Dissertations / Theses: 'Immunité intestinal'

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Rouxel, Ophélie. "Rôles des cellules MAIT (Mucosal Associated Invariant T) dans la physiopathologie du diabète de type 1." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB114.

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Le diabète de type 1 (DT1) est une maladie auto-immune caractérisée par la destruction sélective des cellules β pancréatiques entraînant une hyperglycémie et nécessitant un traitement par insulinothérapie à vie. La physiopathologie du DT1 est complexe et fait intervenir les cellules immunitaires innées et adaptatives dans la pathogenèse et la régulation du DT1. Alors que le développement du diabète peut être associé à des facteurs génétiques, des facteurs environnementaux sont également impliqués dans le déclenchement de cette maladie. Des études récentes ont mis en évidence le rôle du microbiote intestinal dans le développement ou la protection du DT1. Des modifications du microbiote ont par ailleurs été observées chez les patients DT1 avant le déclenchement de la maladie. Plusieurs études ont également décrit des altérations de la muqueuse intestinale chez les souris NOD et chez les patients DT1. Les cellules MAIT sont des lymphocytes T de type inné reconnaissant la molécule de MR1 et exprimant un TCR Va semi-invariant (Vα7.2-Jα33 chez l'homme et Vα19-Jα33 chez la souris). Les cellules MAIT sont activées par des métabolites bactériens, dérivés de la synthèse de la riboflavine. Leur particularité est de produire rapidement diverses cytokines telles que le TNF-α, l’IFN-γ et l’IL-17 et le granzyme B. La localisation et la fonction des cellules MAIT suggèrent qu'elles pourraient jouer un rôle clé dans le maintien de l'intégrité intestinale et le développement des réponses auto-immunes dirigées contre les cellules β. Dans l’ensemble, nos résultats chez les patients DT1 et chez les souris NOD montrent une activation anormale des cellules MAIT chez les patients DT1. Ces anomalies peuvent être détectées avant le déclenchement de la maladie. L'analyse des tissus périphériques de souris NOD souligne le rôle des cellules MAIT dans deux tissus, le pancréas et la muqueuse intestinale. Dans le pancréas, la fréquence des cellules MAIT est augmentée. Dans ce tissu les cellules MAIT semblent participer à la destruction des cellules β. Contrairement au pancréas, les cellules MAIT situées dans la muqueuse intestinale semblent jouer un rôle protecteur grâce à leur production de cytokines IL-22 et IL-17. Nos données chez les souris NOD Mr1-/-, dépourvues de cellules MAIT, soulignent le rôle protecteur des cellules MAIT lors du développement du DT1 en participant au maintien de l'intégrité intestinale. En outre, la présence d'altérations intestinales à mesure que la maladie progresse chez les souris NOD souligne l'importance des cellules MAIT dans le maintien de l'homéostasie intestinale. De manière intéressante, les cellules MAIT pourraient représenter un nouveau biomarqueur de la maladie et permettre de développer des stratégies thérapeutiques innovantes basées sur l’activation locale des cellules MAIT
Type 1 diabetes (T1D) is an auto-immune disease characterized by the selective destruction of pancreatic islet β cells resulting in hyperglycemia and requiring a life-long insulin replacement therapy. The physiopathology of T1D is complex and still not entirely understood. Both innate and adaptive immune cells are involved in the pathogenesis and the regulation of T1D. While diabetes development can clearly be associated with genetic inheritance, environmental factors were also implicated in this autoimmune diseases. Recent studies have highlighted the role of the intestinal microbiota in the development or protection against T1D. Gut microbiota analyses in patients have shown differences before the onset of T1D. Moreover, several studies also described gut mucosa alterations in NOD mice and in T1D patients. MAIT (Mucosal Associated Invariant T) cells are innate-like T cells recognizing the MR1 molecule and expressing a semi-invariant receptor Vα chain (Vα7.2-Jα33 and Vα19-Jα33 in mice). MAIT cells are activated by bacterial metabolites, derived from the synthesis of riboflavin. Their particularity is to rapidly produce various cytokines such as TNF-α IFN-γ, IL-17 and granzyme B. The localization and the function of MAIT cells suggest that they could exert a key role in the maintenance of gut integrity, thereby controlling the development of autoimmune responses against pancreatic β cells. To summarize, our results in T1D patients and in NOD mice indicate an abnormal MAIT cell activation in this pathology, which occurs before disease onset. The analysis of peripheral tissues from NOD mice highlights the role of MAIT cells in two tissues, the pancreas and the gut mucosa. In the pancreas, MAIT cells frequency is elevated and they could participate to the β cells death. In contrast to the pancreas, in the gut mucosa MAIT cells could play a protective role through their cytokines production of IL-22 and IL-17. Our data in Mr1-/- NOD mice, lacking MAIT cells, reveal that these cells play a protective role against diabetes development and in the maintenance of gut mucosa integrity. Moreover, the presence of gut alteration as T1D progress in NOD mice underscores the importance of MAIT cells in maintaining gut mucosa homeostasis. Interestingly, MAIT cells could represent a new biomarker towards T1D progression and open new avenues for innovative therapeutic strategies based on their local triggering

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Sencio, Valentin. "Impact du microbiote intestinal sur les surinfections bactériennes post-grippales." Thesis, Lille, 2020. http://www.theses.fr/2020LILUS030.

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Introduction: Le virus influenza A (IAV) est responsable d’épidémies de grippes chaque année, et de pandémies tous les 10 à 15 ans. Des infections bactériennes graves (infections à pneumocoques) peuvent survenir suite à l’infection grippale et contribuent à la morbidité et à la mortalité excessive de la grippe. L'infection par IAV réduit l'immunité antibactérienne, favorisant le développement local des bactéries et leur dissémination. Il a été démontré que le microbiote intestinal a un impact sur les réponses immunitaires de l'hôte. La déplétion (traitement antibiotique) ou l'absence (souris sans germe) de microbiote augmente la susceptibilité aux infections par IAV et Streptococcus pneumoniae. Nous avons émis l’hypothèse que la perturbation de la composition et de la fonction du microbiote intestinal au cours de l’infection par IAV pourrait influencer les surinfections bactériennes pulmonaires. Résultats: Une analyse métagénomique réalisée au cours de l’infection grippale montre une altération transitoire du microbiote intestinal et une perturbation de son activité de fermentation (acides gras à chaîne courte, AGCC). Des expériences de transfert de flore fécale ont montré que les souris reconstituées avec un microbiote altéré (souris grippées) sont plus sensibles à l'infection bactérienne par rapport aux souris reconstituées avec un microbiote sain. La restauration du défaut de production des AGCC (par apport exogène) chez les souris colonisées et au cours de l'infection grippale réduit la susceptibilité aux (sur)infections bactériennes. C’est principalement l’acétate, AGCC majoritaire dans l’intestin et le sang, qui entraine ces effets bénéfiques sur le contrôle de la charge bactérienne en condition de surinfection. Suite au traitement, les macrophages alvéolaires présentent une capacité plus importante à tuer les bactéries permettant de diminuer la charge bactérienne dans le poumon et diminuer le risque de mortalité au cours de la surinfection. La déplétion d’un des récepteurs de l’acétate, le récepteur couplé à la protéine G 43 (GPR43), inhibe son effet bénéfique. L’utilisation d’agonistes du récepteur GPR43 (mimant l’effet des AGCC) au cours de l’infection grippale réduit également la susceptibilité aux surinfections bactériennes. Conclusion: Ces résultats constituent une avancée majeure dans la lutte contre les surinfections bactériennes et laissent entrevoir des applications thérapeutiques. Notamment par le biais de traitement riche en fibres (source indirect d’AGCC) ou à base de probiotiques producteurs d’AGCC
Introduction: Influenza A virus (IAV) is responsible for epidemics and, every 10-15 years, for pandemics. Secondary bacterial infections (pneumococcus) can develop in the aftermath of influenza and strongly contribute to excessive mortality of influenza. IAV infection leads to dysfunctional pulmonary defense and to altered barrier functions, thus favoring the local bacterial outgrowth and dissemination (bacteriemia). The gut microbiota has a critical role in immune responses. For instance, the depletion of the microbiota by antibiotics or its absence (germ-free animals) leads to enhanced susceptibility to respiratory infections including Streptococcus pneumoniae. We hypothesized that IAV infection may alter the functionality of the gut microbiota to favor secondary bacterial infections. Results: Metagenomic analyses demonstrated a transient alteration of the composition of the gut microbiota during IAV infection and an alteration of its fermentative activity (short chain fatty acids, SCFAs). Fecal transfer experiments revealed that the dysbiotic microbiota (collected from IAV-infected mice) can transfer enhanced susceptibility to bacterial infections in recipient mice. Restoration of SCFAs (exogenous delivery) during IAV infection reduced the incidence of bacterial superinfection. It is mainly the acetate, the main SCFA in the intestine and the blood, which causes these beneficial effects on the control of the bacterial load during superinfection. Following treatment, alveolar macrophages have a greater killing activity that lower the bacterial load in the lung and reduce the risk of mortality during superinfection. Depletion of one of the acetate receptors, GPR43, inhibits its beneficial effect. The use of agonists more specific to GPR43 (mimicking the effect of SCFAs) during influenza infection also reduces the susceptibility to bacterial superinfections. Conclusion: Collectively, these findings provide a novel mechanistic scenario for post-influenza bacterial superinfection and might have therapeutic applications in diseases associated with dysbiosis and secondary bacterial infections

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Stzepourginski, Igor. "Identification of lymph node and intestinal lymphoid stromal cell subsets with key roles in immunity and homeostasis." Paris 7, 2014. http://www.theses.fr/2014PA077148.

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Les cellules stromales lymphoïdes (LSCs) sont des cellules non-hématopoïétiques essentielles à l'initiation et au maintien de réponses immunitaires performantes. Caractérisées par l'expression de la podoplanine (gp38), les LSCs sont présentes à l'état basal dans les organes lymphoïdes secondaires et sont induites par l'inflammation dans tous les tissus périphériques. Dans l'intestin, les cellules exprimant gp38 constituent la majorité des cellules non-hématopoïétiques de la lamina propria. Nous avons montré que l'expression de gp38 définit une population très hétérogène de cellules aux fonctions parfois très distinctes des LSCs. Les cellules gp38+CD34- sont des myofibroblastes sous-épithéliaux situés dns les villi et spécialisés dans la différentiation d l'épithélium. Situées dans les cryptes, les cellules gp38+CD34+VCAM+ sont similaires aux LSCs des ganglions lymphatiques : elles se développent peu après le sevrage et promeuvent l'attraction et la survie des lymphocytes. En revanche les cellules gp38+CD34+VCAM- sont programmées lors du développement embryonnaire et jouent un rôle déterminant dans le maintien de l'activité des cellules souches intestinales. Afin d'identifier les précurseurs des LSCs pendant l'inflammation, nous avons développé une souris transgénique permettant de suivre la descendance des cellules exprimant le récepteur à la lymphotoxine-beta (LTβR), une protéine essentielle au développement des ganglions lymphatiques et à la maturation des LSCs. Nous avons montré pour la première fois qu'une sous-popultion de péricytes exprimant LTβR génère des LSCs dans le ganglion pendant l'inflammation
Lymphoid stromal cells (LSCs) are non-hemaopoietic cells pivotal in building and maintaining efficient immune responses. LSCs are described as podoplanin (gp38)- expressing cells and are present in secondary lymphoid organs at steady state. Moreover, LSCs are induced by inflammation and some tumors in the periphery. In the intestinal lamina propria, gp38+LSCs compose the majority of the non-hematopoietic cells at steady state. We showed that gp38+intestinal stromal cells are very heterogeneous and contain cells distinct from LSCs that populate different niches in the lamina propria. Gp38+CD34- stromal cells are subepithelial myofibroblasts located in the upper lamina propria that promote the differentiation of epithelial cells. In the crypts, gp38+CD34+VCAM+ stromal cells are the equivalent of LSCs found in lymphoid organs : they develop around weaning to attract lymphocytes into the lamina propria and promote their survival. However, gp38+CD34+VCAM- stromal cells develop during ontogeny and maintain the activity of intestinal epithelial stem cells in the crypts. In order to identify LSC progenitors during inflammation we developed a transgenic mouse model allowing for the fate-mapping of cells expressing lymphotoxin beta receptor (LTβR), a key protein involved in the development of lymphoid organs and LSC maturation. We showed for the first time that a subset of pericytes expressing LTβR give rise to LSCs during inflammation-induced expansion of the lymph node

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Cazals, Anaïs. "Étude de l’impact de la génétique de l’hôte et de la composition du microbiote intestinal sur le portage de Salmonella Enteritidis chez la souris et la poule." Electronic Thesis or Diss., université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL096.

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Salmonella enterica Enteritidis (SE) est l’une des principales causes d’intoxication alimentaire humaine, par le biais de la consommation de produits aviaires (viande ou œufs) contaminés. Cette bactérie est portée de manière asymptomatique par la poule, mais peut infecter et rendre malade les consommateurs de ces produits. La sélection génétique et la modulation du microbiote intestinal sont deux moyens prometteurs de diminuer son portage chez la poule et sa propagation en élevage. Les objectifs de cette thèse sont d’identifier les principaux facteurs génétiques et microbiens contrôlant le portage individuel des salmonelles dans deux modèles expérimentaux. Le modèle “poulet” a été utilisé pour l’étude de l’impact du fonds génétique sur la résistance et le microbiote caecal de jeunes individus après une infection par SE. Des analyses de la composition du microbiote et de l’expression des gènes dans les tonsilles caecales ont été menées et ont permis d’identifier des bactéries intestinales (ex. Christensenellaceae), des gènes différentiellement exprimés (ex. Fut2) et des voies de signalisation potentielles (ex. voie des acides gras à chaîne courte) associés avec la réponse à l’infection. Un impact significatif de la lignée sur la composition du microbiote a également été identifié. Le modèle “souris” a été utilisé pour l’identification de régions génomiques de l’hôte contrôlant le portage chronique de SE. Deux populations génétiques de référence, les lignées du Collaborative Cross (CC) et les souris du Diversity Outbred (DO), ont permis d’identifier de nouveaux QTls (Ses11 à Ses17) et des gènes candidats tels que Lingo2 ou Btnl4 associés à la réponse à l’infection par SE. Chez les CC, nous avons également montré une large diversité des charges bactériennes dans le foie et la rate permettant d’identifier des lignées présentant des phénotypes extrêmes à SE, sensibles (ex. CC009/Unc) ou résistantes (ex. CC024/GeniUnc), et pouvant servir de nouveaux modèles expérimentaux. Ce projet a donc permis d'identifier de nouveaux mécanismes associés à la réponse à une infection par SE, grâce à l’exploitation de deux modèles expérimentaux complémentaires
Salmonella enterica Enteritidis (SE) is one of the major human food poisoning causes through the consumption of contaminated poultry products (meat and eggs). This bacterium is carried asymptomatically by chickens, but is able to infect humans and cause diseases. Genetic selection and intestinal microbiota modulation are two promising ways to reduce its carriage in chickens and its spread in poultry farms. The objectives of this thesis are to identify the main genetic and microbial factors controlling individual Salmonella carriage in two experimental models. The "chicken" model was used to study the impact of the genetic background on the resistance and the microbiota composition of young individuals post SE infection. Analyses of caecal microbiota composition and gene expression in caecal tonsils were conducted and led to the identification of intestinal bacteria (e.g. Christensenellaceae), differentially expressed genes (e.g. Fut2) and signalling pathways (e.g. short-chain fatty acid pathway) associated with the response to the infection. A significant impact of the line on microbiota composition was also identified. The "mouse" model was used to identify host genomic regions controlling chronic SE carriage. Two genetic reference populations, the Collaborative Cross (CC) strains and the Diversity Outbred (DO) mice, allowed the identification of new QTls (Ses11 to Ses17) and candidate genes such as Lingo2 or Btnl4 associated with the response to SE infection. In CC strains, we showed a high diversity of bacterial loads in liver and spleen, allowing the identification of strains with extreme phenotypes to SE, either susceptible (e.g. CC009/Unc) or resistant (e.g. CC024/GeniUnc), that could be used as new experimental models. This project has therefore allowed the identification of new mechanisms associated with the response to SE infection thanks to the use of two complementary experimental models

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Ettreiki, Chourouk. "Impact de la supplémentation en fer sur la réponse inflammatoire et l'orientation de la réponse immunitaire au niveau intestinal : rôle de l'écosystème intestinal et de la régulation épigénétique." Rouen, 2012. http://www.theses.fr/2012ROUENR09.

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A la naissance, notre système digestif est immature. L'exposition de ce système à l'environnement ambiant et spécialement à l'aliment, contribue à sa maturation et à l'établissement d'un profil immunitaire de tolérance stable. Cette matrice alimentaire joue aussi un rôle très important dans le développement et la diversification du microbiote intestinal qui participe lui aussi à la maturation de la barrière muqueuse intestinale et contribue à l'orientation du système immunitaire. Le maintien de cet équilibre s'accomplit nécessairement au travers ces différents acteurs. Une perturbation de cet équilibre est à l'origine de plusieurs pathologies inflammatoires notamment au niveau intestinal. Aussi, dans ce travail, pour la compréhension de ces mécanismes au cours de cette fenêtre critique de la période périnatale, nous avons choisi d'évaluer l'effet de l'administration répétée d'un additif alimentaire, le fer, clairement impliqué dans ces phénomènes, dans l'évaluation de la perturbation de la balance immunitaire et le maintien du profil du microbiote intestinal au cours de deux pathologies inflammatoires de profil Thl (colite) et de profil Th2 (allergie alimentaire). A l'aide de modèles murins, et en utilisant une formulation de pyrophosphate de fer micro-encapsulé, qui optimise l'assimilation sans occasionner les effets secondaires, nous avons mis en évidence les caractéristiques physiopathologiques potentiellement modifiées par ce composé alimentaire à l'aide de bio-marqueurs pertinents. Ensuite, nous avons comparé dans deux espèces l'évolution du profil du microbiote au cours de ces perturbations. 'Et enfin, nous nous sommes intéressés à la modulation de l'orientation de la réponse immunitaire par l'étude de l'expression des facteurs de transcription impliqués dans cette différentiation et par l'évaluation du contrôle épigénétique dans la régulation de l'expression de ces gènes. Ainsi, après la mise au point d'un nouveau modèle d'allergie alimentaire de profil Th2 et la validation locale du modèle de la colite de profil Thl , l'ingestion continue de pyrophosphate de fer micro-encapsulé (Fe3+) a permis, dans ces deux modèles de rongeurs de : a) limiter de façon dose-dépendante la réponse inflammatoire, b) maintenir l'eubiose et c) prévenir la dérégulation de la balance immunitaire par le maintien des niveaux d'expression des facteurs de transcription en charge de l'orientation immunitaire en maintenant, au moins pour partie, les niveaux de méthylation des régions promotrices des gènes étudiés
At birth, the gastro-intestinal tract is not completely mature. The immune Th2 profile is largely predominant. During the development, the environment and particularly food helps this system to acquire maturation and an equilibrium with others profile. In parallel, they also are responsible for the development and the diversification of the intestinal microbiota. This microbiota is also involved for maturation of the mucosa barrier. Maintaining this intestinal homeostasis is accomplished necessarily through these actors. A disturbance of this stability may contribute to several inflammatory pathologies among which in the intestine. In this work, to understand how these mechanisms act during this critical stage of the perinatal period, we chose to evaluate the effect of a repeated administration of a food additive, iron, clearly involved in these phenomena, in assessing the disruption of the immune balance and the microbiota profile in two inflammatory Thi profile (colitis) and Th2 profile (food allergy). Using murine models, and using a particular formulation of microencapsulated ferric iron, which optimizes assimi ation without causing side effects, we checked firstly, with relevant biomarkers, the pathophysiological features potentially modified by this alimentary compound. Then, we compared in two rodent species (mice and rats), the specific evolution of the microbiota profile under these disturbances. And finally, we were interested in the modulation of the immune response orientation by studying the expression of transcription factors involved in the lymphocyte differentiation and by assessing the epigenetic control governing the regulation of these genes expression. Following the development of a new model of food allergy characterised by the Th2 profile and following the local validation of the colitis model characterised by the Thl profile, continuous ingestion of microencapsulated pyrophosphate iron (Fe34) has showed contribution, in both the two rodent models on, a) the limitation of the inflammatory response, b) the maintenance of an healthy microbiota profile, and c) the prevention of the immune balance dysregulation by maintaining the normal expression levels of transcription factors responsible for the immune orientation and the preservation of adequate levels of methylation in the promoter regions of the genes studied

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Viaud, Sophie. "Etude des effets du cyclophosphamide sur l’immunité anti-tumorale : relations avec le microbiote intestinal." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T064.

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Les chimiothérapies conventionnelles anticancéreuses ont été développées dans le but de traiter le cancer par élimination directe et/ou par inhibition de croissance les cellules tumorales en division. Les cellules endothéliales en prolifération à l’origine de la vascularisation intra-tumorale sont également connues pour être sensibles aux effets cytotoxiques des agents anticancéreux. Depuis, de nombreuses études ont montré que certaines thérapies conventionnelles peuvent être exploitées pour leurs capacités anti-angiogéniques (Browder et al. Cancer Research 2000). La stratégie mise en place consiste à suivre des protocoles où la thérapie est administrée à des doses faibles non myéloablatives et plus fréquemment que les thérapies conventionnelles, appelés dosages métronomiques (Hanahan et al. JCI 2000, Gasparini et al. Lancet Oncology 2001). Le cyclophosphamide (CTX) est un agent alkylant communément utilisé en chimiothérapie dans des protocoles à dosage métronomique. Dans les années 1980, 2 études ont montré que le CTX utilisé à dose métronomique pouvait avoir aussi un rôle sur l’immunité en réduisant la fonction suppressive d’une population de lymphocytes T CD4+ dans un modèle expérimental de tumeur (Awwad et al. Cancer Research 1989) et chez des patients atteints de cancer (Berd et al. Cancer Research 1987). Depuis, les connaissances ont progressé et à présent le CTX métronomique est reconnu pour pouvoir limiter l’expansion et les fonctions des lymphocytes T régulateurs (Treg) (Ghiringhelli et al. EJI 2004, Lutsiak et al. Blood 2005) conduisant à une polarisation des cellules T auxiliaires vers un profil Th1 (Matar et al. Eur J cancer 2000 et Cancer Immunol Immunother 2002). Utilisé en association, le CTX métronomique s’avère donc être un outil intéressant dans le traitement anticancéreux (Hermans et al. Cancer Research 2003, Taieb et al. JI 2006). Nos résultats montrent l’importance des lymphocytes T CD4+ sécréteurs d’IL-17 et d’IFNg dans les effets du CTX
Conventional cancer chemotherapies were developed to target cancer cells either by directly eliminating them or by inhibiting the growth of dividing tumor cells. Proliferating endothelial cells at the origin of intratumoral vascularization are known to be sensitive to the cytotoxic effects of antineoplastic agents. Many studies have shown that some conventional therapies can be exploited for their anti-angiogenic capabilities (Browder et al. Cancer Research 2000). The adopted strategy, called metronomic chemotherapy, consists of administering low doses of drug that do not induce myelosuppression, on a more frequent schedule as compared to conventional therapies (Hanahan et al. JCI 2000, Gasparini et al. Lancet Oncology 2001). Cyclophosphamide (CTX) is an alkylating agent commonly used as a metronomic chemotherapy. In the 1980s, two studies demonstrated that when used at a metronomic dosing, CTX could impact the immune response particularly in reducing the suppressive function of a CD4+ T lymphocyte population in an experimental tumour model (Awwad et al. Cancer Research 1989) and in cancer patients (Berd et al. Cancer Research 1987). Since then, knowledge has evolved and now CTX used as a metronomic or low-dose therapy is administered to limit expansion and functions of regulatory T cells (Treg) (Ghiringhelli et al. EJI 2004, Lutsiak et al. Blood 2005), leading to a helper T cell polarization toward a Th1 profile (Matar et al. Eur J cancer 2000 et Cancer Immunol Immunother 2002). When used in combination, CTX turns out to be a potent drug in the antineoplastic treatments armamentarium (Hermans et al. Cancer Research 2003, Taieb et al. JI 2006). Our results demonstrate the importance of CTX effects on IL-17 and IFNg secreting CD4+ T lymphocytes

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Martin, Ève. "Étude de l'immunité intestinale de la truite arc-en-ciel (Oncorhynchus mykiss) et perspectives de modulation par des additifs alimentaires : approches cellulaires et moléculaires." Thesis, Université de Lorraine, 2013. http://www.theses.fr/2013LORR0125/document.

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L'impact de la nutrition sur l'immunité intestinale de la truite arc-en-ciel est encore mal connu. C'est pourquoi cette thèse avait pour objectifs de mieux caractériser son système immunitaire intestinal et d'évaluer les possibilités de modulation de la réponse immune intestinale par l'ajout de nucléotides libres dans son alimentation. Nos résultats indiquent que les phagocytes intestinaux présentent une activité de phagocytose plus faible que ceux du rein antérieur. La cytotoxicité naturelle mesurée au niveau intestinal est deux fois plus élevée que celle du rein antérieur et cette observation est corrélée à une augmentation du transcrit codant NKEF (Natural Killer Enhancement Factor). Nous avons également montré que les lymphocytes intestinaux ne répondent pas à une stimulation mitogénique in vitro et que ceci n'est pas due à l'apoptose des cellules. Une forte expression des transcrits codant CD8a et CD3 a été détectée dans les leucocytes intestinaux, ce qui suggère une importante proportion de lymphocytes T exprimant la forme homodimérique aa de CD8 dans ce tissu. Enfin, nous avons montré que l'ajout de nucléotides libres à l'alimentation de truites saines stimule la prolifération spontanée ainsi que la phagocytose des leucocytes intestinaux in vitro. Par contre, aucune modulation de la cytotoxicité naturelle ou de l'expression des transcrits codant les marqueurs spécifiques des lymphocytes T et B et les cytokines inflammatoires n'a été observée. Il serait à présent intéressant de renouveler ces essais en utilisant des poissons infectés afin de pouvoir observer l'effet des nucléotides sur la réponse inflammatoire et sur la réponse spécifique
The impact of nutrition on rainbow trout intestinal immunity, a farmed fish with high economic value, remains unclear. Consequently, the objectives of this thesis were to better characterize the intestinal immune system of that fish and to determine if it is possible to modulate its intestinal immune response by dietary free nucleotides. Our results show that intestinal phagocytes are less activated by yeast cells but when they are activated they can ingest as many yeast cells as their head kidney (HK) counterparts. We noted that the natural cytotoxic activity of intestinal leukocytes is twice higher than the one of HK leukocytes. This natural cytotoxic activity is correlated with an increase of transcripts encoding the natural killer enhancement factor (NKEF). Intestinal leukocytes did not respond to an in vitro mitogenic stimulation. This lack of response is not due to apoptosis. We also observed a high expression of CD8a and CD3 transcripts in gut leukocytes, suggesting that the intestine could contain a high proportion of T cells expressing the aa homodimeric form of CD8. Finally, we observed that dietary free nucleotides stimulate the spontaneous proliferation and the phagocytic activity of intestinal leucocytes in vitro. However, they did not modulate natural cytotoxicity activity nor did they affect the amounts of transcripts encoding specific markers of T and B lymphocytes and inflammatory cytokines. In the future, it will be interesting to repeat these experiments using infected fish in order to study the effect of nucleotides on the inflammatory and specific immune responses

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Zarnitzky, Pauline. "Les Lymphocytes intraépithéliaux dans la rectocolite hémorragique." Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS051.

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La rectocolite hémorragique (RCH), comme la maladie de Crohn (MC), fait partie des maladies inflammatoires chroniques de l'intestin (MICI). La RCH est une maladie multifactorielle complexe dont l’étiologie est inconnue. L’inflammation chronique est associée à des modifications majeures et permanentes de l’épithélium, qui à leur tour perturbent à la fois l’homéostasie de la barrière intestinale et la réponse immunitaire. Cependant, bien que les lésions de la muqueuse affectent principalement l’épithélium intestinal, les cellules immunitaires résidentes dans l’épithélium, les lymphocytes intraépithéliaux (LIE), ont été jusqu’alors très peu étudiés dans la RCH. Quelques études suggèrent que l’homéostasie des LIE est perturbée dans la RCH, mais le rôle des LIE dans la physiopathologie de la maladie reste encore à élucider. Les objectifs de cette thèse étaient (i) de caractériser la perturbation de l’homéostasie des LIE, (ii) de comprendre comment le remodelage de l’épithélium impactait l’homéostasie des LIE et enfin (iii) d’évaluer la fonction cytotoxique des LIE résiduels issus de patients atteints de RCH dans un essai fonctionnel.À partir de prélèvements chirurgicaux de patients atteints de RCH et de MC sévères et de patients contrôles non atteints de MICI, nous avons comparé la fréquence et la composition des LIE CD103+, qui définissent classiquement les LIE, par cytométrie en flux et immunohistochimie. En parallèle, certaines anomalies de l’épithélium colique des patients atteints de RCH ont été mises en évidence par RT-qPCR, immunohistochimie et single cell. Pour mieux caractériser le défaut d’homéostasie des LIE dans la RCH et déterminer leurs rôles dans la physiopathologie de la RCH un modèle original de co-culture d’organoïdes intestinaux humains en monocouche avec des LIE autologues a été développé. Enfin, la cytotoxicité des LIE résiduels de RCH a été testée dans ce modèle de co-culture en utilisant la vidéo-microscopie.Ici, nous montrons à la fois une diminution des LIE CD103+ ainsi qu’une diminution des sous-populations de LIE TCRαβ+ CD8+ et des LIE TCRγδ+ dans l’épithélium colique des patients atteints de RCH. Cette diminution est spécifique à la RCH et n’a pas été retrouvée dans la MC. Nos données suggèrent que le recrutement des LIE CD103+ n'est pas altéré dans la RCH. La diminution des LIE CD103+ serait due à un défaut de rétention médié par une perte de l’expression de l’E-cadhérine. Enfin, nous démontrons que l’adhésion des LIE CD103+ résiduels issus de RCH ne dépend que partiellement de CD103 dans notre modèle de co-culture d’organoïdes intestinaux et LIE autologues. Nous montrons également que les LIE CD103+ résiduels de RCH sont plus cytotoxiques vis-à-vis des cellules épithéliales que les LIE CD103+ issus d’individus contrôles dans notre modèle de co-culture. Cependant, d'autres travaux sont maintenant nécessaires pour mieux définir le rôle des sous-populations de LIE CD103+ dans la physiopathologie de la RCH.Ce travail permet une meilleure compréhension des conséquences de l’inflammation chronique sur les interactions entre l’épithélium intestinal et les LIE au cours de la RCH
Ulcerative colitis (UC), like Crohn's disease (CD), is a chronic inflammatory bowel disease (IBD). UC is a complex, multifactorial disease with unknown etiology. Chronic inflammation is associated with major and permanent changes in the epithelium, which in turn disrupt both intestinal barrier homeostasis and the immune response. However, although mucosal damage primarily affects the intestinal epithelium, the immune cells resident in the epithelium, intraepithelial lymphocytes (IELs), have so far been little studied in UC. A few studies suggest that IELs homeostasis is disrupted in UC, but the role of IELs in UC pathophysiology remains to be elucidated. The aims of this thesis were (i) to characterize the disruption of IELs homeostasis, (ii) to understand how epithelial remodeling impacts IELs homeostasis, and (iii) to evaluate the cytotoxic function of residual IELs from UC patients in a functional assay.Using surgical specimens from patients with severe UC and CD and control patients without IBD, we compared the frequency and composition of CD103+ IELs, which classically define IELs by flow cytometry and immunohistochemistry. In parallel, abnormalities in the colonic epithelium of UC patients were highlighted by RT-qPCR, immunohistochemistry and single cell. To better characterize the lack of IELs homeostasis in UC and to determine its impact on colitis, an original model of co-culture of human intestinal organoids in monolayer with autologous IELs was developed. Finally, the cytotoxicity of residual UC LIE was tested in this co-culture model using video-microscopy.Here, we show both a decrease in CD103+ LIE as well as a decrease in TCRαβ+ CD8+ and TCRγδ+ IELs subsets in the colonic epithelium of UC patients. This decrease is specific to UC and was not found in CD. Our data suggest that CD103+ IELs recruitment is not impaired in UC. The decrease in CD103+ IELs is thought to be due to a retention defect mediated by a loss of E-cadherin expression. Finally, we demonstrate that adhesion of residual CD103+ IELs from UC is only partially dependent on CD103 in our co-culture model of intestinal organoids and autologous LIE. We also show that residual CD103+ IELs from UC are more cytotoxic towards epithelial cells than CD103+ LIE from individual controls in our co-culture model. However, further work is now required to better define the role of CD103+ LIE subsets in UC pathophysiology. This work provides a better understanding of the consequences of chronic inflammation on the interactions between intestinal epithelium and IELs during UC

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Dupraz, Louise. "Régulation des lymphocytes T innés par le microbiote intestinal Enterobacteriaceae are essential for the modulation of colitis severity by fungi Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS598.

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Dès la naissance, un très grand nombre de micro-organismes commensaux tels que bactéries, levures et virus colonise le tractus gastro-intestinal humain. Ce microbiote intestinal est essentiel pour développer les défenses immunitaires de l'hôte contre les infections, permettre une réparation tissulaire et un métabolisme nutritionnel adéquat. Les lymphocytes T gamma-delta, ou lymphocytes T innés sont des cellules T résidentes dans les tissus, impliquées dans l’inflammation intestinale telle que les maladies inflammatoires chroniques de l’intestin (MICI). Placée à l’interface entre l’immunité innée et adaptative, cette population présente des capacités d’activation et des propriétés fonctionnelles qui lui confère des fonctions à la fois bénéfiques et délétères. Décoder leur régulation est cruciale pour prévenir les réponses immunes inappropriées sans compromettre les mécanismes protecteurs intrinsèques. Au cours de ma thèse, nous avons mis en évidence que les acides gras à chaine courte (AGCC), métabolites produits par le microbiote intestinal, sont capables d’inhiber la production d’IL-17 et d’IL-22 par les lymphocytes T innés in vitro et in vivo en diminuant l’activité des histones déacétylases (HDACs) (Dupraz et al. soumis). Ces résultats contribuent à une meilleure compréhension de la physiologie intestinale ainsi que des mécanismes environnementaux impliqués dans les MICI, ce qui ouvre potentiellement des perspectives thérapeutiques
From birth, a very large number of commensal microorganisms such as bacteria, yeasts and viruses colonize the human gastrointestinal tract. This gut microbiota is essential to develop the immune defences of the host against the infections, to allow a tissue repair and an adequate nutritional metabolism. Gamma-delta T lymphocytes, or innate T lymphocytes, are resident T cells in tissues, implicated in intestinal inflammation such as inflammatory bowel disease (IBD). Placed between innate and adaptive immunity, this population has activation capacities and functional properties, that give it functions both beneficial and deleterious. Decoding their regulation is crucial to prevent inappropriate immune responses without compromising intrinsic protective mechanisms. During my PhD, we have highlighted that short chain fatty acids (SCFA), metabolites producted by the gut microbiota, inhibit IL-17 and IL-22 productions by innate T cells, in vitro and in vivo by decreasing histone deacetylases (HDACs) (Dupraz et al. submit). These data contribute to a better understanding of the intestinal physiology as well as the environmental mechanisms involved in IBD and thus will open potentially new therapeutic perspectives

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Nawrot, Margaux. "Rôle du récepteur nucléaire Farnesoid X Receptor intestinal dans la fonction immune de l’intestin dans le contexte physiopathologique de la stéatohépatite non alcoolique." Thesis, Université de Lille (2018-2021), 2021. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2021/2021LILUS053.pdf.

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L’homéostasie énergétique est le résultat d’un dialogue constant entre les différents organes métaboliques, notamment entre l’intestin et le foie. L’intestin est une interface entre l'organisme et le milieu extérieur. Son rôle de barrière est possible grâce aux jonctions entre ses cellules et à un système immunitaire complexe. Dans les maladies métaboliques comme le diabète de type 2 et la stéatohépatite non alcoolique (NASH), on observe une augmentation de l'inflammation à bas bruit systémique et en particulier intestinale ainsi qu’une augmentation de la perméabilité intestinale. Le récepteur nucléaire aux acides biliaires, Farnesoid X Receptor (FXR), est exprimé dans les organes métaboliques. Les souris FXR Knock-Out (KO) soumises à un régime standard présentent une augmentation de la perméabilité intestinale par rapport à leurs contrôles de portée, bien qu'elles soient protégées contre l'obésité et l'insulinorésistance induites par un régime riche en graisse. Le rôle de FXR dans l’intestin est rapporté de façon plus contradictoire car selon les études son inactivation dans l’épithélium diminuerait la synthèse de céramides protégeant alors le foie de la stéatose, et son activation induirait le browning du tissu adipeux réduisant l’obésité et l’insulinorésistance. Dans ce contexte, nous avons voulu comprendre si les fonctions immunitaires de l'intestin sont sous le contrôle de FXR intestinal dans un contexte nutritionnel induisant la NASH.Au début de ma thèse, j’ai participé à la mise en place au laboratoire de l’élevage des souris déficientes en FXR uniquement au niveau de l’intestin (intFXR KO) par un système cré-lox. Le modèle a été validé et l’état métabolique des souris sous un régime standard a été vérifié. Bien que les souris intFXR KO semblent présenter des caractéristiques histologiques hépatiques équivalentes aux souris contrôles, l’expression des gènes liés à l’immunité innée nous a laissé penser que la déficience intestinale en FXR pouvait modifier l’état inflammatoire hépatique et global. L’immunophénotypage intestinal nous a permis de montrer que les souris intFXR KO présentaient une augmentation des lymphocytes cytotoxiques (LT CD8+) intestinaux. Nous avons identifié que cette modification proviendrait d’une augmentation de LT CD8 + circulants ciblés vers l’intestin. Cette perturbation de l’immunité intestinale peut être due à la diminution d’expression des protéines des jonctions serrées qui faciliterait le passage des produits microbiens. L’étude du microbiote intestinal des souris intFXR KO montre une augmentation d’une population bactérienne rapportée comme impliquée dans les colites.L’objectif suivant a été d’étudier les conséquences de la déficience en FXR intestinal dans un contexte nutritionnel induisant la NASH en 24 semaines. Nous avons constaté que les souris intFXR KO étaient bien protégées contre la stéatose hépatique, l’analyse transcriptomique de l’intestin nous permettant d’émettre l’hypothèse d’une modulation du métabolisme lipidique intestinal. Elles ne sont cependant pas protégées contre le développement de la NASH et la déficience en FXR au niveau de l’intestin amplifierait même l’expression dans le foie des gènes liés à l’inflammation par rapport aux souris contrôles. Chez les souris intFXR KO, nous observons une augmentation des LT CD8+, une augmentation de marqueurs de perméabilité intestinale et des populations bactériennes intestinales décrites dans les maladies inflammatoires de l’intestin.Ainsi, bien que protégeant contre la prise en poids et la stéatose hépatique, la déficience intestinale en FXR semble amplifier l’inflammation hépatique dans des conditions nutritionnelles standards mais également induisant la NASH. La modulation de l’immunité intestinale par des agonistes de FXR semble donc une approche intéressante pour moduler le dialogue intestin-foie dans le traitement de la NASH
Energy homeostasis is the result of a dialogue between metabolic organs, especially gut and liver. The intestine is an interface between the organism and the external environment. Its role as a barrier is possible thanks to a complex immune system and intercellular junctions. In metabolic diseases such as type 2 diabetes and non-alcoholic steatohepatitis (NASH), there is an increase in systemic low-grade inflammation, particularly in intestine, and an increase in intestinal permeability. The nuclear bile acid receptor, Farnesoid X Receptor (FXR), is expressed in metabolic organs. FXR Knock-Out (KO) mice fed a standard diet show increased intestinal permeability compared to their littermate controls, although they are protected against high-fat diet-induced obesity and insulin resistance. The role of FXR in the intestine is reported in a more contradictory way in the literature because according to the studies its inactivation in the epithelium decreases the synthesis of ceramides which would then contribute to protect the liver from steatosis, and its activation induces the browning of adipose tissue, reducing obesity and insulin resistance. In this context, we wanted to understand whether gut immune functions are under the control of intestinal FXR in a nutritional context inducing NASH.At the beginning of my thesis, I participated in the establishment in the laboratory of the breeding of mice deficient in FXR only in the intestine (intFXR KO) by a cre-lox system. The model was validated and the metabolic status of the mice on a standard diet was checked. Although intFXR KO mice appeared to have similar hepatic histological characteristics to control mice, the expression of genes related to innate immunity is perturbed suggesting that intestinal FXR deficiency may alter the hepatic and global inflammatory state. By immunophenotyping, we showed that cytotoxic lymphocytes (CD8+ TL) are increased in the intestine of intFXR KO mice. This change may be due to an increase in circulating CD8+ TL targeting the intestine. This disruption of intestinal immunity may be due to a decrease in the expression of tight junction proteins that would facilitate the passage of microbial products. The study of the gut microbiota of intFXR KO mice shows an increase in a bacterial population reported to be involved in colitis.Our next objective was to study the consequences of intestinal FXR deficiency in a nutritional context inducing NASH in 24 weeks. We found that were well protected against hepatic steatosis, gut transcriptomic analysis suggesting a modulation of intestinal lipid metabolism. However, intFXR KO mice are not protected against the development of NASH and FXR deficiency in the gut would even amplify the expression of inflammation-related genes in the liver compared to control mice. In intFXR KO mice, we observed an increase in CD8+ TLs, an increase in intestinal permeability markers and intestinal bacterial populations described in inflammatory bowel disease.Thus, while protecting against weight gain and hepatic steatosis, intestinal FXR deficiency appears to amplify hepatic inflammation under standard and also NASH nutritional conditions. Modulation of intestinal immunity by FXR agonists therefore appears to be an interesting approach to modulate the gut-liver dialogue in the treatment of NASH

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Plantamura, Emilie. "Rôle de la voie des hélicases de type RIG dans la régulation de l'homéostasie du microbiote intestinal et des réponses inflammatoires « stériles »." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10251.

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La voie des RLR (RIG-I like Receptors) joue un rôle essentiel dans la détection des virus à ARN, déclenchant une réponse immunitaire antivirale grâce au recrutement de la protéine adaptatrice mitochondriale MAVS (Mitochondrial AntiViral Signaling protein). Nous avons mis en évidence que les souris déficientes pour la protéine MAVS (MAVS KO) présentaient un phénotype proallergénique dans un modèle d'inflammation stérile d'hypersensibilité retardée de contact (HSRC) qui reproduit la dermatite allergique de contact (DAC) chez l'homme. Nous avons caractérisé le système immunitaire des souris MAVS KO en condition d'équilibre et durant la réponse d'HSRC. Nous avons identifié un rôle du microbiote intestinal des souris MAVS KO dans l'exacerbation de réponse d'HSRC et mis en évidence une dysbiose du microbiote bactérien. Nous avons démontré que la dysbiose était responsable du phénotype inflammatoire observé, phénotype transmissible à des souris sauvages par des expériences de cohébergement et de transplantation fécale. Cette dysbiose induit une augmentation de la perméabilité intestinale chez les souris MAVS KO lors de la réponse d'HSRC, aboutissant à une translocation bactérienne dans les organes lymphoïdes et à la modulation des réponses immunitaires à l'origine de l'exacerbation de réponse d'hypersensibilité. La 2ème partie de ma thèse vise à étudier les conséquences de la déficience en MAVS sur le métabolisme glucidique. Nos expériences ont démontré que les souris MAVS KO développaient une surcharge pondérale et une insulino-résistance sous régime riche en lipides et sucrose, dépendants de la dysbiose intestinale. Au niveau cellulaire, une altération des interactions aux points de contact entre la mitochondrie et le réticulum endoplasmique a été observée. Nos résultats permettent d'envisager le développement de nouvelles approches thérapeutiques des pathologies allergiques et métaboliques humaines par la modulation du microbiote intestinal
RIG-I like receptors (RLRs) play a major role in response to cytosolic viral RNAs by initiating an antiviral immune response through the recruitment of the mitochondrial adaptor protein MAVS (Mitochondrial AntiViral Signaling protein). We showed that MAVS-deficient mice developed an exacerbated response in a sterile inflammatory model of Contact Hypersensitivity (CHS), that reproduces the pathophysiology of allergic contact dermatitis (ACD) in human. We characterized the immune system of MAVS KO mice at steady state and during CHS response. We found that MAVS deficiency leads to changes in the gut bacterial composition suggesting an unexpected role of the RLR pathway in the regulation of intestinal homeostasis. We demonstrated that intestinal dysbiosis is responsible for the increased CHS response, and showed that the inflammatory phenotype of MAVS KO mice can be transferred to WT mice by cohousing and fecal transplantation. We demonstrated that the dysbiotic gut microbiota exerts its effect due to an increased intestinal permeability during DTH sensitization. The ensuing bacterial translocation within lymphoid organs enhances characteristic cytokines production that increases CHS response. The 2nd part of my thesis aimed to study the consequences of MAVS deficiency on glucose metabolism. Our experiments showed that MAVS KO mice exhibit disorders of glucose homeostasis during high fat diet (HFD) associated with the development of overweight and insulin resistance. We also observed alterations of MAM (Mitochondria-associated endoplasmic reticulum membranes), contact poins between mitochondria and endoplasmic reticulum. Recent preliminary data suggested that the metabolic disorders associated with MAVS deficiency are due to intestinal dysbiosis. Our results highlight a new role for the RLR pathway and allow to consider the development of new therapeutic approaches to human allergic and metabolic diseases by modulation of the intestinal microbiota

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Daillere, Romain. "Impact du microbiote intestinal sur l’efficacité anti-tumorale de la chimiothérapie par cyclophosphamide." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS073.

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Plus de 50 ans après son approbation par les agences réglementaires, le cyclophosphamide (CTX) reste une drogue aux propriétés variées et aux effets pléiotropiques couramment utilisée en clinique. Cet agent cytotoxique, administré en cancérologie, possède des propriétés immuno-modulatrices et stimule les réponses immunitaires anti-tumorales. A doses métronomiques, le CTX induit notamment une polarisation des splénocytes CD4+ vers un profil Th1 et Th17, caractérisés par la sécrétion d’IFNet d’IL-17, nécessaire à l’activité tumoricide du CTX. Comme tout agent cytotoxique, le CTX cible les cellules en prolifération, qu’elles soient normales ou cancéreuses. Le CTX compromet ainsi l’intégrité de la barrière intestinale et l’homéostasie du tractus digestif. Nous avons démontré que l’individu sous CTX a une fragilisation de la barrière intestinale qui permet la rupture de la tolérance de celui-ci à sa flore commensale et son immunisation contre certaines espèces bactériennes. L’immunisation anti-bactérienne est composée de lymphocytes effecteurs CD4+, appelés « Th17 pathogéniques » et producteurs d’IL-17 et d’IFN, qui aident les lymphocytes anti-tumoraux à endiguer la croissance de tumeurs chez la souris. Nous avons mis en évidence que la stérilisation des animaux avec des antibiotiques à large spectre ou ciblant certaines populations bactériennes comme la vancomycine (ciblant les Gram+) et la colistine (ciblant les Gram-), abrogent l’efficacité anti-tumorale du CTX. Par ailleurs, nous avons identifié deux bactéries, une bactérie Gram+ Enterococcus hirae, capable de restaurer l’efficacité de cette chimiothérapie en induisant la polarisation de réponses Th1 et pTh17 stimulant la mise en place de réponses lymphocytaires T CD4 et T CD8 dirigées contre des antigènes tumoraux et une bactérie Gram- Barnesiella intestinihominis, impliquée dans la mise en place de réponses mémoires induites par la combinaison CTX+vaccin. Ces travaux démontrent ainsi l’importance de la flore intestinale dans la réponse à la chimiothérapie par CTX
More than 50 years after its approval by the Food and Drug Administration, cyclophosphamide (CTX) remains a drug with miscellaneous properties currently used in anti-cancer chemotherapy. This cytotoxic agent has immuno-modulatory properties and stimulate anti-tumoral immune responses. At metronomic doses, CTX induces the polarisation of splenocytes toward a Th1 and Th17 profile, characterized by the secretion of IFN et IL-17, both mandatory for the tumoricidal activity of this drug. CTX, as cytotoxic agent, targets proliferating cells, either normal or tumoral. Indeed, CTX is responsible for disrupting the gut barrier integrity as well as intestinal homeostasis. We have shown that people treated with CTX have a weaker intestinal barrier which breaks the tolerance toward the intestinal microbiota and leads to its immunization against some bacterial strains. This immunization is composed of CD4+ effector lymphocytes called « pathogenic Th17 » producing IFN and IL-17, which helps tumor-infiltrating lymphocytes to control the tumor growth in mice. Broad spectrum antibiotics as well as vancomycin (which mainly kills Gram positive bacteria) and colistin (which mainly eliminates Gram negative bacteria) all compromised the full-blown anticancer activity of CTX in vivo. Moreover, we have identified two bacteria, Enterococcus hirae and Barnesiella intestinihominis, able to rescue the efficacy of CTX abolished with antibiotics. E. hirae, a Gram+ bacterium, elicits Th1 immune responses and pathogenic Th17 cells capable of enhancing tumor-specific CD4+ and CD8+ T cell responses against candidate tumor antigens associated with tumor control. B. intestinihominis, a Gram- bacterium, was able to rescue the long term cognate responses lost with broad spectrum antibiotics or colistin treatment. Our data underscore the role of the gut microbiota in the efficacy of chemotherapy by CTX

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Silva, Nuno Emanuel de Oliveira Figueiredo da. "Nutrição do intestino, imunidade intestinal e resistência a parasitas do intestino em cães." Bachelor's thesis, Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária, 2009. http://hdl.handle.net/10400.5/1639.

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Dissertação de Mestrado Integrado em Medicina Veterinária
A presente dissertação é o resultado do estágio realizado na Faculdade de Ciências Agrárias e Veterinárias da Universidade Estadual Paulista “Júlio de Mesquita Filho”, Campus de Jaboticabal, São Paulo, Brasil. É composta por uma descrição resumida das actividades desenvolvidas durante o estágio, exposição breve da casuística acompanhada, seguida de uma revisão bibliográfica do tema proposto. Esta revisão incide sobre as funções do intestino na nutrição do animal e destaca o papel essencial da dieta na nutrição do intestino. Estuda-se a importância do intestino na imunidade, relacionando os mecanismos de resistência a parasitas intestinais (endo e extracelulares) em cães. No âmbito do tema escolhido, são referidos os efeitos específicos das deficiências de nutrientes a nível molecular ou de produção de citoquinas específicas. Há muitas pesquisas que demonstram que a má nutrição e a infecção ocorrem em conjunto. Não podem ser feitas generalizações sobre os efeitos de diversos nutrientes sobre os vários componentes da resposta imune, e a falta de compreensão da base de imunidade funcional contra nemátodes, torna difícil identificar as deficiências nutricionais que deveriam ser de maior preocupação. Neste estudo, o foco é centrado no intestino, que é o local da digestão e absorção de nutrientes e de permanência da maioria dos parasitas. Como complemento do tema, procede-se ao estudo dos aspectos nutricionais de sete casos clínicos acompanhados pelo autor com a respectiva discussão. Por fim, salientam-se as conclusões obtidas. Em Portugal, o autor realizou um inquérito a Médicos Veterinários sobre Nutrição Clínica, demonstrando-se que é uma área subvalorizada no nosso país. É abordada a importância de profissionais nesta área e de cursos de Nutrição Clínica para os veterinários. O tecido linfóide associado ao intestino é o maior componente do sistema imunitário do organismo. Há uma relação dinâmica entre nutrição, imunidade e doença e esta área interdisciplinar de investigação necessita de uma maior cooperação entre veterinários, parasitologistas, nutricionistas, imunologistas, biólogos moleculares e profissionais de saúde pública.
ABSTRACT - GUT NUTRITION, INTESTINAL IMMUNITY AND RESISTANCE TO INTESTINAL PARASITES OF DOGS - This thesis is the result of the training held at the Faculty of Agriculture and Veterinary Sciences, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Jaboticabal Campus, São Paulo, Brazil. The description of the activities undertaken during the training, brief overview of the casuistic, followed by a literature review of the proposed theme are presented. This review focuses on the functions of the gut in animal nutrition and highlights the essential role of diet in the nutrition of the intestine. The importance of gut immunity and the relationship between mechanisms of resistance to intestinal parasites (endo and extracellular) in dogs are mentioned. As a complement of the subject, a study of nutritional aspects of seven clinical cases are referred and followed by discussion and conclusions. Considering the aim of the present work the specific effects of nutrient deficiencies at the molecular level or production of specific cytokines are highlighted. There are many studies showing that malnutrition and infection occur together. No generalizations can be made on the effects of various nutrients on the various components of the immune response. The knowledge of functional immunity basis against nematode is needed to clear identify nutritional deficiencies. In this study, the focus is centred in the intestine, an organ were absorption and digestion of nutrients as well as localization of a large number of parasites do occur. In Portugal, the author conducted a questionnaire to Veterinarians about Clinic Nutrition. The results allowed to conclude that this area is undervalued in our country and it must be taken into account the need of experts and training courses in clinical nutrition for veterinarians. The lymphoid tissue associated with the intestine is the major component of the body's immune system. There is a dynamic relationship between nutrition, immunity and disease, and this interdisciplinary research requires greater cooperation between veterinarians, parasitologists, nutritionists, immunologists, molecular biologists and public health professionals.

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Bonnay, François. "Caractérisation des mécanismes de régulation de la voie IMD au cours de la réponse immunitaire chez Drosophila melanogaster." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ019/document.

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Le système immunitaire inné est un mécanisme de défense commun à tous les métazoaires. Chez l’Homme comme chez la drosophile, son activation peut être délétère lorsqu’elle est incontrôlée. L’étude des mécanismes qui sous-Tendent cet équilibre entre l’activation ou non de la réponse immunitaire innée est à la base de mes travaux de thèse. En utilisant le modèle Drosophila melanogaster, j’ai caractérisé la protéine Big-Bang comme un acteur important de la balance immunitaire intestinale. Mes résultats démontrent que Big-Bang est un constituant des jonctions obturantes de l’épithélium intestinal. Son absence provoque une rupture de tolérance immunitaire envers la flore bactérienne endogène et d’autre part une sensibilité accrue aux pathogènes invasifs. Mes travaux de thèse ont également permis de caractériser Akirine, une protéine nucléaire qui agit au niveau des facteurs NF-ΚB de la drosophile à l’Homme. Mes résultats démontrent qu’Akirine est un sélecteur qui agit de concert avec le complexe de remodelage de la chromatine SWI/SNF et NF-ΚB pour transcrire un sous-Ensemble de gènes pro-Inflammatoires
The innate immune response is required by all metazoan to defend themselves against microorganisms. When abnormally activated however, innate immune responses cause deleterious chronic inflammation. The study of the fragile equilibrium between immune responses and tolerance has fundamentally shaped the projects of my PhD work.First, using Drosophila melangoaster as a model, I characterized Big-Bang as a major player of the immune balance in the gut. I could show that Big-Bang is a bona fide component of midgut epithelium septate junctions. Consequently, big-Bang deficient flies have an impaired tolerance against commensal microorganisms and are susceptible to invasive gut pathogens, ultimately leading to a premature death of flies.I focused the second part of my PhD work on the characterization of Akirin, a nuclear protein required for the activation of NF-ΚB response from Drosophila to humans. My results showed that Akirin is a selector molecule, acting together with NF-ΚB and the SWI/SNF chromatin-Remodeling complex to sustain the transcription of a subset of pro-Inflammatory genes

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15

Carissimo, Guillaume. "Caractérisation et rôle de l'immunité antivirale des anophèles dans la compétence vectorielle pour les arbovirus et parasites." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066293.

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Dans une ère où les moustiques modifiés commencent à être utilisés ou envisagés pour contrôler les épidémies de Dengue ou malaria, le manque de connaissance sur l’immunité des insectes vecteurs envers certains pathogènes se fait cruellement ressentir. Pourtant la possibilité de changements de vecteurs, dû à un changement de leur immunité, provoquée par l’Homme est réelle. Pour déterminer la contribution de l’immunité dans différents compartiments du vecteur contre divers pathogènes avons étudié la réponse antivirale dans la première barrière de transmission chez le moustique vecteur de la malaria après une infection par un repas sanguin. Nous montrons que les réponses antivirales sont différentes entre compartiments, et proposons un modèle où des interactions tripartites entre le virus, l’immunité du moustique et la flore entérique interagissent pour contrôler l’infection précoce du moustique après le repas sanguin. De façon surprenante, nous avons également montré que la voie de l’ARN interférence n’a pas d’effet antiviral dans ce compartiment. Nous suggérons que cette voie est utilisée par le parasite Plasmodium pour détourner la réponse antiparasitaire médiée par Toll, grâce à un facteur de virulence de nature ARN double brin. Nous avons également montré que des biais expérimentaux lors de l’infection des insectes ont conduit à l’élaboration d’un dogme disant que la voie de l’ARN interférence est la voie antivirale principale des insectes, mais nos resultats suggèrent que malgré l’importance de cette voie pour controler l’intensité de la réplication virale lors de l’infection disséminée, cette voie n’a aucune fonction antivirale lors de l’infection initiale du tube digestif. Néanmoins, le séquençage des produits de cette voie permet d’assembler de-novo des génomes de virus commensaux. Les résultats de ces travaux montrent très clairement qu’il faut évaluer le rôle et l’impact de toute modification d’insectes vecteurs pour plusieurs classes de pathogènes. Cela ouvre également de nombreux nouveaux champs de recherches et pose de nombreuses nouvelles questions
In an era where modified mosquitoes are starting to be used in nature for controlling malaria and Dengue, lack of knowledge about immunity of mosquito vectors to some pathogen classes are becoming more evident. The risks for human-provoked vector shifts of pathogens transmission have not been examined. To fill these gaps, we assessed the antiviral immunity of the malaria vector, Anopheles gambiae, in the strongest mosquito bottleneck for pathogens, the midgut infection barrier after an infective bloodmeal. This work shows that the antiviral responses are different and highly compartmentalized between the midgut and systemic immunity. We propose a model where tripartite interactions between virus, mosquito immunity and enteric flora control early arboviral infection in the midgut. Surprisingly, we showed that while the siRNA pathway had no evident anti-arbovirus activity in the midgut, it was used by Plasmodium to evade mosquito immunity. A virus-like elicitor of double strand RNA nature is transferred from the parasite at the ookinete stage to the mosquito midgut cells, resulting in a shift of immune balance from anti-parasite response to an antiviral-like response. Importantly, our work shows that biases in experimental infection methods led to the misconstruction of a dogma stating that siRNA is the main antiviral pathways in insects, at least in the midgut compartment. And that the use of the pathway products can be successfully used to de-novo assemble previously unknown viruses from the virome. This work indicates that immune modifications in vectors need to be evaluated for changes of vectorial competence to different pathogens. It also opens numerous avenues of research and raises a lot of interesting questions that will need to be investigated in the future

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16

Atindehou, Ménonvè. "Caractérisation structurale et biologique de nouveaux agents antibactériens naturels actifs dans les infections intestinales : des peptides de la chromogranine A et des principes actifs de Chromolaena odorata." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00856585.

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Les premières souches bactériennes résistantes aux antibiotiques sont connues depuis 70 ans et se sont multipliées ces dernières années posant un grave problème de santé publique. Parmi les nombreux types d'infections induites par ces bactéries, nous nous sommes intéressés aux infections intestinales qui peuvent dégénérer en maladies inflammatoires de l'intestin et cancers. Notre travail de thèse a consisté à proposer des outils thérapeutiques dans le traitement des pathologies intestinales infectieuses : des peptides antimicrobiens dérivés de la chromogranine A et des extraits de plantes de la médecine traditionnelle béninoise. La chromogranine A est une protéine libérée par les cellules nerveuses, neuroendocrines et immunitaires au cours d'un stress et maturée en peptides. Des peptides actifs contre quatre souches bactériennes pathogènes (Klebsiella oxytoca, Salmonella enterica, Shigella sonnei et Vibrio cholera non O1) ont été identifiés et l'interaction bactérie-peptide analysée. L'étude de la combinaison peptide-antibiotique montre que la cateslytine permet de réduire les doses d'antibiotiques nécessaires. Ensuite, nous avons étudié l'implication de deux peptides sur un modèle de cellules neuroendocrines, les cellules BON. La chromofungine provoque la stimulation des cellules BON en induisant un influx de calcium extracellulaire, tandis que la catestatine est capable de bloquer l'activité de la chromofungine.Après un screening des extraits de 14 plantes du Bénin, nous avons isolé deux molécules, la sinensétine et l'O-tétraméthyléther scutellaréine, responsables de l'activité antibactérienne de Chromolaena odorata contre les pathogènes étudiés.

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17

This, Sébastien. "Régulation des réponses immunitaires adaptives par l'intégrine αvβ8 - Implications pour l'immunité des muqueuses et la réponse humorale." Thesis, Lyon, 2020. http://www.theses.fr/2020LYSEN011.

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A la suite d’une infection, la capacité de l’hôte à produire une réponse immunitaire efficace et adaptée est cruciale pour se défendre et générer une réponse mémoire permettant de se protéger contre une future réinfection. En revanche, il est absolument nécessaire que cette réponse soit correctement régulée afin d’éviter sa persistante ou son activation incontrôlée pouvant mener au développement de maladies immunitaires. Le système immunitaire comprend un ensemble complexe de cellules et de molécules immunitaires. En particulier, la capacité des cellules immunitaires à produire et à répondre aux cytokines est absolument critique pour l’orchestration des réponses immunitaires. Mon travail de thèse s’est intéressé à une molécule particulière, la cytokine Transforming Growth Factor β ou TGFβ. Contrairement à la plupart des autres cytokines, le TGFβ est produit sous une forme latente et doit être activé afin de pouvoir se lier à son récepteur et induire une réponse sur la cellule cible. Nous avons montré par le passé que l’intégrine αvβ8 joue un rôle clé dans le processus d’activation du TGFβ et ainsi dans la régulation des réponses immunitaires dépendantes du TGFβ.Plus précisément, j’ai cherché au cours de ma thèse à comprendre le rôle de l’intégrine αvβ8 dans la régulation des réponses immunitaires intestinales et la régulation des réponses humorales.Mon travail s’est plus particulièrement concentré sur la compréhension de trois processus : 1/ l’induction de lymphocytes TREG et TH17 dans l’intestin nécessaires au maintien de l’homéostasie immunitaire intestinale, 2/ la régulation des réponses humorales de classe A (IgA) intestinales et 3/ la régulation des réponses humorales T-dépendantes au cours de la réaction du Centre Germinatif
The ability of a host to generate an appropriate immune response is critical to provide protection against a particular pathogen and to provide long-lasting memory against future reinfection. However, this immune response must be tightly regulated to prevent its persistence or inadequate activation which can lead to the development of immune pathologies. Mammalian immune system comprises a wide array of immune cells and molecules. In particular, the ability ofimmune cells to secrete and respond to cytokines is central to the orchestration of immune responses. My PhD project has focused on the role of a particular cytokine named Transforming Growth Factor β (TGFβ). Unlike most other cytokines, TGFβ is secreted in a latent form and must be activated to bind its receptor and induce response on target cell. Our team and others have shown that αvβ8 integrin plays a critical role in TGFβ activation and thus the regulation of TGFβ-dependent immune responses. More precisely, I investigated the role of αvβ8 integrin in the regulation of intestinal immunityand humoral B cell responses. In particular, my work focused on three immune processes: 1/ the induction of TREG and TH17 in Mucosal Associated Lymphoid Tissues and 2/ the regulation ofintestinal IgA humoral responses and 3/ the regulation of T-dependent B cell responses during the germinal center reaction

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18

Carissimo, Guillaume. "Caractérisation et rôle de l'immunité antivirale des anophèles dans la compétence vectorielle pour les arbovirus et parasites." Electronic Thesis or Diss., Paris 6, 2014. http://www.theses.fr/2014PA066293.

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Abstract:

Dans une ère où les moustiques modifiés commencent à être utilisés ou envisagés pour contrôler les épidémies de Dengue ou malaria, le manque de connaissance sur l’immunité des insectes vecteurs envers certains pathogènes se fait cruellement ressentir. Pourtant la possibilité de changements de vecteurs, dû à un changement de leur immunité, provoquée par l’Homme est réelle. Pour déterminer la contribution de l’immunité dans différents compartiments du vecteur contre divers pathogènes avons étudié la réponse antivirale dans la première barrière de transmission chez le moustique vecteur de la malaria après une infection par un repas sanguin. Nous montrons que les réponses antivirales sont différentes entre compartiments, et proposons un modèle où des interactions tripartites entre le virus, l’immunité du moustique et la flore entérique interagissent pour contrôler l’infection précoce du moustique après le repas sanguin. De façon surprenante, nous avons également montré que la voie de l’ARN interférence n’a pas d’effet antiviral dans ce compartiment. Nous suggérons que cette voie est utilisée par le parasite Plasmodium pour détourner la réponse antiparasitaire médiée par Toll, grâce à un facteur de virulence de nature ARN double brin. Nous avons également montré que des biais expérimentaux lors de l’infection des insectes ont conduit à l’élaboration d’un dogme disant que la voie de l’ARN interférence est la voie antivirale principale des insectes, mais nos resultats suggèrent que malgré l’importance de cette voie pour controler l’intensité de la réplication virale lors de l’infection disséminée, cette voie n’a aucune fonction antivirale lors de l’infection initiale du tube digestif. Néanmoins, le séquençage des produits de cette voie permet d’assembler de-novo des génomes de virus commensaux. Les résultats de ces travaux montrent très clairement qu’il faut évaluer le rôle et l’impact de toute modification d’insectes vecteurs pour plusieurs classes de pathogènes. Cela ouvre également de nombreux nouveaux champs de recherches et pose de nombreuses nouvelles questions
In an era where modified mosquitoes are starting to be used in nature for controlling malaria and Dengue, lack of knowledge about immunity of mosquito vectors to some pathogen classes are becoming more evident. The risks for human-provoked vector shifts of pathogens transmission have not been examined. To fill these gaps, we assessed the antiviral immunity of the malaria vector, Anopheles gambiae, in the strongest mosquito bottleneck for pathogens, the midgut infection barrier after an infective bloodmeal. This work shows that the antiviral responses are different and highly compartmentalized between the midgut and systemic immunity. We propose a model where tripartite interactions between virus, mosquito immunity and enteric flora control early arboviral infection in the midgut. Surprisingly, we showed that while the siRNA pathway had no evident anti-arbovirus activity in the midgut, it was used by Plasmodium to evade mosquito immunity. A virus-like elicitor of double strand RNA nature is transferred from the parasite at the ookinete stage to the mosquito midgut cells, resulting in a shift of immune balance from anti-parasite response to an antiviral-like response. Importantly, our work shows that biases in experimental infection methods led to the misconstruction of a dogma stating that siRNA is the main antiviral pathways in insects, at least in the midgut compartment. And that the use of the pathway products can be successfully used to de-novo assemble previously unknown viruses from the virome. This work indicates that immune modifications in vectors need to be evaluated for changes of vectorial competence to different pathogens. It also opens numerous avenues of research and raises a lot of interesting questions that will need to be investigated in the future

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19

Al-Dahwi, Zaineb. "Impairment of protective immunity to intestinal helminthiases." To access this resource online via ProQuest Dissertations and Theses @ UTEP, 2007. http://0-proquest.umi.com.lib.utep.edu/login?COPT=REJTPTU0YmImSU5UPTAmVkVSPTI=&clientId=2515.

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20

Pinaud, Silvain. "Aspects fonctionnel et évolutif de l'immunité mémoire chez les invertébrés : l'escargot vecteur de la Bilharziose intestinale Biomphalaria glabrata comme nouvel organisme modèle ?" Thesis, Perpignan, 2017. http://www.theses.fr/2017PERP0037/document.

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Le clade des invertébrés cristallise en 2017 de grandes problématiques sociétales à la fois économiques et sanitaires. En effet un certain nombre des organismes présent dans ce groupe phylétique sont des vecteurs des grandes pandémies infectieuses telles que le paludisme (Anopheles sp), Zika, Chinkungunya, Fièvre jaune, etc (Aedes sp), Chagas (Triatoma sp) ou encore la bilharziose (Biomphalaria sp, Bulinus sp). La compréhension du système immunitaire de ces organismes vecteurs doit aider la communauté scientifique à proposer des solutions pour réduire la transmission de toutes ces maladies sur le terrain. Biomphalaria glabrata est le vecteur unique de la Bilharziose intestinale (Schistosomamansoni) en Amérique Latine. Depuis un premier cas de résistance induite par une première infection en 1998, de nombreux travaux ont exploré la réponse immunitaire mémoire innée de cet escargot tropical d’eau douce. Dans le cadre de ce travail de thèse, différents aspects de cette immunité (également appelé priming, résistance acquise) ont été explorés, de la mise en place phénotypiques, aux bases moléculaires et cellulaires. En premier lieu,nous avons pu démontrer qu’elle était dépendante d’une bascule phénotypique (d’une réponse cellulaire d’encapsulation à une réponse humorale) et transcriptomique qui lui permet de mieux répondre lors d’une seconde infection. La spécificité de cette réponse est portée par la production de répertoire complexe de récepteurs et d’effecteurs immunitaire spécifiques qui sont capables de différencier jusqu’aux différents stades de développement parasitaire d’une même espèce de parasite. Nous avons également pu montrer que cette interaction dépendait de microARN circulants ainsi que de Biomphalysines, des ß-PFT acquises par transferts horizontaux depuis le monde bactérien. Enfin, cette résistance semble posséder une proximité avec l’immunité mémoire entraînée des cellules immunitaires innées des vertébrés en particulier sur la base des mécanismes moléculaires sous-jacent qui seraient liés chez Biomphalaria comme chez les Vertébrés à unereprogrammation épigénétique des cellules du système immunitaire innée
Invertebrates focus in 2017 among the major economical and societal issuesacross Earth. Some members are vectors of important infectious pandemic as malaria(Anopheles sp), Zika, Chinkungunya, Yellow fever, etc (Aedes sp), Chagas (Triatoma sp) andtrematodes (Biomphalaria sp, Bulinus sp). Comprehension of immune system of thesevectors has to help scientist to decrease transmission on endemic area. Biomphalariaexposed first failure to be reinfected following first infection as soon as 1998. In my thesiswe explore this immune priming (innate immune memory) and describe an immune shiftfrom cellular to humoral immune response both in phenotype and transcriptomic response.A specificity is handle by specific immune receptor and effector repertoire to distinguish upto different developmental stage of same parasite species. This interaction is alsodependent of mRNAs and Biomphalysin, a ß-PFT coming from bacterial kingdom. Finally,this resistance seems to look alike the trained immune memory of innate cells in vertebrates

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Roach, Tamara I. A. "Immunity to Trichuris muris in the mouse." Thesis, University of Nottingham, 1986. http://eprints.nottingham.ac.uk/12886/.

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Quantitative and qualitative analyses of the serum antibody responses of NIH, C57BL/10, BALB/c, DBA/2 and CFLP mice infected with Trichuris muris have been made using ELISA and immunoprecipitation techniques. No correlation was found between specific serum antibody titres measured using T. muris E/S products and the time of onset of expulsion in the different mouse strains examined. However, there were some differences in the antigen recognition profiles of some sera as determined by immunoprecipitation analyses. In all the strains of mice examined significant increases in detectable specific serum antibody to the parasite E/S products occurred around day 15 to 20 postinfection and continued to rise, as measured up to at least day 40 and even up to day 65. Cortisone acetate treatment during larval development, in infected CFLP mice, in order to establish heavy adult worm burdens, did not reduce specific antibody titres to T. muris E/S products. In responding and tolerant DBA/2 mice there was no marked difference in either the kinetics of specific serum antibody production during primary and secondary infections, or in the antigen specificities of secondary infection sera. The "defect" in mechanism in the tolerant DBA/2 mice, which allows primary infections of T. muris to develop to patency, was shown to be permanent as secondary infections with the parasite could also establish in these animals. An investigation was made of the phenomenon of tolerance in the DBA/2 model- system and in the cortisone treated CBA mice. The capacity of MLNC from different groups of animals to produce IL-2 in vitro upon mitogen stimulation was investigated, on the basis that IL-2 deficit during antigen presentation may result in immune tolerance. Although no differences were found in the responding and tolerant DBA/2 cell-Vpopulations, there was an apparently synergistic interaction between cortisone administration and T. muris infection which dramatically reduced the IL-2 producing capacity of the MLNC. However, IL-2 cannot yet be ruled out as a factor in the inherent tolerance of a proportion of the DBA/2 population as IL-2 receptor expression by the 2 groups of cells assayed was not examined. Basic analyses of the antigens of T. muris were performed. The major protein of adult male homogenate (AMA) was also the major protein of the excretory/secretory (E/S) products and the surface antigen preparations. In addition several common E/S and surface antigens were shown to have proteolytic enzyme activities against gelatin and/or casein. The relationship between T. muris and Trichinella spiralis was examined in greater detail, and the m. wts. of the cross-reacting antigens were determined. Evidence suggested that the stichosomes of these worms may be the source of these antigens. Both Trichuris muris adults and Trichinella spiralis infective larvae each had common major E/S and surface antigens, indeed, both were shown to have surface proteases. These studies were extended to examine the possibility of cross-reactivity between Trichuris muris and T. trichiura; mouse infection sera and human infection sera respectively were able to cross-react with heterologous antigen preparations. The demonstration that anti-Trichinella spiralis 48 kD and 50/55 kD stichocyte antigen MoAbs also reacted with Trichuris trichiura adult homogenate in ELISA supports the suggestion that common stichocyte antigens may exist amongst the trichuroid nematodes Trichuris muris, Trichuris trichiura and Trichinella spiralis. Monoclonal antibodies were produced against the E/S products of Trichuris muris, which were characterized in terms of isotype and antigen specificities. Initial experiments indicated that one of the IgA MoAbs recognizing 34,22,20 and 18 kD E/S proteins may be effective in the passive transfer of immunity.

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Lantier, Louis. "Les cellules dendritiques CD103+ intestinales : maîtres d'oeuvres du contrôle naturel de la cryptosporidiose et cibles de choix pour l'immunostimulation protectrice contre la maladie." Thesis, Tours, 2013. http://www.theses.fr/2013TOUR4051.

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A la naissance, le système immunitaire des nouveau-nés est encore en plein développement. La première partie du travail de thèse a consisté à étudier les spécificités du système immunitaire intestinal des nouveau-nés qui conduisent à leur plus grande susceptibilité à l’infection par Cryptosporidium parvum. Ce protozoaire constitue un excellent modèle pour étudier les réponses immunitaires mucosales. En effet, son développement est restreint à l’épithélium intestinal et est strictement relié au statut immunitaire de son hôte ce qui explique que cet agent zoonotique affecte tout particulièrement les nouveau-nés et les immunodéficients. Nous avons démontré que les cellules dendritiques (DC) CD103+ étaient indispensables au contrôle de la phase aigüe de l’infection et que leur faible représentation dans la lamina propria de l’iléon chez les nouveau-nés était responsable de leur susceptibilité à l’infection. Nous avons identifié avec précision le mécanisme CXCR3 dépendant permettant le recrutement des DC CD1O3+ dans la muqueuse infecté et leur capacité à produire de l’IL-12 et de l’IFNǳ, deux cytokines majeures impliquées dans le mécanisme de protection. La deuxième partie de ce travail a consisté à utiliser une stratégie d’immunostimulation basée sur l’utilisation de ligands de TLR capables d’activer fortement les cellules dendritiques du nouveau-né. Cette approche permet un contrôle rapide et très efficace d’une infection par C. parvum
At birth, the neonatal immune system is still developing. In the first part of the thesis we investigated the characteristics of the intestinal immune system of neonates that lead to their greater susceptibility to infection by Cryptosporidium parvum. This protozoan is an excellent model for studying mucosal immune responses. Indeed, its development is restricted to the intestinal epithelium and is strictly related to the immune status of its host which explains the particular susceptibility of neonates and immunocompromised to this zoonotic agent. We have demonstrated that CD103+ dendritic cells (DC) are essential for the control of the acute phase of infection and their low representation in the ileal lamina propria of neonates was responsible for their higher susceptibility to infection. We have accurately identified the CXCR3-dependent mechanism for the recruitment of DC CD1O3+ in the infected mucosa and their ability to produce IL -12 and IFNǳ, two major cytokines involved in the mechanism of protection. The second part of this work was to use an immunostimulatory strategy based on administration of TLR ligands that can strongly activate neonatal DC of the intestine. This approach allows a fast and highly effective control of an ongoing C. parvum infection

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Brady, Jessica. "Protection and stimulation of intestinal innate immunity using mannan oligosaccharides." Taylor & Francis, 2010. http://hdl.handle.net/1993/4774.

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Necrotic enteritis (NE) caused by Clostridium perfringens is a re-emerging disease of economic importance in areas of the world where antibiotic growth promoters have been banned. Various alternatives to antibiotic growth promoters are being tested including prebiotics known as mannan oligosaccharides (MOS) which have been shown to mitigate the effects of NE and potentially boost the immune system, though the mechanism is not completely understood. The objective of this study is to test the effectiveness of MOS on balance of microbial populations, gut morphology and immune system ability; specifically: C. perfringens genetic populations, villi architecture and TLR2 and TLR4 activity. This study focuses on organic broiler chickens fed MOS at 0, 2, 4, 6 and 8g/kg feed and challenged with an inoculation of C. perfringens isolated from an outbreak on a local organic farm. Toxinotype and 16S phylogenetic analysis of C. perfringens were reviewed as well as feed efficiency, gut morphology and gene expression of Toll Like Receptors 2 and TLR4 using qRT-PCR. All field isolates were found to be Type A C. perfringens, as were most experimental isolates except for two isolates taken pre-innoculation, which were more likely attributed to contamination of the experiment room by cattle which were housed there previously. No association between pathogenecity and toxin genes cpb2 or netB could be established during this study. 16S analysis found all C. perfringens isolates to be highly related, though there seemed to be a change in populations post inoculation which did match the field isolate used for inoculation. Gut morphology readings including villi height, width and area, crypt depth and lymphocyte and goblet cell concentrations showed some significant effect though it was not in a common area of the intestine and was often due to the interaction between treatments and time. These results also failed to reproduce effects found by other authors. TLR2 and 4 were not found to be significantly different between treatments, though certain trends were noted. The lack of significant treatment effects as well as the low reproducibility of these outcomes leads to the conclusion that, though MOS may contribute to gut health and maturity based on these and conclusions found by other authors, its effect is hinging on other factors such as management and nutrition.

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Sallam, Jamal A. "Intestinal humoral immunity in man : IgA and anti-salmonella antibodies." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/20766.

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Studies of gut immunity must be carried out on intestinal fluid and jejunal biopsies. Recent work from Edinburgh has shown that the use of Whole Gut Lavage (WGL) technique is a non-invasive, direct and reliable method of obtaining intestinal fluids. My thesis describes the use of WGL technique in a variety of studies on gastro-intestinal mucosal immunity. The effect of the newly licensed oral live typhoid vaccine Ty21a on gut immunity was investigated in a group of 22 healthy British volunteers. Later on, the intestinal immune responses to naturally acquired Salmonella infection were investigated in a group of patients who had had the infection within the preceding 12 months. Results obtained in these studies were compared with results obtained from healthy individuals, patients with inflammatory bowel disease (IBD) and African children from Sierra Leone. I investigated further the effect of heavy smoking and non-smoking in healthy volunteers on gut immunity and the effect of administration of the live oral vaccine Ty21a on the intestinal mucosal immune responses of smokers and non-smokers. I also studied agglutinating antibodies in WGL fluids and sera. Patients with a variety of GI diseases and patients who had had Salmonella infection were tested against a panel of 11 Salmonella antigens using a modified Widal test in microtitration plates. In the course of the above studies, I found that there were patients who had very low or absent intestinal IgA but had normal levels of IgA in the serum. Therefore, I investigated further this phenomenon by counting plasma cells in the lamina propria of intestinal biopsies from patients with "intestinal IgA deficiency" and normal controls using image analysis.

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Meillet, Dominique. "IGA fécales : isolement, caractérisation et dosage des principales formes moléculaires. Intérêt en physiopathologie digestive fonctionnelle et infectieuse." Paris 5, 1988. http://www.theses.fr/1988PA05P623.

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Srinivasan, N. "The role of inflammasomes in intestinal inflammation." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:04ad577c-a8dd-46eb-811a-79a3980ff806.

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Single Nucleotide Polymorphisms (SNPs) in the intracellular pattern recognition receptor gene NLRP3 are associated with susceptibility to Crohn’s disease, a form of inflammatory bowel disease (IBD). Following cell damage or infection, NLRP3 triggers the formation of inflammasomes, a multimolecular protein complex containing NLRP3, ASC and caspase-1, which mediate secretion of IL-1β and IL-18. NLRP3 inflammasome activation in macrophages has been implicated in protection against several pathogens, but whether NLRP3 activation in tissue cells contributes to protective immunity against bacterial pathogens is unknown. We show that upon infection with the attaching/effacing (A/E) intestinal pathogen Citrobacter rodentium, Nlrp3-/- and Asc-/- mice displayed higher bacterial colonization, more weight loss and exacerbated intestinal inflammation. We further show that Nlrp3 inflammasome activation in intestinal epithelial cells (IECs) acts rapidly after infection to limit bacterial replication and penetration, and inhibits the development of inflammatory pathology in the gut. We also show that epithelial Nlrp3-mediated protection is independent of the classical inflammasome cytokines IL-1β and IL-18. Thus an Nlrp3-Asc circuit in IECs regulates early defense against a mucosal pathogen and limits inflammation in the intestine. Nlrp3 inflammasome activation has also been implicated in protection in acute models of experimental colitis, but its role in chronic models of colitis is unknown. We found that Asc signaling is necessary for the development of innate chronic intestinal inflammation driven by Helicobacter hepaticus. Thus while deficient inflammasome signaling in tissue cells increases susceptibility towards enteric pathogens, excessive inflammasome activation can drive chronic intestinal inflammation.

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Graham, Suzanne. "Intestinal immunity and pathology in animal models of type 1 diabetes." Thesis, University of Glasgow, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402005.

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Bains, Manpreet. "Genetic Disruption of VIP Signaling Alters Intestinal Microbial Structure and Immunity." Diss., North Dakota State University, 2018. https://hdl.handle.net/10365/28788.

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Vasoactive intestinal peptide (VIP) regulates clock gene expression in the brain that synchronizes diurnal feeding behaviors in mammals. In the gastrointestinal (GI) tissues, VIP influences host nutrient absorption from ingested food, and regulates host metabolic functions. VIP signaling ensures efficient nutrient absorption by influencing ghrelin and leptin expression to balance caloric intake. Importantly, obese humans have elevated plasma VIP levels, supporting its association with fat mass accumulation. In contrast, VIP deficiency leads to weight loss and reduced adiposity, while disrupting epithelial cell nutrient absorption, tight junctions and mucus secretion. Moreover, VIP regulates host glucose metabolism as VIP knockout mice are pre-diabetic with elevated blood glucose and insulin levels. In addition to metabolism, VIP is anti-inflammatory and when knocked out results in exacerbated inflammatory bowel disease (IBD) pathology. The GI track is also home to ?40 trillion bacteria, called the gut microbiota, which unlock additional calories from fiber for the host. Microbiota dysbiosis is caused by dysfunction in biological systems downstream from VIP signaling, including dysregulated expression of host clock genes, metabolic hormones, immune-relevant mediators and metabolic and inflammatory disease states, like obesity and IBD. It is not known, however, whether the VIP signaling axis contributes to the maintenance of the gut microbiota structure and diversity. We hypothesized that VIP deficiency will cause gut dysbiosis, lower bacterial diversity and reduce its energy extraction potential. To this end, we isolated fecal samples from VIP knockout mice (VIP-/-) and employed 16S rRNA sequencing. VIP deficiency (VIP-/- and VIP-/+) resulted in marked gut microbial compositional changes and reduced bacterial diversity compared to male and female VIP+/+ littermates (n=48). Increased abundance of Bacteroides, Parabacteroides and Helicobacter genera (gram-negative, GN), with reductions of Lachnospiraceae NK4A136, Oscillibacter and Ruminiclostridium genera (gram-positive, GP), were the driving force for the observed increase in the GN/GP ratio. A predicted algorithm program, called PICRUSt, showed changes in microbial metabolism consistent with elevated lipopolysaccharide metabolism and reduced intake of fiber in VIP-/- mice. These data support that VIP regulates intestinal homeostasis by maintaining microbiota balance, diversity and energy harvesting potential, while upholding an anti-inflammatory tone by limiting lipopolysaccharide biosynthesis.

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Bours, Martijn Jan Leo. "Role of extracellular ATP in immunity and intestinal defence effects on intestinal permeability and enterocyte-driven inflammatory response /." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Universiteit Maastricht [host], 2007. http://arno.unimaas.nl/show.cgi?fid=9328.

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Harvey, Joanna E. "T cell and macrophage differentiation markers in the normal and inflamed human intestine." Thesis, University of Southampton, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236511.

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Harrison, Oliver J. "The role of IL-18 in intestinal immune regulation." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:adcd849b-6a08-4ba9-b7db-0743a29cb377.

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Elevated levels of the cytokine interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD). However, the role of IL-18 in mucosal immunity and inflammation is not well understood. At mucosal and environmental interfaces, Th17 cells have been shown to contribute to protection from pathogenic infection. In contrast, regulatory T (Treg) cells maintain intestinal homeostasis by preventing aberrant inflammatory responses to the resident microbiota. We demonstrate that under homeostatic conditions, colonic Th17 cells highly express IL-18 receptor (IL-18R1) and that intestinal epithelial cell production of IL-18 acts directly on CD4⁺ T cells to limit colonic Th17 differentiation. Furthermore, whilst IL-18R1-signalling is dispensable for induction of colitis, we observed a critical role for IL-18R1-signalling in Foxp3⁺ Treg mediated control of colitis. Together, these studies demonstrate that the intestinal epithelium regulates colonic CD4⁺ T cell responses through production of the cytokine IL-18.

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Barbosa, José Guilherme Morschel. "Efeitos da suplementação de levedura autolisada de Saccharomyces cerevisiae sobre o desempenho e a imunidade intestinal de frangos de corte." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/11/11139/tde-18052017-152408/.

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O objetivo do estudo foi avaliar os efeitos da suplementação de levedura autolisada de Saccharomyces cerevisiae fornecida em duas diferentes inclusões em dietas para frangos de corte como alternativa a um antimicrobiano sobre desempenho zootécnico e avaliação do sistema imune intestinal pela realização da enumeração bacteriana, citometria de fluxo e expressão intestinal de genes ligados à resposta imune intestinal. Neste estudo foram utilizados 1260 pintos de corte machos de um dia de idade da linhagem ROSS AP95® em um experimento de 1 a 35 dias de idade alojados em galpão climatizado com cama de casa de arroz nova. O experimento foi realizado em delineamento inteiramente aleatorizado, com 4 tratamentos e 7 repetições, com 45 aves por boxe. Os tratamentos utilizados foram: T1: ração basal e sem aditivo - controle negativo; T2: ração basal suplementada com 55 ppm de bacitracina de zinco - controle positivo; T3: controle negativo + 2 kg/t de levedura autolisada; T4: controle negativo + 4 kg/t de levedura autolisada. As dietas foram à base de milho e farelo de soja, sendo adicionados às rações 5% de farelo de trigo e 5% de farinha de penas e vísceras (sem tratamento prévio) com objetivo de impor um desafio nutricional aos animais. Ainda visando estimular imunologicamente os animais, aos 7 dias de idade, todas as aves foram desafiadas via ocular com uma vacina viva contendo oocistos de Eimeria sp. na dose recomendada pelo fabricante. Aos 8 dias de idade e 21 dias de idade, uma ave de cada unidade experimental, sem jejum prévio, teve sangue coletado e foi sacrificada para coleta de conteúdo intestinal ileal e cecal para realização da emumeração bacteriana de Enterococus sp., Escherichia coli e Lactobacillus sp., e para a coleta do segmento ileal para avaliar a expressão gênica intestinal de Claudin-1, IL-1β, IL-4, TLR4 e MUC-2 através da PCR em tempo real. Em relação ao desempenho das aves, o tratamento T3 propiciou melhor conversão alimentar em relação a T1 até os 21 dias de idade. Para o período cumulativo, o tratamento T4 propiciou conversão alimentar semelhante ao T2, sendo esta variável melhor para estes tratamentos em relação ao controle negativo. Na enumeração de bactérias no íleo, aos 8 dias de idade, os tratamentos T3 e T4 modularam de forma distinta a contagem de Enterococus sp., e para o gênero Lactobacillus sp., ambos os grupos de levedura apresentaram menor contagem em contraste com o controle positivo. No conteúdo do ceco foi encontrado um menor número de E. coli para os animais grupo T3, diferentemente para o T2 que propiciou maior contagem. Aos 21 dias de idade, foi encontrado diferença na enumeração do gênero Enterococus sp. ileal, cuja contagem foi menor para o T2 em relação ao T1. Na na análise de citometria de fluxo, tendências foram observadas aos 8 dias de idade para o percentual de linfócitos T auxiliares (P=0,16) e para o percentual de linfócitos B (P=0,12) havendo redução com a suplementação de levedura autolisada. A mesma tendência (P=0,19) foi observada aos 21 dias de idade para a contagem de células T citóxicos. Sobre a PCR em tempo real, não foram detectadas diferenças para a expressão de Claudin-1. T2 e T4 propiciaram aumento da expressão gênica de IL-1β aos 21 dias de idade em relação ao controle negativo, sendo que T2 também promoveu aumento de TLR-4 aos 8 dias de idade. Tendências foram observadas com a maior expressão de IL-4 (P=0,06) aos 21 dias de idade pelo T2 e aumento na expressão de MUC-2 (P=0,09) pelo T4 aos 8 dias de idade. Os diferentes padrões de ativação ou não de citocinas revela uma estimulação da via Th2 pelo controle positivo (aumento de IL-1β e IL-4) e da via Th17 pelo tratamento suplementado com 4 kg/t de levedura autolisada (aumento de IL-1β).
The objective of this study was to evaluate the effects of a Saccharomyces cerevisiae autolyzed yeast supplementation in substitution of AGP in broiler diets on performance and immune system (on two different feed inclusions for broilers diets in replacing AGP on broiler performance and evaluation of immune system trough bacterial enumeration, flux citometry and intestinal gene expression. For that, 1260 one-day-old male Ross AP95 chicks were raised from 1 to 35 days of age in a poultry house with new rice husk as litter. The experiment was arranged in a completely randomized design with 4 treatments and 7 replications, with 45 birds per pen. The treatments were: T1: basal diet and no additive - negative control; T2: basal diet supplemented with 55 ppm of zinc bacitracin - positive control; T3: negative control + 2 kg/t of autolyzed yeast; T4: negative control + 4 kg/t of autolyzed yeast. The corn-soybean meal based diets contained 5% wheat bran and 5% poultry by-product meal (with no previous treatment) in order to impose a nutritional challenge to the animals. To impose a further immunological challenge, at 7 days of age, all the birds were eye drop-vaccinated with live vaccine containing Eimeira sp. oocysts at the manufacturer recommended dosis. At 8 and 21 days of age, one chick per experimental unit, with no fasting, had the blood collected and was sacrificed for sampling the ileal and cecal intestinal contents for enumeration of Enterococus sp., Escherichia coli and Lactobacillus sp. Also, the ileal segment was sampled for intestinal gene expression of Claudin-1, IL-1β, IL-4, TLR4 e MUC-2 by RNA extraction through real time PCR. For the performance results at 21 days of age, T3 had the same feed conversion rate of T1. For the cumulative grow-out, T4 had the same feed conversion rate as T2, being this variable better for the aforementioned tretaments in comparison to negative control. For ileal bacterial enumeration, at 8 days of age, T3 and T4 modulated distinctly the enumeration of Enterococus sp., and reduced the counts of Lactobacillus sp. in comparison to the positive control. In the cecal contents, the enumeration for E. coli was the lowest for T3, differing from the positive control. At 21 days of age, there was a difference in ileal Enterococus sp., with higher counts for T2 relative to T1. In the flux citometry, tendencies were observed at 8 days of age for T helper cells (P=0,16) and for B cells (P=0,12), which were reduced in the autolyzed yeast treatments. The same tendency (p=0.19) was seen at 21 days of age for T activated cytotoxic cells. For the real time PCR, there was no difference in the expression of Claudin-1 (P<0,05). T2 and T4 promoted upregulation of IL-1β at 21 days of age (P<0,05) in comparison to the negative control; additionally, the antibiotic tretatment also upregulated the expression of TLR-4 at 8 days of age (P<0,05). Tendencies were observed as upregulation of IL-4 (P=0,06) at 21 days of age by positive control and upregulation of MUC-2 (P=0,09) by the treatment with 4 kg/t of autolyzed yeast at 8 days of age. The different profiles in activating or not cytokines reveals a stimulation of Th2 pathway for the positive control (upregulation of IL-1β and IL-4) and Th17 pathway for the treatment supplemented with 4 kg/t of autolyzed yeast (upregulation of IL-1β).

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Kawano(Akitake), Reiko. "Inhibitory role of Gas6 in intestinal tumorigenesis." Kyoto University, 2013. http://hdl.handle.net/2433/180339.

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Wilson, A. D. "Cell mediated immunity in the intestine of the pig." Thesis, University of Bristol, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375389.

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Roberts, Morgan. "The role of the Lyn tyrosine kinase in innate immunity and intestinal inflammation." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54079.

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The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
Science, Faculty of
Microbiology and Immunology, Department of
Graduate

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Wang, Gaochan. "Diarrheagenic Escherichia coli signaling and interactions with host innate immunity and intestinal microbiota." Diss., Kansas State University, 2017. http://hdl.handle.net/2097/35735.

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Doctor of Philosophy
Department of Diagnostic Medicine/Pathobiology
Philip R. Hardwidge
Diarrheagenic Escherichia coli (E. coli) strains are common etiological agents of diarrhea. Diarrheagenic E. coli are classified into enterotoxigenic E. coli (ETEC), Shiga toxin-producing E. coli (STEC or enterohemorrhagic E. coli [EHEC]), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), enteroaggregative E. coli (EAEC), diffuse-adherent E. coli (DAEC), and adherent invasive E. coli (AIEC). In addition to encoding toxins that cause diarrhea, diarrheagenic E. coli have evolved numerous strategies to interfere with host defenses. In the first project, we identified an ETEC-secreted factor (ESF) that blocked TNF-induced NF-[kappa]B activation. One of the consequences of TNF-induced NF-[kappa]B activation is the production of pro-inflammatory cytokines that help to eliminate pathogens. Modulation of NF-[kappa]B signaling may promote ETEC colonization of the host small intestine. In this study, we fractionated ETEC supernatants and identified flagellin as necessary and sufficient for blocking the degradation of the NF-[kappa]B inhibitor I[kappa]B[alpha] in response to TNF[alpha]. In the second project, we attempted to identify an ETEC cAMP importer. ETEC diarrhea leads to cAMP release into the lumen of the small intestine. cAMP is a key secondary messenger that regulates ETEC adhesin expression. We hypothesized that a cAMP importer is present in ETEC, accounting for its hypersensitivity to extracellular cAMP. We used Tn5 transposome-mediated mutagenesis to construct a mutant library and screen for cAMP-hyporesponsive mutants. However, none of the 17,956 mutants we screened were cAMP-hyporesponsive. In the third project, we focused on gut microbiota and the T3SS effector NleH. We used the mouse-specific pathogen C. rodentium and transplanted performed microbiota between different mouse strains. We evaluated microbiota populations as a function of infection with WT and [Delta]nleH C. rodentium strains before and after microbiota transplantation. Microbiota transfer altered the resistance to WT C. rodentium infection in C57BL/10ScNJ mice and the NleH effector promoted host resistance to C. rodentium.

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Wang, Xin. "INTESTINAL IMMUNITY AND GUT MICROBIOTA IN ALDO-KETO REDUCTASE 1 B8 DEFICIENT MICE." OpenSIUC, 2019. https://opensiuc.lib.siu.edu/dissertations/1723.

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Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death in the United States. Aldo-keto reductase 1 B10 (AKR1B10) is highly expressed in colon and small intestine of normal humans, but its expression is lost or markedly down-regulated in tissues of patients with ulcerative colitis (UC) and CRC. AKR1B10 is a monomeric cytosolic enzyme with strong enzymatic activity to α, β-unsaturated carbonyl compounds, protecting cells from carbonyl lesions; AKR1B10 also mediates de novo synthesis of long chain fatty acids and membrane lipids, such as phosphatidylinositol 4,5-bisphosphate (PIP2). To study the etiopathogenic role of AKR1B10 in UC and CRC, our lab generated AKR1B8 deficient (AKR1B8 -/-) mice. AKR1 B8 is the orthologue in mice of human AKR1B10,

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Forsberg, Göte. "Innate and adaptive immunity in childhood celiac disease /." Umeå : Umeå universitet, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-874.

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Echeverry, Andrea. "Innate and Adaptive Immunity in Murine Neonates Infected with the Intestinal Pathogen Yersinia enterocolitica." Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_dissertations/480.

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Neonates are generally thought to be more likely to suffer from gastrointestinal disease, owing in part to diminished immune cell function. To gain insight into the development of mucosal immune responses during early life, we developed a model of orogastric infection with the Gram-negative bacterium Yersinia enterocolitica using murine neonates. Remarkably, neonatal mice of either the BALB/c or C57BL/6 mouse strains showed markedly enhanced survival after infection compared to adult mice. Both innate and adaptive immune components appear to contribute to this phenomenon. First, the increased resistance of neonates coincided with containment of the bacteria in the intestinal tissue with low dissemination into the spleen and liver. In contrast, the bacteria readily disseminated to the peripheral tissues in adult mice. Flow cytometric and histological studies revealed increased levels of neutrophils and macrophages in the neonatal mesenteric lymph nodes (MLN) compared to adult mice. Similar results were obtained using two different high virulence Y. enterocolitica strains. The rapid mobilization of innate cells sequestered the bacteria to the intestinal tissue, since in vivo neutrophil depletion led to efficient dissemination of Y. enterocolitica to the spleen and liver of neonates. Together, these results support the hypothesis that the neonatal intestinal immune system is competent to mount a strong antibacterial response by rapidly mobilizing innate phagocytes and thereby confining the bacterial infection to the gut, resulting in a high level of resistance. Second, we have also demonstrated that the adaptive immune system was mobilized during primary and secondary infection with this pathogen and that some of these factors may contribute to the enhanced resistance of neonatal mice to infection. Primary infection in neonates led to increased levels of antigen presenting cells, B and T cells with an activated phenotype in the MLN. MLN CD4+ Th cells from infected neonates were found to produce greater levels of IFN-gamma and IL-17A, compared to CD4+ Th cells from adult mice. These Th responses are likely to be functionally significant because neonatal mice deficient in CD4+ T cells were found to be more susceptible than adult mice to primary infection. CD4+ T cells adoptively transferred into CD4 deficient mice rescued the majority of mice from lethal infection and led to the production of IFN-gamma and IL-17A by MLN cells. In addition, primary T cell-dependent IgG1 and IgG2a serum antibodies specific for the Yersinia immunogen LcrV were increased compared to adult mice, and the absence of B cells partially increased the susceptibility of neonatal mice to primary infection. During secondary infection, however, neonatal and adult mice mounted quantitatively and qualitatively similar Yersinia-specific memory antibody responses, demonstrating that infection with Y. enterocolitica promotes mature B cell responses in neonatal mice. Finally, primed neonatal and adult mice were protected from colonization of the Peyer's patches, weight loss and mortality after a lethal infection in adulthood, demonstrating the development of long-lived protective memory responses at the intestinal interface. Together, these results indicate that both B and T cell responses, in particular Th1 and Th17 associated immunity, are important for the development of long lasting immunity to this pathogen in early life. Third, infection of neonatal mice with a Y. enterocolitica strain deleted of the anti-inflammatory protein YopP led to massive infiltration and/or accumulation of innate phagocytes in the intestine and MLN. This effect was not detectable in infected adult mice. Thus, we have identified a novel negative regulator of intestinal inflammation which might be valuable in preventing or ameliorating inflammatory conditions. This model system has revealed the unprecedented potential of neonatal mice to develop protective inflammatory innate and adaptive immunity at mucosal surfaces. The combined results presented here demonstrate that neonatal mice may be well equipped to mount robust innate and adaptive intestinal inflammatory responses that are highly protective toward Y. enterocolitica. These findings have implications for understanding how pediatric intestinal adaptive immune responses develop in response to naturally occurring gastroenteric pathogens and offer a new biological platform for development of vaccines aimed at improving mucosal and systemic immunity in early life.

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Martin-Gallausiaux, Camille. "Impact du microbiote sur les fonctions immuno-régulatrices des cellules épithéliales intestinales humaines." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS124.

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Les échanges avec le microbiote intestinal sont indispensables au développement du système immunitaire et à l’homéostasie intestinale. Les bactéries produisent des molécules perçues par les cellules épithéliales de l’intestin qui mettent à l’épreuve en permanence notre immunité. En réponse, ces cellules sécrètent des facteurs immuno-régulateurs qui contribuent à la tolérance intestinale mais dont les mécanismes sont encore peu compris. Nous nous sommes intéressés à la régulation par les bactéries des gènes TGFb1 et IDO1 et à l’activation du facteur de transcription NFκB, indépendamment des TLR. Pour mieux caractériser ses échanges, nous avons étudié les activités de bactéries commensales sur des lignées de cellules épithéliales intestinales humaines. Nous avons démontré que les acides à chaînes courtes, en particulier le butyrate présent dans les surnageants bactériens des Clostridiales et des Fusobacterium, est un puissant modulateur de TGFb1 et d’IDO1 par ses propriétés inhibitrices d’histone déacétylase. Le butyrate active la transcription de TGFb1 par un mécanisme dépendant du facteur de transcription SP1. En outre, le butyrate inhibe la transcription d’IDO1 par deux mécanismes distincts, l’un ciblant la voie STAT1/IFNγ et le second agissant indépendamment de l’IFNγ. Enfin, certaines bactéries intestinales activent NFκB, indépendamment des acides gras à chaînes courtes, des TLR et de MYD88. Une partie de ces bactéries stimulent la voie NOD1 tandis que d’autres utilisent la voie ALPK1-TIFA-TRAF6, jusqu'à présent activée uniquement par des pathogènes. Ce travail met en valeur le rôle des cellules épithéliales dans la régulation de la symbiose hôte-microbiote
Exchange with the gut microbiota are key for immune system development and host intestinal homeostasis. Bacterial molecules sensed by epithelial cells in the intestine are challenging permanently the host immune system. In response, epithelial cells secrete numerous immuno-regulator factors favouring gut tolerance. However, the molecular mechanisms involved in these processes, remain poorly understand. We studied bacterial-dependent regulation of TGFB1 and IDO1 genes as well as the TLR independent activation of the NFκB pathway, in epithelial cells. We screened the activities of a hundred of gut bacterial species on human epithelial cell lines. We showed that short chain fatty acids, and specially butyrate secreted by Clostridiales and Fusobacterium, were potent modulators of TGFb1 and IDO1 via their histone deacetylase inhibition properties. Butyrate upregulated TGFB1 by a mechanism dependent of the SP1 transcription factor. Moreover, butyrate inhibited IDO1 by two distinct mechanisms, by down-regulating the STAT1/IFNγ pathway and by preventing IDO1 expression independently of IFNγ. Eventually, we described that specific group of gut bacteria activated NFκB in a short-chain fatty acids, TLR and MYD88 independent manner. Interestingly, some Gram+ bacteria stimulated NFκB via the NOD1 pathway. Furthermore, we identified for the first time in a non-pathogenic context, commensal bacteria promoting NFκB by the newly discovered ALPK1-TIFA-TRAF6 axis. Overall, our work support the specific functions of the intestinal epithelial cells in the regulation of the host-microbiote symbiosis

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Jugdé, Fabrice. "Caractéristiques fonctionnelles des lymphocytes T dans la muqueuse intestinale saine et pathologique : profil de production des chimiokines MDC et TARC, comparaison de l'activation et de la co-stimulation des cellules sanguines et intestinales par les oligodésoxyribonucléotides CpG." Rennes 1, 2003. http://www.theses.fr/2003REN10092.

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Les maladies inflammatoires chroniques de l'intestin (MICI) incluent la maladie de Crohn (MC) et la recto-colite hémorragique. Ce travail a participé à une meilleure compréhension de leurs mécanismes physiopathologiques. Les chimiokines étant impliquées dans le recrutement de lymphocytes T dans la muqueuse intestinale, nous avons d'abord montré une augmentation significative de l'expression des ARN messagers de MDC (Macrophage-Derived Chemokine) et TARC (Thymus and activation-regulated Chemokine) dans les tissus inflammatoires de sujets MC. Puis, les motifs cytosine-guanosine (CpG) de l'ADN bactérien jouant un rôle dans l'immunité, la stimulation de cellules mononucléées par des oligodésoxyribonucléotides (ODN) CpG induisait une prolifération, significativement augmentée des cellules de tissus inflammatoires de sujets MICI. Mais, aucune co-stimulation par les ODN des lymphocytes T activés par les voies CD2 ou CD3 n'a été observée, les ODN entraînant une inhibition de leur activation.

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Ambrose, Timothy James William. "Serine hydrolase activity and roles for monoacylglycerol lipase in innate immunity and intestinal inflammation." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:f7a12796-ae8f-4121-ab1a-26778261ac78.

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Detection of evolutionarily conserved pathogen motifs by pattern recognition receptors (PRRs), particularly on dendritic cells (DCs), is crucial for adequate immune responses. Defects in DC function are known to be associated with inflammatory bowel disease (IBD). The endocannabinoid system (ECS) is the system through which exocannabinoids such as Δ⁹-tetrahydrocannabinol and cannabidiol signal. Regarding inflammation, cannabinoids generally exert anti-inflammatory effects, including on experimental colitis. However, most work has been performed in animal models and less is known about the function of this system in human immune cells, particularly DCs. Monoacylglycerol lipase (MGLL) is the key enzyme for hydrolysis of the endocannabinoid 2-arachidonoylglycerol, and a member of the serine hydrolase enzyme superfamily. This thesis defines the activity of serine hydrolase enzymes for the first time in human DCs upon stimulation by NOD2/TLR2 ligands using activity-based protein profiling (ABPP). MGLL is shown to be ubiquitously upregulated upon stimulation of DCs and in monocyte-derived macrophages. Through pharmacological inhibition studies, MGLL is demonstrated to regulate cellular and secreted lipids, not limited to endocannabinoids. However, overall DC function is independent of this enzyme suggesting that the effects of lipid modulation may be on bystander cells. Challenging the current literature, MGLL inhibition with a novel inhibitor worsens murine Citrobacter rodentium colitis. Finally, ABPP demonstrates a rich serine hydrolome in colonic tissue from human IBD with many enzymes previously undefined in this disease. Gene expression of ECS components suggests the enzymes ABHD12 and DAGLα/β may be potential markers of field change in IBD.

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Ou, Gangwei. "Human intestinal epithelial cells in innate immunity : interactions with normal microbiota and pathogenic bacteria." Doctoral thesis, Umeå : Umeå University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-18388.

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Cima, Igor. "Glucocorticoid synthesis in the intestinal mucosa and its role in local T cell immunity /." [S.l.] : [s.n.], 2005. http://www.zb.unibe.ch/download/eldiss/04cima_i.pdf.

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Le, Bourgot Cindy. "La supplémentation périnatale en fibres prébiotiques (fructo-oligosaccharides à courte chaîne, scFOS) modifie le microbiote intestinal et programme le phénotype métabolique et immunitaire du porc, pris comme modèle de l’Homme." Thesis, Rennes, Agrocampus Ouest, 2016. http://www.theses.fr/2016NSARB285/document.

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La nutrition périnatale conditionne durablement les fonctions physiologiques, avec des conséquences sur la susceptibilité à développer des maladies métaboliques à l’âge adulte. Le microbiote représente un des acteurs de cette empreinte nutritionnelle. L’objectif est de déterminer chez le porc l’impact d’une supplémentation périnatale en fructo-oligosaccharides à courte chaîne (scFOS) sur le développement des fonctions immunitaires et endocrines intestinales et les conséquences sur la santé métabolique de l’adulte en situation de déséquilibre nutritionnel.La supplémentation maternelle en scFOS, en modifiant le microbiote de la mère et de la descendance et la qualité du lait, accélère la maturation du système immunitaire intestinal des porcelets allaités.La fenêtre d’exposition (maternelle vs post-sevrage) conditionne la nature des modifications immunes induites par les scFOS. La supplémentation périnatale en scFOS modifie la réponse métabolique de l’adulte à un régime déséquilibré en stimulant la fonction endocrine intestinale et la sensibilité du pancréas au glucose, en réduisant les risques d’inflammation, et en modifiant l’homéostasie métabolique, associé à des modulations du microbiote.En résumé, la consommation périnatale de prébiotiques programme le phénotype métabolique et immunitaire de l’adulte via des modulations persistantes du microbiote. L'approche intégrée des données a permis d’identifier des acteurs moléculaires impliqués dans l’adaptation différentielle des individus à un régime déséquilibré en fonction de leur alimentation périnatale
Perinatal scFOS supplementation modifies metabolic response to an unbalanced diet in adults by stimulating intestinal endocrine function and pancreas sensitivity to glucose, by reducing risks of inflammation, and in fine by changing metabolic homeostasis in association with modifications of microbiota.In summary, prebiotic consumption during perinatal life programs the immune and metabolic phenotype of adults through persistent modulations of intestinal microbiota. The integrated approach of data enables us to identify molecular actors involved in the differential adaptation of individuals to an unbalanced diet according to their perinatal nutrition

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46

Mesnard, Bruno. "Réponse immunitaire intestinale au cours de l'allergie alimentaire." Lille 2, 1991. http://www.theses.fr/1991LIL2M076.

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47

Picherot, Mélanie. "Etude de la réponse immunitaire du porc vis-à-vis de l'infection par Trichinella spiralis." Paris 6, 2006. http://www.theses.fr/2006PA066401.

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La réponse immunitaire du porc a été étudiée sur 2 races différentes. Les premiers anticorps spécifiques apparaissent au niveau intestinal où le rapport IgG1/IgG2 tout et le taux d’IgA sont forts, suggérant la dominance d’une réaction humorale. Les cytokines produites dans la muqueuse intestinale, les ganglions jéjunaux et la rate montrent un profil Th1/Th2. La réponse immunitaire est retardée chez certains porcs, qui en outre montrent une protection moindre contre T. Spiralis. Des mastocytes porcins ont été stimulés par des antigènes de T. Spiralis. Alors que les molécules du CMH ne sont pas modulées, une dégranulation est observée dès 15 minutes de contact avec les antigènes. Parmi eux, le TSL-1 se fixe à la surface des cellules et module des cytokines Th2, le TNF-a et des molécules de co-stimulation. Les mastocytes porcins pourraient être des cellules clés entre l’immunité innée et spécifique contre T. Spiralis
The immune response was studied in vivo on 2 different strains of pigs. Specific antibodies appear first at mucosal level, where the humoral response is dominant: the IgG1/IgG2 ratio is high and IgA are strongly produced. Cytokines expressed by mucosa, in jejunal lymph nodes and spleen show concomitant Th1/Th2 profiles. Both antibody and cytokine responses are delayed in Iberian pigs, which do not express TNF-a. The larval burden is thus higher in Iberian than in German Yokshire pigs. Pig mast cells were activated with T. Spiralis antigens. MHC molecules are not modulated, but a degranulation is observed as soon as 15 minutes of stimulation. Among the antigens tested, TSL-1 binds to mast cell surface, and induces the production of Th2 cytokines as well as TNF-a and co-stimulatory molecules. Our analysis of pig mast cell activation by parasitic antigens evidences a potential key role of these cells as a link between innate and specific anti-T. Spiralis immunity

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Nyangahu, Donald D. "Alterations in preconception, antenatal, and postnatal maternal gut microbiota influence offspring intestinal microbiota and immunity." Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/25479.

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Maternal microbiota during pregnancy, as well as maternal disease state, may impact offspring gut bacterial colonisation. Here, we explore the impact of maternal antibiotics during gestation and/or nursing on offspring gut microbiota. Further, we investigate the effect of preconception helminth infections on maternal and infant gut microbiota. For maternal antibiotic experiments, dams were fed vancomycin, polymyxin B, or both, in drinking water during gestation, nursing or gestation plus nursing, and their offspring microbiota analysed at 14 days of life, alongside immunity in the spleens. Offspring born to vancomycin treated mothers had significantly higher relative abundance of Proteobacteria and Tenericutes while maternal oral polymyxin B led to significantly lower abundance of Proteobacteria and Deferribacteres in infants. Maternal oral vancomycin led to significant reduction in proportions of infant central memory CD4+ T cells (CD4+CD44hiCD62Lhi) regardless of antibiotic timing. Effector memory CD4+ T cells were significantly lower in pups born to dams treated with polymyxin B while nursing while proportions of central memory CD4 T cells were significantly increased in gestation only or gestation plus nursing pups. In addition, oral vancomycin in dams during nursing resulted in significantly reduced proportions of both total and follicular B cells in offspring born to antibiotic treated dams. Pups born to Vancomycin treated mothers had a significant delay in growth when infected with Respiratory Syncytial Virus (RSV). On the other hand, pups born to mothers treated with Polymyxin B during gestation or gestation plus nursing were susceptible to Nippostrongylus brasiliensis (Nb) infection. In the second study, we infected female BALB/c mice with 500Nb L3 three weeks prior to mating and examined the effect of preconception helminth infection on offspring microbiota and immunity. Preconception Nb infections led to alterations of maternal gut microbiota during pregnancy. In addition, we observed dramatic differences in offspring microbiota in pups born to previously helminth infected dams. Coriobacteriaceae were predominant in pups born to previously Nb infected dams when compared to uninfected dams. Overall, manipulation of maternal microbiota during gestation or lactation profoundly impacts offspring growth, intestinal microbiota and immunity to RSV and helminths.

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Coakley, Gillian. "Characterisation of secreted exosomes from the intestinal nematode Heligmosomoides polygyrus." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/23464.

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The parasite secretome has been shown to play a key role in both pathogenicity and the regulation of host defence, allowing pathogens, such as helminths, to establish a chronic infection within the host. The recently discovered presence of extracellular vesicles within parasite-derived excretory-secretory products introduces a new mechanism of potential cross-species communication. Extracellular vesicles (EVs), such as exosomes, facilitate cellular communication through the transfer of small RNAs, lipids and proteins between cells and organisms across all three kingdoms of life. In addition to their roles in normal physiology, EVs also transport molecules from pathogens to hosts, presenting parasite antigens and transferring infectious agents. Here, I examine secreted vesicles from the murine gastrointestinal nematode Heligmosomoides polygyrus, and their potential role in the host-helminth interactions. Transmission electron microscopy reveals vesicle-like structures of 50- 100 nM in the ultracentrifuged secretory product, and potential evidence of multi-vesicular bodies in the worm intestine. This, coupled with information from the exoproteome, helped support the hypothesis that exosomes originate from the parasite intestinal tract. I have completed a series of studies looking at the fundamental properties of exosome-cell interactions, providing comparative studies between mammalian and H. polygyrus-derived exosomes. I have determined some of the key factors influencing exosome uptake, including time of incubation, cell type and exosome origin. Through microarray analysis of H. polygyrus exosome-treated small intestinal epithelial cells, we see significant gene expression changes, including those involved in the regulation of signalling and the immune response, such as DUSP1 (dual-specificity phosphatase) and IL1RL1 (the receptor for IL-33). The modest reduction of inflammatory cytokine responses by exosomes in small intestinal cell lines was amplified in immune cells, such as macrophages. Exosomes can significantly reduce expression of classical activation markers, as well as inflammatory cytokine production in the macrophage cell line RAW 264.7, and this is further supported by similar responses in bone marrow-derived macrophages. Owing to their suppressive nature, I demonstrate that immunization of mice with an exosome/alum conjugate generates significant protection from a subsequent H. polygyrus larval challenge, as seen through a reduction in egg counts and worm burden. I have investigated the role of the IL33 receptor (IL-33R); a key molecule associated with parasitic resistance that is suppressed by exosomes in type-2 associated immune responses. Uptake of H. polygyrus-derived exosomes by alternatively activated macrophages caused the suppression of type 2 cytokine/protein release and the reduction of key genes associated with this phenotype. In addition, there was also significant repression of both transcript and surface T1/ST2, a subunit of the IL-33R). Using a model of lung inflammation, in vivo studies demonstrate that, in both prophylactic and co-administration experiments, exosomes modulate the innate cellular response. This is represented by changes in the number of innate lymphoid cells (ILCs), bronchoalveolar lavage eosinophils and type-2 cytokine output. In this system, the expression of T1/ST2 on type 2 ILCs was also significantly reduced. I have extended the investigation on exosome-IL-33R responses by using T1/ST2 knockout mice. Despite generating strong antibody responses, vaccination against exosomes could not protect T1/ST2 knockout mice against a subsequent infection. This work suggests that exosomes secreted by nematodes could mediate the transfer and uptake of parasite products into host cells, establishing cross-species communication to suppress the host ‘danger’ or inflammatory response.

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Morris, Bruce C. "Intestinal Mucosal Mast Cell Immune Response and Pathogenesis of Two Eimeria Acervulina Isolates in Broiler Chickens." Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/36228.

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Five experiments were conducted comparing differential intestinal immune responses to two isolates of Eimeria acervulina (EA), EA1 and EA2. In three experiments, broiler chicks were divided into control (non-challenged), EA1, or EA2 challenged (14 days of age) groups. On day 6 post-challenge (PC), changes in body weight were determined, intestinal lesions were scored, and duodenal tissue was evaluated for morphometric alterations and mucosal mast cell responses. EA1 produced duodenal lesions and reduced villus height to crypt depth ratios when compared to controls; however, no differences were found in mast cell counts. EA2 produced differing results, and observed data were suggestive of an intestinal secretory response when compared to EA1 or controls. In Experiment 4, tissues were analyzed from day 2 through day 6 PC. Villus atrophy and crypt hyperplasia were heightened on day 5 PC in both challenged groups. Mast cell counts were significantly greater on days 3 and 4 PC in EA1 birds. In Experiment 5, EA2 oocysts were cleaned with 5.25% sodium hypochlorite to evaluate the possibility of a bacterial contaminant contributing to the pathogenesis of intestinal alterations. Weight gains were decreased by challenge and villus heights and crypt depths were significantly altered in challenged birds, resulting in lower villus to crypt ratios, however, there were no differences in mast cell number. These data are indicative of differential host response and immunovariability between different isolates of the same Eimeria species and are suggestive of mast cell involvement in coccidial immunity in broiler chickens.
Master of Science

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Dissertations / Theses on the topic 'Immunité intestinal'

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