survival, and number of circulating Tregs. Furthermore, T-cell proliferation was restored after monocyte depletion. Myeloid-dependent T-cell suppression was attributed to a release of interleukin-10 and S100A12 and increased PD-L1 expression. In summary, we identified expanded MDSC subsets in DLBCL, as well as new mechanisms of immunosuppression in DLBCL