Neonate Intestinal Immune Response to CpG Oligodeoxynucleotide Stimulation

Background: The development of mucosal vaccines is crucial to efficiently control infectious agents for which mucosae are the primary site of entry. Major drawbacks of these protective strategies are the lack of effective mucosal adjuvant. Synthetic oligodeoxynucleotides that contain several unmethylated cytosine-guanine dinucleotide (CpG-ODN) motifs are now recognized as promising adjuvants displaying mucosal adjuvant activity through direct activation of TLR9-expressing cells. However, little is known about the efficacy of these molecules in stimulating the intestinal immune system in neonates. Methodology/Principal Findings: First, newborn mice received CpG-ODN orally, and the intestinal cytokine and chemokine response was measured. We observed that oral administration of CpG-ODN induces CXC and CC chemokine responses and a cellular infiltration in the intestine of neonates as detected by immunohistochemistry. We next compared the efficiency of the oral route to intraperitoneal administration in stimulating the intestinal immune responses of both adults and neonates. Neonates were more responsive to TLR9-stimulation than adults whatever the CpG-ODN administration route. Their intestinal epithelial cells (IECs) indirectly responded to TLR9 stimulation and contributed to the CXC chemokine response, whereas other TLR9-bearing cells of the lamina-propria produced CC chemokines and Th1-type cytokines. Moreover, we showed that the intestine of adult exhibited a significantly higher level of IL10 at homeostasis than neonates, which might be responsible for the unresponsiveness to TLR9-stimulation, as confirmed by our findings in IL10-deficient mice. Conclusions/Significance: This is the first report that deciphers the role played by CpG-ODN in the intestine of neonates. This work clearly demonstrates that an intraperitoneal administration of CpG-ODN is more efficient in neonates than in adults to stimulate an intestinal chemokine response due to their lower IL-10 intestinal level. In addition we report the efficiency of the oral route at inducing intestinal chemokine responses in neonate that might be taken into consideration for further vaccine development against neonatal diseases

Future Aircraft and the Future of Aircraft Noise

In order to cope with increasing air traffic and the requirement to decrease the overall footprint of the aviation sector - making it more sustainably and acceptable for the whole society - drastic technology improvements are required beside all other measures. This includes also the development of novel aircraft configurations and associated technologies which are anticipated to bring significant improvements for fuel burn, gaseous and noise emissions compared to the current state and the current evolutionary development. Several research projects all over the world have been investigating specific technologies to address these goals individually, or novel - sometimes also called "disruptive" - aircraft concepts as a whole. The chapter provides a small glimpse on these activities - mainly from a point of view of recent European funded research activities like Horizon2020 projects ARTEM, PARSIFAL, and SENECA being by no-way complete or exhaustive. The focus of this collection is on noise implications of exemplary novel concepts as this is one of the most complicated and least addressed topics in the assessment of aircraft configurations in an early design stage. Beside the boundary layer ingestion concept, the design process for a blended wing body aircraft is described, a box-wing concept is presented and an outlook on emerging supersonic air transport is given

Immunostimulation d'animaux nouveau-nés pour les protéger contre la cryptosporidiose

An immunostimulation approach by oral route was investigated with a model of newborn mice in order to stimulate the maturation of the intestinal immune system and allow a quick control of C. parvum develpment. We evaluated the immunostimulants potential administrated by oral route to C57BL/6 neonates of one day of age. An administration of the treatments the day proceding the infection allows reducing the parasitic load to 6 days post-infection (p.i.) on the order of 90% for a CpG-ODN-1668 administration. These particularly encouraging results lead us to focus the remainder of our works on the property of this treatment. This work allowed identifying two different mechanisms by which an important control of the parasitic development can be obtained. The mechanism induced after the oral administration of non-CpG is original and moreover effective one in apparent absence of inflammation. After optimisation, the use of this immunostimulant coud be precious for the treatment of the cryptosporidiose.Une approche d'immunostimulation par voie orale a été envisagée avec un modèle de souriceaux nouveau-nés afin de stimuler la maturation du sytème immunitaire intestinal et permettre un contrôle rapide du développement de C. parvum. Nous avons évalué le potentiel immunostimulants administrés par voie orale à des souriceaux C57BL/6 âgés d'un jour. Une administration des traitements le jour précédant l'infection permet de réduire la charge parasitaire à 6 jours post-infection (p.i.) de l'ordre de 90% pour une administration de CpG-ODN-1668. Ces résultats particulièrement encourageants nous ont conduits à focaliser le reste de nos travaux sur les propriétés de ce traitement. Ce travail a permis d'identifier deux mécanismes différents par lesquels un contrôle important du développement parasitaire peut être obtenu. Le mécanisme induit suite à l'administration orale de non-CpG est original de de plus efficace en absence apparente d'inflammation. Après optimisation, l'utilisation de ce type d'immunostimulant pourrait se réveler précieuse pour le traitement de la cryptosporidiose.TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Etude descriptive des pratiques d’apprentissage d’étudiants en quatrième année de médecine dans une faculté française et de leurs performances à résoudre un problème

Contexte : Les activités d’enseignement et d’apprentissage en petits groupes deviennent difficiles à maintenir en raison de l’augmentation du numerus clausus imposée par la législation française. Avant d’envisager d’autres alternatives pédagogiques compatibles avec les principes d’une pédagogie active et dans le contexte d’une épreuve sommative et normative classante nationale, nous avons réalisé une étude prospective chez des étudiants en 4e année de médecine pour décrire leurs approches d’apprentissage (profondeur et surface), leurs stratégies d’apprentissage (SA) et de résolution de problème (SRP) et leurs performances à résoudre un problème simulés par écrit. Matériel et méthodes : Pour un thème donné (« épilepsie ») du programme de l’épreuve classante nationale, l’approche d’apprentissage a été évaluée par le questionnaire de Biggs. Les SA et SRP ont été évaluées par deux questionnaires construits d’après les récentes données de la littérature. Les performances à résoudre un problème ont été évaluées au cours d’une séance pendant laquelle les étudiants devaient résoudre deux problèmes cliniques d’épilepsie sous forme de vignettes-papier. Résultats : L’approche d’apprentissage en profondeur prédomine. Les SA métacognitives sont déjà développées en 4e année. Le répertoire des SRP n’est pas utilisé de façon éclectique. Une corrélation entre l’approche en profondeur, les stratégies d’apprentissage de niveau 3 (stratégies de catégorisation des informations) et les performances à résoudre un des deux problèmes cliniques a été observée. Conclusion : La prédominance d’une approche d’apprentissage en profondeur, le développement de SA de type métacognitif et le constat de certaines limites dans l’utilisation de SRP nous font envisager la généralisation de l’apprentissage autonome à partir de référentiels didactiques, du tutorat et de séances d’entraînement au raisonnement médical

Natural killer cells induce eosinophil activation and apoptosis.

Eosinophils are potent inflammatory cells with numerous immune functions, including antigen presentation and exacerbation of inflammatory responses through their capacity to release a range of largely preformed cytokines and lipid mediators. Thus, timely regulation of eosinophil activation and apoptosis is crucial to develop beneficial immune response and to avoid tissue damage and induce resolution of inflammation. Natural Killer (NK) cells have been reported to influence innate and adaptive immune responses by multiple mechanisms including cytotoxicity against other immune cells. In this study, we analyzed the effect of the interaction between NK cells and eosinophils. Co-culture experiments revealed that human NK cells could trigger autologous eosinophil activation, as shown by up-regulation of CD69 and down-regulation of CD62L, as well as degranulation, evidenced by increased CD63 surface expression, secretion of eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN). Moreover, NK cells significantly and dose dependently increased eosinophil apoptosis as shown by annexin V and propidium iodide (PI) staining. Direct contact was necessary for eosinophil degranulation and apoptosis. Increased expression of phosphorylated extracellular signal-regulated kinase (ERK) in cocultured eosinophils and inhibition of eosinophil CD63 expression by pharmacologic inhibitors suggest that MAPK and PI3K pathways are involved in NK cell-induced eosinophil degranulation. Finally, we showed that NK cells increased reactive oxygen species (ROS) expression by eosinophils in co-culture and that mitochondrial inhibitors (rotenone and antimycin) partially diminished NK cell-induced eosinophil apoptosis, suggesting the implication of mitochondrial ROS in NK cell-induced eosinophil apoptosis. Pan-caspase inhibitor (ZVAD-FMK) only slightly decreased eosinophil apoptosis in coculture. Altogether, our results suggest that NK cells regulate eosinophil functions by inducing their activation and their apoptosis

Toll-Like Receptor 2 Is Required for Optimal Control of Listeria monocytogenes Infection

The control of Listeria monocytogenes infection depends on the rapid activation of the innate immune system, likely through Toll-like receptors (TLR), since mice deficient for the common adapter protein of TLR signaling, myeloid differentiation factor 88 (MyD88), succumb to Listeria infection. In order to test whether TLR2 is involved in the control of infections, we compared the host response in TLR2-deficient mice with that in wild-type mice. Here we show that TLR2-deficient mice are more susceptible to systemic infection by Listeria than are wild-type mice, with a reduced survival rate, increased bacterial burden in the liver, and abundant and larger hepatic microabscesses containing increased numbers of neutrophils. The production of tumor necrosis factor, interleukin-12, and nitric oxide and the expression of the costimulatory molecules CD40 and CD86, which are necessary for the control of infection, were reduced in TLR2-deficient macrophages and dendritic cells stimulated by Listeria and were almost abolished in the absence of MyD88, coincident with the high susceptibility of MyD88-deficient mice to in vivo infection. Therefore, the present data demonstrate a role for TLR2 in the control of Listeria infection, but other MyD88-dependent signals may contribute to host resistance

Mucosal immune responses after CpG-ODN treatment in the intestine.

<p>CpG-ODN was administered by the oral route in 8-day-old neonates (n = 5 for each group). Six hours later, ilea were removed for RNA extraction. (A) We used an RT-PCR microarray to analyze a pool of RNA for each group. CC, CXC chemokines and cytokines/receptor data for values with greater than 3-fold-increases are represented. (B) Neonates (n = 5) and adults (n = 5) received 20 µg/g CpG-ODN orally and 10 µg/g intraperitoneally. The mice were killed 6 hours later and the ilea were removed. RNAs were extracted and RT-PCR analyses were performed for CCL2, CCL7, CXCL1 and CXCL10 expression. These data are representative of two independent experiments. Data were submitted to the non-parametric Mann-Whitney test (*, p<0.05).</p

Natural Killer Cells from Allergic Donors Are Defective in Their Response to CCL18 Chemokine

International audienceNatural killer (NK) cells were originally described as cytolytic effector cells, but since then have been recognized to possess regulatory functions on immune responses. Chemokines locate NK cells throughout the body in homeostatic and pathological conditions. They may also directly stimulate immune cells. CCL18 is a constitutive and inducible chemokine involved in allergic diseases. The aim of this study was to evaluate CCL18’s effect on NK cells from allergic and nonallergic donors in terms of both chemotactic and immune effects. Results showed that CCL18 was able to induce migration of NK cells from nonallergic donors in a G-protein-dependent manner, suggesting the involvement of a classical chemokine receptor from the family of seven-transmembrane domain G-protein-coupled receptors. In contrast, NK cells from allergic patients were unresponsive. Similarly, CCL18 was able to induce NK cell cytotoxicity only in nonallergic subjects. Purified NK cells did not express CCR8, one of the receptors described to be involved in CCL18 functions. Finally, the defect in CCL18 response by NK cells from allergic patients was unrelated to a defect in CCL18 binding to NK cells. Overall, our results suggest that some NK cell functions may be defective in allergic diseases

Natural Killer Cells from Allergic Donors Are Defective in Their Response to CCL18 Chemokine

Natural killer (NK) cells were originally described as cytolytic effector cells, but since then have been recognized to possess regulatory functions on immune responses. Chemokines locate NK cells throughout the body in homeostatic and pathological conditions. They may also directly stimulate immune cells. CCL18 is a constitutive and inducible chemokine involved in allergic diseases. The aim of this study was to evaluate CCL18’s effect on NK cells from allergic and nonallergic donors in terms of both chemotactic and immune effects. Results showed that CCL18 was able to induce migration of NK cells from nonallergic donors in a G-protein-dependent manner, suggesting the involvement of a classical chemokine receptor from the family of seven-transmembrane domain G-protein-coupled receptors. In contrast, NK cells from allergic patients were unresponsive. Similarly, CCL18 was able to induce NK cell cytotoxicity only in nonallergic subjects. Purified NK cells did not express CCR8, one of the receptors described to be involved in CCL18 functions. Finally, the defect in CCL18 response by NK cells from allergic patients was unrelated to a defect in CCL18 binding to NK cells. Overall, our results suggest that some NK cell functions may be defective in allergic diseases.</jats:p