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Toufik, Jamila. "Interactions de copolymères fonctionnels dérivés du Sephadex avec le système du complément et les monocytes humains." Paris 13, 1994. http://www.theses.fr/1994PA132010.
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Chez les patients en état d'insuffisance rénale, les membranes d'hémodialyse à base de cellulose activent le système du complément et induisent la production d'interleukine-1 (il-1) par les monocytes. Le sephadex (seph) a été utilisé comme modèle de la cellulose. C'est un activateur du complément par la voie alterne; cette activation dépend de la présence d'anticorps anti-dextrane et de la surface de contact. Les carboxymethyle seph (cmseph) sont des inhibiteurs de cette activation. Les dérivés de seph: cmseph, cmbseph portant des groupes cmbenzylamide, cmbso3seph portant des groupes cmbsulfonates et deaeseph portant des groupes diethylaminoethyle, substitués à des taux variables, ont été choisis comme surfaces polysaccharidiques modèles d'étude de l'activation et de l'inhibition du complément et de l'induction de la production et de la sécrétion d'il-1par les monocytes humains. Les dosages hémolytiques ch50, radioimmunologiques de c3a et immuno-electrophoretiques de c3 ont montré que les cmbseph et cmbso3seph sont des activateurs du complément. Les deaeseph sont des inhibiteurs; cet effet est du au moins en partie au fait que les anticorps anti-dextranes ne reconnaissent plus les deaeseph. Après contact de tous ces dérivés avec des monocytes humains en absence de sérum, et en présence ou non de stimulateur microbien (lps), les dosages elisa d'il-1 intra et extracellulaires, montrent que seph et cmseph n'ont pas d'effet sur la production et la sécrétion d'il-1, cmbs03seph et surtout cmbseph stimulent la sécrétion, et surtout la production d'il-1 par les monocytes, deaeseph inhibe cette production.
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Bonnefont-Rebeix, Catherine. "Obtention et caractérisation de cellules dendritiques canines issues de monocytes." Lyon 1, 2006. http://www.theses.fr/2006LYO10292.
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Les cellules dendritiques (DC) sont largement étudiées chez l’homme et dans d’autres espèces animales, du fait de leur rôle central dans la régulation du système immunitaire. Leur forte capacité à présenter l’antigène a conduit à leur utilisation en immunothérapie vaccinale anti-tumorale. Le chien étant un très bon modèle dans les maladies auto-immunes, les greffes et les cancers, une meilleure caractérisation des DC canines (cDC) serait utile. Dans la première partie de ce travail, les cDC issues de monocytes (cMo-DC) et obtenues avec les facteurs de croissance cGM-CSF et cIL-4 expriment la molécule de costimulation CD86, spécifiquement induite par l’IL-4 canine (cIL-4), et le blocage du CD86 entraîne une inhibition de la prolifération induite par les cMo-DC en MLR. Dans la seconde partie, l’expression du TLR3 est explorée, ce récepteur étant fonctionnellement important et plus spécifiquement présent sur les DC humaines. Il s’avère que seules les cMo-DC montrent une forte expression intracellulaire du TLR3, comparativement aux autres leucocytes. Ainsi, étant donné le manque de marqueurs canins spécifiques, ce travail contribue à une meilleure caractérisation des cMo-DC, pouvant aider à leur utilisation en immunothérapieDentritic cells (DC) are widely investigated in human and many species, since they play a key role in the regulation of the immune system with their unique capacity of priming naïve T cells. Their high potency in antigen presentation has led several investigators to use them as vaccine adjuvants in therapy against tumors. Since dog is considered as a very interesting model in immune-mediated diseases, grafts and cancers, a better characterization of canine DC (cDC) is required. In the first part of this study, the expression of the costimulatory molecule CD86 was shown to be induced specifically by canine IL-4 on canine monocyte-derived DC (cMo-DC) in the presence of cGM-CSF plus cIL-4. The blocking of this CD86 led to the inhibition of cMo-DC-induced proliferation in MLR. The second part investigated the TLR3, a member of functionally important receptors family found to be more specifically expressed in human DC. TLR3 expression was strongly revealed at intracellular level in cMo-DC in comparison with other white blood cells. Therefore, since there is a lack of canine specific markers, these results contribute to a better characterization of cMo-DC, and may help for their use in immunotherapy
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Miranda, de Carvalho Camila. "Génération in vitro et caractérisation immunophénotypique des cellules dendritiques canines obtenues à partir de monocytes." Lyon 1, 2004. http://www.theses.fr/2004LYO10208.
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Actuellement, les cellules dendritiques (DCs) sont très étudiées chez l'homme et chez la souris. Cependant, les travaux expérimentaux restent assez pauvre pour la majorité des autres espèces animales. Le chien présente des pathologies cancéreuses et auto-immunes spontanées comparables à celles de l'homme. De ce fait, il paraît être un bon modèle animal potentiel pour évaluer la validité de l'immunomodulation par l'intermédiaire des cellules dendritiques. Dans un premier temps, nous avons développé une méthode visant à purifier les monocytes canins. Dans ce travail, nous avons pu mettre au point une méthode de purification des monocytes canins en combinant une technique d'élutriation et d'immunopurification complémentaire par des billes magnétiques. Ensuite, nous avons produit et caractérisé des Mo-DCs en utilisant de l'IL-4 et du GM-CSF de chien. Nous avons établi que la molécule CD86 était un marqueur spécifique de ces cellules dans cette espèce. Ces cellules dendritiques canines sont très fortement stimulantes en MLR et expriment aussi de façon importante les molécules CMH de Classe II et le CD32. Le marquage spécifique CD86 permettra de mieux purifier et analyser les fonctions de ces cellules chez le chien. Ces travaux permettrons de mieux caractériser et produire des cellules dendritiques canines pour envisager leur utilisation en immunothérapie et ouvrir les perspectives de recherche thérapeutiques chez cette espèce
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Nicolas-Gaulard, Isabelle. "Activité immunomodulatrice d'une protéine, l'hypodermine A, sur les cellules sanguines mononucléées des bovins." Paris 12, 1995. http://www.theses.fr/1995PA120031.
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Parmi les grandes maladies parasitaires qui affectent le cheptel bovin francais, l'hypodermose est responsable de pertes economiques importantes. Le premier stade larvaire de l'insecte responsable de cette parasitose provoque une desorganisation des systemes de defense de l'hote. Ces defaillances sont causees par les secretions larvaires et principalement par l'hypodermine a (ha). L'objet de ces travaux est l'etude de l'activite immunomodulatrice de l'ha sur les cellules sanguines mononucleees des bovins. L'ha inhibe la proliferation des lymphocytes apres stimulation par une lectine mitogene ou par un agent chimique et agit sur la phase precoce de l'activation cellulaire. De plus, l'indometacine, qui inhibe la synthese des prostaglandines, restaure la reponse proliferative des pbmc. La production en pge#2 est augmentee par l'ha dans les cultures de pbmc ou de monocytes. Les concentrations en pge#2 equivalentes a celles dosees dans les cultures en presence d'ha sont inhibitrices de la reponse proliferative a la phytohaemagglutinine. L'ha agirait donc sur la diminution de la reponse des pbmc par une voie dependante des prostaglandines. L'ha induit une baisse de la production d'il2 et beaucoup moins importante de l'ifn dans ces cultures stimulees par la phytohaemagglutinine. Une restauration de la proliferation des lymphocytes est observee par adjonction de surnageant enrichi en il2. La fonction accessoire des monocytes et la production de no, qui sont impliquees dans la proliferation des lymphocytes, sont inhibees par l'ha. L'ha module egalement l'expression de differents marqueurs a leur surface. Tous ces mecanismes decrits in vitro pourraient expliquer les phenomenes d'echappement du parasite au systeme immunitaire du bovin
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Baudesson, de Chanville Camille. "Rôle des monocytes dans la régulation de la réponse inflammatoire au cours du sepsis." Electronic Thesis or Diss., Sorbonne université, 2018. http://www.theses.fr/2018SORUS376.
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Le sepsis est une pathologie fréquente et grave. Il est défini comme un dysfonctionnement organique causé par une réponse dérégulée de l’hôte envers une infection. Une phase hyperinflammatoire précoce fait suite à la reconnaissance de l’agent pathogène et est progressivement remplacée par une immunosuppression à long terme entrainant une sensibilité prolongée des patients aux infections nosocomiales. Nos travaux ont montré que les Mo inflammatoires étaient fortement impliqués dans le contrôle de l’inflammation durant les phases précoces et tardives au cours d’un sepsis polymicrobien murin. En effet, lors de la phase « hyper-aiguë » la mobilisation des Mo participe à la surveillance et à la protection des tissus rénaux grâce à des mécanismes d’adhésion cellulaire dépendant du récepteur CX3CR1. La seconde phase du sepsis est le plus souvent décrite comme « immunosuppressive ». Nous avons mis en évidence une accumulation systémique des Mo et des PMN durant cette dernière phase. La caractérisation de leur localisation a montré que ces cellules s’accumulaient spécifiquement dans le réseau vasculaire des organes sans infiltrer les tissus. Les Mo Ly6Chigh et leurs récepteurs aux chimiokines CCR2 et CX3CR1 ont été identifiés comme essentiels à la surveillance pulmonaire lors d’une infection secondaire au sepsis. Cependant, la capacité de ces cellules à stimuler et à réguler les réponses immunitaires semble être altérée. Ainsi, l’état d’activation des Mo inflammatoires ne permettrait pas une protection efficace contre les infections opportunistes pulmonaires secondaires au sepsisSepsis is a common and life-threatening pathology. It is defined as an organic dysfunction caused by a dysregulated host response to infection. An initial hyper-inflammatory phase follows recognition of the pathogen and is progressively replaced by long-term immunosuppression leading to prolonged sensitivity to superinfections. Monocytes (Mo) are one of the first lines of phagocytic cells in the lung. Understanding how these cells participate in pulmonary supervision during sepsis would allow the development or improvement of treatments for enhancing resistance to secondary nosocomial infections. We showed that monocytes are strongly involved in the control of inflammation during the early and late phases of murine polymicrobial sepsis. Indeed, during the acute phase of sepsis, inflammatory monocyte mobilization participates to the monitoring of renal tissues and has a protective effect via a CX3CR1-dependent adhesion mechanism. The second phase of sepsis is most often described as “immunosuppressive”. We demonstrated a systemic accumulation of myeloid cells during this last phase. Characterization of their localization showed that these cells accumulated specifically in the vascular network of the organs without infiltrating the tissues. Ly6Chigh monocytes and their chemokine receptors CCR2 and CX3CR1 have been identified as essential for pulmonary supervision during first and second infection. However, the ability of these cells to stimulate and regulate immune responses appears to be impaired. Thus, the activation state of inflammatory Mo would not protect against a second pulmonary infections post sepsis
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Menasria, Rafik. "Caractérisation de la réponse immunitaire innée médiée par les monocytes/macrophages dans un modéle murin d'encéphalite herpétique." Thesis, Université Laval, 2013. http://www.theses.ulaval.ca/2013/29754/29754.pdf.
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Faivre, Valérie. "Régulation immunitaire au cours du sepsis altérations monocytaires et différenciation en sous populations de cellules dendritiques." Paris 7, 2007. http://www.theses.fr/2007PA077233.
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Le sepsis est une pathologie fréquente en réanimation. La mortalité est encore proche de 50% (cas les plus sévères). Il met en jeu une réaction pro- et anti-inflammatoire systémique, consécutive à une infection. Le rôle du système immunitaire est majeur, avec évolution possible vers un excès inflammatoire nocif mettant en danger les organes à distance du foyer infectieux, ou vers une réponse anti-inflammatoire trop intense favorisant les surinfections. Le but de ce travail a été de préciser les mécanismes de cette susceptibilité à l'infection, en particulier au niveau du monocyte. Les résultats montrent que les monocytes de patients (péritonite) sont capables de se différencier in vitro, et de façon accélérée, en cellule dendritique (DC). Dans ces DC, une sous population CD la- apparaît, en proportion très augmentée chez les patients. Des cellules T stimulées par des DC CD 1a- de donneurs contrôles ou de patients ne prolifèrent pas. Par contre, les DC CD 1a- contrôles induisent une polarisation Th2 et régulatrice, alors qu'avec les DC CD 1a- des patients l'orientation est plutôt Th1. Ceci pourrait favoriser la lutte contre l'infection mais aussi la destruction tissulaire des organes à distance. A l'inverse, les DC CD1a+ des patients semblent induire, avec une augmentation d'expression de FoxP3 dans les T en prolifération, un profil régulateur plus fort que les DC CD1a+ contrôles. Ces résultats suggèrent l'existence d'un contrôle de la réponse inflammatoire et immunitaire au cours du sepsis par l'apparition de populations monocytaires à définir, suite à un processus durable de reprogrammation cellulaire. La participation de ce processus dans les surinfections est à préciserSepsis is frequently observed in intensive care, with mortality around 50% (most severe cases). This pathology involves a systemic inflammatory response that occurs following infection. The immune System plays a major role in this inflammatory syndrome, with a potential progression toward an excessive response, dangerous for peripheral organs, or toward inadequate anti-inflammatory control and re-infections. The aim of this work was to precise mechanisms involved in this infection susceptibility, especially those related to monocyte. Results showed that peritonitis patients monocytes are able to differerentiate in vitro into dendritic cells (DC), in an accelerated manner. Ànalysis of these DC showed the emergence of a CD la- DC subset, which proportion is strongly increased in patients. T cells stimulated with control donors or patients CD la- DC do not proliferate. However, T cells cultured with control CD la- DC display Th2 and regulatory polarization, whereas patients CD la- DC favored Th1 profile. This polarization switch could enhance immune response against infection, but also peripheral tissue injury. By contrast, patients CDla+ DC potentially induced a stronger regulatory response in proliferating T cells, as suggested by increased Foxp3 expression, than did control CDla+ cells. These results suggest an additionnal and complex control of inflammatory and immune responses during sepsis, that could take place via the development of monocytes subsets, which remains to be characterized, and could result from a long-lasting cellular reprogramming process. The involvement of this process in the occurrence of secondary infections needs further investigations
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García, Téllez Thalia Alejandra. "Study of inflammasome activation in monocytes, macrophages and epithelial cells during SIV infection in a pathogenic and a non-pathogenic model." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC300.
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Chez les individus infectés par le VIH on observe une augmentation de l’inflammation et de l’activation immunitaire (AI) qui est associée à la progression vers le SIDA. Même en présence de traitements antirétroviraux, les niveaux d’AI restent élevés et sont associés à une morbidité et une mortalité accrues. Les mécanismes moléculaires derrière l’AI ne sont pas bien caractérisés. L’activation des macrophages (Mφ ) et monocytes et la translocation bactérienne peuvent jouer un rôle important. Contraire aux humains, et au model pathogène de l’infection (macaques, MAC), les hôtes naturels du SIV (Singes vertes d’Afrique, AGM), résoudraient l’inflammation aiguë, ils montrent un niveau plus bas de cytokines inflammatoires comme l’IL-1β et l’IL-18 et l’IA chronique est absente. L’IL-1β et l’IL-18 sont produits par le Mφ et les cellules épithéliales de l’intestine (IEC) auprès l’activation de l’inflammasome. Nous avons étudié l’activation de l’inflammasome chez les hôtes naturels, dans quel tissues ceci peut avoir lieu et s’il existe des différences entre les deux modelés d’infection. Pour cela, nous avons mesuré les niveaux plasmatiques de l’IL-1β et l’IL-18 au cours de l’infection ; nous avons analysé le marquage des Mφ , IEC et IL-18 par microscopie confocale; nous avons mis en place des essaies fonctionnels pour l’activation in vitro de l’inflammasome et nous avons développé les outils pour le phenotypage et l’isolation de Mφ et IEC du sang, du poumon, du LAB, des ganglions et de l’intestine. Nous avons montré que l’inflammasome est activé lors de l’infection par SIV dans les modèles pathogène et non-pathogène, en particulier dans l’intestine grêle. Notre étude indique une production plus notable d’IL-18 dans le jéjunum des MAC infectés en comparaison avec des AGM. Nous avons montré que l’inflammasome peut être activé dans les macrophages par des signaux de l’environnement présent lors de la translocation bactérienne et le stress cellulaire, comme le LPS et l’ATP. Nous avons montré de différences au niveau de régulation de la réponse liée à l’inflammasome. Les niveaux d’IL-18BP et l’IL-1RA, les antagonistes de l’IL-18 et l’IL-1β respectivement, sont été plus élevés chez les AGM que chez les MAC. On a trouvé une corrélation entre les niveaux de IL-18BP/IL-1Ra et les niveaux plasmatiques des agonistes chez les hôtes naturelles mais pas chez les MAC, ce qui est indicative de une régulation potentiellement plus efficace chez les AGMChronic immune activation drives progression toward AIDS in HIV infection and still remains in low levels in antiretroviral-treated patients increasing the risk of non-communicable diseases. Such non-AIDS co-mobility and mortality is associated with markers of monocyte/macrophage (Mφ ) activation and microbial translocation, but the molecular bases of this phenomenon remain unknown. In contrast to humans and pathogenic animal models of HIV (i.e. macaques, MAC), natural hosts of SIV (i.e. African Green Monkeys, AGM) quickly resolve SIV-induced inflammation and display lower levels of IL-1β and IL-18. IL-1β and IL-18 can be produced by Mφ or intestinal epithelial cells (IEC) upon inflammasome activation with potential multiple roles. Therefore, we studied whether the inflammasome activation upon SIV-infection occurs in natural hosts, in which tissues it might take place and if it differs between models. To do so, we measured plasmatic IL-1β and IL-18 levels along SIV-infection; we performed microscopy staining of Mφ , IEC and IL-18 in tissues, we set-up functional assays for inflammasome activation in-vitro and we developed tools for phenotyping and isolating Mφ and IEC from blood, lung, BAL, LN and gut. We showed inflammasome activation in vivo during pathogenic and non-pathogenic SIV infection evaluated by IL-18 in the gut of MAC and AGM, particularly in the small intestine, as well as by the levels of IL-18 and IL-1β in plasma. Our study indicated higher IL-18 production in the jejunum of SIV-infected MAC as compared to SIV-infected AGM. We showed that signals that might be in the environment during pathogenic SIVmac infection, in particular LPS and ATP as a result of microbial translocation and stress activate the inflammasome of MAC and AGM macrophages. We revealed differences at the level of the regulation between both models, observed by higher levels of IL-18BP and IL-1RA in AGM compared to MAC and correlations between IL-18, IL-1β and their respective antagonists only in AGM but not in MAC
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Le, Pan Yanaëlle. "Étude de la biocompatibilité des surfaces artificielles au cours de l'hémodialyse." Compiègne, 1998. http://www.theses.fr/1998COMP1105.
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Nous avons étudié, in vitro et in vivo, si le complément et l'activation des leucocytes chez des patients dialysés étaient directement liés. Nous avons montré que les anaphylatoxines induisent la production de cytokines proinflammatoires et préférentiellement MCP-1. De plus, la sécrétion d'IL-1 et de son antagoniste naturel est dans un rapport ne contrebalançant pas les effets biologiques de l'IL-l. Dans un protocole clinique, 6 patients ont été dialysés chacun sur 3 types de membranes activant le complément à divers degrés. Nous avons mesuré l'activation du complément, l'expression des molécules d'adhérence, la leucopénie, la production de cytokines et les gaz du sang. Le nombre de neutrophiles et de monocytes diminue après 5 et 15 minutes de dialyse en fonction du type de membrane utilisée. Cette margination ne corrélait pas avec l'activation du complément sauf chez les dialysés sur la membrane la moins activatrice du complément. Un pourcentage important de cellules contenant des cytokines proinflammatoires (IL-1 , IL-1 , IL-8, TN) chez les patients dialysés avec la cuprophane a été détecté. Les cellules qui stockent de l'IL-1 ne produisent pas toutes de l'IL-lra et peuvent donc avoir in vivo un potentiel proinflammatoire. En accord avec d'autres études, nous suggérons que d'autres facteurs que le C3a interviendraient dans l'augmentation de l'expression membranaire de C11 b sur les neutrophiles. Nous n'avons trouvé aucune corrélation entre l'expression des molécules d'adhérence membranaires ou solubles et l'activation du complément, entre l'expression des molécules d'adhérence solubles et membranaires, entre les variations des pO2 et pCO2 et l'activation du complément. Contrairement à d'autres études nous n'avons pas trouvé de lien entre le nombre de cellules circulantes et l'activation du complément. L'activation du complément n'est donc pas en relation directe avec la modulation des paramètres immunologiques, que nous avons étudiés, au cours de la dialyse.
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Hastir, Jean-Francois. "Study of the fate of resident macrophages and monocytes upon partial liver resection and their impact on hepatocarcinoma outgrowth." Doctoral thesis, Universite Libre de Bruxelles, 2020. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/308316.
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Partial hepatectomy (PH) is a treatment of choice for patients suffering from early stage hepatocellular carcinoma (HCC). Ablation of large proportion of the liver is rendered possible because of the ability of the liver to regenerate. Yet, a significant number of patients will experience recursion of the disease. Such relapses are unfortunately rather frequent and constitute a bad prognosis. The development of new strategies aiming at reducing the risk of recursion of HCC is thus a paramount element of the surgery-based treatment. Some previous studies have proposed that the regenerative process as well as the fate of the immune cells during the liver regeneration process is linked to this recurrence phenomenon.In this study, we investigated the impact of PH on HCC development in a pre-clinical murine model. We implanted Hepa1-6 hepatocarcinoma cells (a murine hepatocarcinoma cell line) directly in the liver of mice and compared a non-resected group with a group undergoing 40% PH one week following tumor implantation. Analysis were relying on bioluminescence imaging and flow cytometry. We demonstrated that liver regeneration increases tumoral proliferation. This proliferation was associated with a reduction in the number of liver resident macrophages, i.e. Kupffer cells (KC). KC anti-tumoral activity was also proved using conditional ablation model. We further studied the mechanisms leading to this disappearance and demonstrated that, under normal regeneration conditions, PH-induced KC number reduction was dependent on tumor necrosis factor-α (TNF-α), receptor interacting protein kinase (RIPK) 3 and caspase-8 activation whereas interleukin (IL)-6 acted as a KC pro- survival signal. In mice with previous Hepa 1-6 encounter, the KC reduction changed toward a TNF-α-RIPK3-caspase-1 activation. This data suggest a switch from apoptosis to pyroptosis induction in KC following PH. Moreover, KC disappearance associated with caspase-1 activity induced the recruitment of monocyte derived cells that are beneficial for tumor growth while caspase-8 dependent reduction did not, underlying the importance of macrophages activated death-pathway in regulating the anti-tumoral immune response. Our results show the necessity for comprehensive multidisciplinary treatment approach following PH and propose new targets in order to reduce the relapse of the disease occurring after surgery.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished
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Benyebdri, Fethia. "Rôle des nucléotides extracellulaires dans la migration des neutrophiles induite par des déterminants pathogéniques." Thesis, Université Laval, 2011. http://www.theses.ulaval.ca/2011/27839/27839.pdf.
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Mehraj, Vikram. "A transcriptional approach to define new biomarkers : application to q fever." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5021/document.
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Les macrophages sont fonctionnellement polarisés en macrophages inflammatoires et microbicides (M1) ou immunorégulateurs (M2). Que les monocytes circulants soient polarisables n’est pas démontré. Nous avons étudié la signature transcriptionnelle par microarray et RT-PCR en temps réel de monocytes humains stimulés par l’IFN-γ, un inducteur des macrophages M1 et l’IL-4, un inducteur des macrophages M2. Leur profil de réponse précoce est dépendent de l’agoniste alors que la réponse tardive des monocytes est similaire qu’ils soient stimulés par l’IFN-γ ou l’IL-4. Cette approche dynamique de la réponse monocytaire permet probablement une étude bien plus pertinente des patients atteints d’une fièvre Q que le modèle de polarisation macrophagique. Par ailleurs, la prévalence de la fièvre Q est plus importante chez l’homme que chez la femme. Comme il a été montré que des gènes associés au cycle circadien sont modulés chez les souris infectées par Coxiella burnetii, la bactérie responsable de la fièvre Q, nous avons étudié ces gènes au cours de la fièvre Q. C’est ainsi que le gène Per2 est fortement exprimé chez les hommes atteints d’une fièvre Q aiguë. Ces résultats suggèrent donc que la modulation de gènes circadiens est associée à une maladie infectieuse chez l’homme. L’expression des gènes LNX1 and LNX2, qui codent deux enzymes impliquées dans le catabolisme des protéines, est accrue dans l’endocardite de la fièvre Q mais pas dans la fièvre Q aiguëMacrophages are functionally polarized into inflammatory and microbicidal (M1) and immunoregulatory (M2) cells. If circulating monocytes may be polarized is not known. We determined the transcriptional signatures of human monocytes stimulated with IFN-γ and IL-4, known to induce the polarization of macrophages into M1 and M2 cells, respectively, using microarrays and real-time RT-PCR. We found that monocytes exhibited an early pattern of activation specific to IFN-γ or IL-4 and a late pattern of activation common to both agonists. The selected biomarkers of early and late responses were tested in patients with Q fever. We showed that the kinetic model of monocyte activation enables a dynamic approach for the evaluation of patients with acute Q fever or Q fever endocarditis. On the other hand, it is known that the prevalence of Q fever is related to sex and is higher in men than in women. Based on previous studies on an experimental model of infection by Coxiella burnetii, the agent of Q fever, we hypothesized that circadian genes are differently modulated in men and women with Q fever. We showed that the expression of the Per2 gene was significantly increased in males with acute Q fever compared with healthy volunteers but did not differ in females with Q fever and healthy females. These results suggest that that the modulation of circadian genes is associated with a human infectious disease. We also found that the expression of LNX1 and LNX2 genes that encode two enzymes involved in protein degradation is increased in Q fever endocarditis but not in acute Q fever
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Uhel, Fabrice. "Cellules suppressives d'origine myéloïde au cours du sepsis." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B002/document.
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Le sepsis est à l’origine d’une dysfonction immunitaire prolongée responsable d’infections nosocomiales et d’une mortalité tardive élevée. Sa physiologie complexe demeure mal connue et il n’existe aucun traitement spécifique en dehors de l’antibiothérapie et des thérapeutiques de suppléance d’organes. Nous nous sommes intéressés au rôle des cellules myéloïdes dans cette dysfonction immunitaire. Nous avons pu montrer qu’il existe chez les patients atteints de sepsis une augmentation du nombre de cellules suppressives d’origine myéloïde monocytaires (M-MDSC) CD14+HLA-DRlow/- et granulocytaires (G-MDSC) identifiées comme des granulocytes de faible densité CD14-CD15+. Ces cellules sont responsables d’une activité Indoléamine 2,3-dioxygénase (IDO) et arginase 1, et leur déplétion permet de restaurer la prolifération des lymphocytes T in vitro. L’augmentation précoce des G-MDSC prédit la survenue ultérieure d’infections nosocomiales. De même, l’augmentation de l’activité IDO et de l’arginase 1 plasmatique sont associées à un mauvais pronostic. Au total, nous avons pu démontrer que les cellules myéloïdes acquièrent un phénotype suppresseur en partie responsable de l’immunodépression acquise et du pronostic péjoratif chez les patients septiques. Afin de restaurer les capacités immunitaires des patients, les MDSC pourraient devenir une future cible thérapeutiqueSepsis results in a sustained immune dysfunction responsible for poor prognosis and nosocomial infections. Sepsis physiology remains poorly understood and no treatment exists currently, excepted from antibiotherapy and life-support techniques. We asked if myeloid cells could play a role in this sustained immune dysfunction. We demonstrated that Peripheral CD14+HLA-DRlow/- monocytic-myeloid-derived suppressor cells (MDSCs) and CD14-CD15+ low-density granulocytes identified as granulocytic- (G-)MDSCs were increased in septic patients. In vitro, arginase and IDO activities relied on MDSCs and depletion of both subsets restored T-cell proliferation. The initial proportion of G-MDSC predicted occurrence of nosocomial infections. Similarly, high plasma Indoleamine 2,3-dioxygenase (IDO) activity and arginase 1 level were associated with poor outcome. Altogether, our results demonstrate that myeloid cells acquire suppressive functions during sepsis, partially responsible for the sustained immune dysfunction and poor outcome. MDSCs may become a future therapeutic target to restore the immune capacities of septic patients
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Gorvel, Laurent. "Cellules dendritiques : infection et immunité tissulaire." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5089.
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Les cellules dendritiques (DCs) jouent un rôle essentiel dans la réponse immunitaire. En effet leur fonction de présentation de l’antigène les place au cœur de l’induction de la réponse immunitaire adaptative. Ceci, les rends vulnérables aux attaques des agents pathogènes. En effet de nombreux agents pathogènes détournent la réponse des DCs. Je me suis donc proposé d’étudier la réponse des DCs à Tropheryma whipplei, Coxiella burnetii, Brucella abortus et Orientia tsutsugamushi. J’ai pu mettre en évidence un défaut de maturation des DCs infectées par C. burnetii et B. abortus, liée à un défaut de la voie de l’interféron (IFN) de type I et de secretion de l'IFN-b. La deuxième partie de ma thèse replace le système immunitaire inné dans le cadre de l’immunité tissulaire humaine. Je me suis premièrement intéressé aux macrophages placentaires. J’ai pu démontrer que la capacité des macrophages placentaires à former des MGCs est altérée lors d’une chorioamniotite, ce qui laisse supposer que ces cellules géantes jouent un rôle dans le maintient de la tolérance fœto-maternelle. Deuxièmement je me suis intéressé aux DCs placentaires (plaDCs). J’ai ainsi put démontrer que les plaDCs sont de véritables DCs myéloïdes conditionnées par leur environnement direct ou hormonal au cours de la grossesse. Mon travail illustre deux concepts, le premier démontre la nécessité d’utiliser des techniques à haut débit pour identifier les perturbations induites par plusieurs agents pathogènes. Le deuxième démontre que l’environnement des cellules immunitaires participe fortement à leurs réponses face à des agents pathogènes mais également sur leur phénotype et fonctionDendritic cells (DCs) play a key role in the immune response. Indeed, their antigen presenting function allows them to be considered as the main inducers of adaptive response. This pivotal role also makes vulnerable to pathogen attacks. Indeed, numerous pathogens target DC response to avoid a microbicidal adaptive immunity to take place. To understand these mecanisms, I investigated the response of DCs to T. whipplei, C. burnetii, B. abortus and O. tsutsugamushi. I could highlight a phenotypic but not functional defect of maturation in DCs infected by C. burnetii and B. abortus, which was related to a defect in type I IFN response. Indeed, C. burnetii and B. abortus did not induce the production of IFN-b and induced an abnormal phosphorylation of MAPKs, known to participate to DC maturation. In this study, I could demonstrate that C. burnetii and B. abortus interfere with type I IFN response. The second part of my thesis dealt with innate immune system in the human tissue. First I interested myself in placental macrophages. I demonstrated that placental macrophages ability to form MGCs was altered in chorioamnionitis, suggesting that MGCs play a role in tolerance as they disappear in an infectious pathology. Second, I interested myself in placental DCs (plaDCs) for which I could conclude that plaDCs are true myeloid DCs that are polarized by their microenvironment. My work highlight two concepts, the first one demonstrate the necessity of high throughput methods for the analysis of cell response to several pathogens. The second concept demonstrates that direct environment or hormones can affect immune cells response to pathogen but also their phenotype and function
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Zare, Fatemeh. "Tumors and Ly6Chigh Monocytes." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/291941.
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Cancer immunotherapy represents a treatment strategy which is being clinically tested to complement surgery, radiotherapy and chemotherapy – the current cornerstones of our fight against cancer. It has become clear now, that tumors not only escape immune recognition but also actively suppress antitumor immune responses. In order to improve cancer immunotherapy, effective manipulation of the immune system to break self-tolerance need to be designed and approaches that counteract immunosuppressive mechanisms need to be developed. The tumor microenvironment encompasses a wide variety of immune cells, which macrophages comprise the most dominant portion of them and thus are the major players in the connection between inflammation and cancer. These tumor-associated macrophages (TAMs) are derived from blood monocyte precursors and subsequently acquire distinct characteristics as a result of tumor micro-environmental cues. Monocytes are a heterogeneous population in the blood with an enormous plasticity whose fate and functions are dictated by the microenvironment. Therefore, the roles of specific Monocytes subsets in tumor progression and the molecular mechanisms for their impacts need to be elucidated. Ly6Chigh and Ly6Clow are two main different types of murine monocytes subsets that have been defined by distinct phenotypes and immunoregulatory functions. Recent data demonstrates that Ly6Chigh monocytes can recruit to inflammation loci while Ly6Clow monocytes are patrolling cells. We have developed a method to produce large number of Ly6Chigh monocytes in vitro. In our study we observed that, injection of these cells affects tumor progression in breast cancer and C26 colon carcinoma. Activation of Ly6Clow monocytes by pro- or anti-inflammatory cytokines, results in a genetic expression profile, corresponding to pro- or anti-inflammatory genes, respectively. Injection of pre- activated Ly6Clow monocytes toward pro- or anti-inflammatory polarization in C26 colon carcinoma showed that anti-inflammatory activated monocytes are more beneficial in delaying cancer cachexia. Increased knowledge of monocytes improves the chances to find therapies against a broad spectrum of diseases including cancer, where monocytes have opposing roles of either being beneficial or detrimental to the host.
Using C26 cancer model we were interested to study the impact of activation of Ly6Chigh monocytes toward pro or anti-inflammatory phenotype on the progression of cancer. We conducted the C26 cancer model injecting Ly6Chigh monocytes treated with IL-4 or INF-. before injection. Among the groups of treatment, Ly6Chigh monocytes activated with IL-4 were the most beneficial on cancer progression, since they had the highest survival rate and the least tumor volume rise among all groups. Since the whole cachectic muscles are inflamed and injured in C26-bearing mice and activated Ly6Chigh monocytes injected in this cancer model apart from recruiting to tumor site have played substantial role by affecting cachectic muscle repair.
In summary, we defined a new regulatory role of recruiting Ly6Chigh monocytes in cancer, which might be clinically relevant in developing novel immunotherapeutic strategies. Although, underlying mechanism by which Ly6Chigh monocytes influences the tumor progression have yet to be established and it requires further studies to characterize the phenotype of these cells after recruitment in cancer. So far, since the inflammatory genes involved in tumor progression were differently regulated in tumors infiltrated with Ly6Chigh monocytes, our hypothesis is that the recruitment of Ly6Chigh monocytes, alter the balance of pro-inflammatory/anti-inflammatory pool of macrophages in the cancer and this is the main reason why modulation impacts occur in this study. While pro-inflammatory macrophages will be able to induce wound hilling and revascularization, the anti-inflammatory macrophages will block the tumor growth through the production of fibrosis.
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Golden, Jackelyn B. "Abnormalities in the Adhesion and Aggregation Profiles of Circulating Monocytes in Psoriasis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1441361209.
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Owen, Caroline Ann. "Monocyte adherence to fibronectin : role of CD11/CD18 integrins and relationship to other monocyte functions." Thesis, University of Birmingham, 1993. http://etheses.bham.ac.uk//id/eprint/36/.
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Regulated adherence of monocytes to extracellular matrix macromolecules is a prerequisite for their accumulation at sites of pulmonary infection and inflammation. To begin to assess the pathobiological importance of alterations in monocyte adherence to extracellular matrix in inflammatory lung diseases, the adherence properties of monocytes from patients with an inflammatory lung disease (bronchiectasis) and healthy subjects to a representative matrix component (fibronectin) were compared. Spontaneous adherence of monocytes from the control subjects was 20 to 25%, whereas that of the patients' cells was 2 to 3-fold higher and correlated with the severity of airway inflammation. Endotoxin (LPS) and cytokines from areas of airway disease are likely to be responsible for the observed monocyte activation since: 1) LPS was detected in plasma from all of the patients but none of the control subjects; and 2) LPS and cytokines produced dose-related increases in the adherence of normal monocytes in vitro. Monocyte adherence to fibronectin was substantially mediated by CD11/CD18 integrins, via both RGD-dependent and RGD-independent mechanisms. These data indicate that signals arising from foci of pulmonary inflammation are likely determinants of the accumulation of monocytes in the lungs of patients with chronic inflammatory lung diseases. There was a striking relationship between the adherence properties of monocytes and functions that are of biological importance at sites of inflammation. Spontaneously adherent monocytes had an "inflammatory effector" phenotype, non-adherent cells had an "immune modulatory" phenotype and monocytes that could stimulated to adhere by LPS (LPS-adherent cells) had an intermediate phenotype. In addition, only the adherent monocyte subpopulations were replete with HLE and these cells contained a substantial (10 to 11-fold) molar excess of HLE compared with the physiological inhibitor of this enzyme (a1-antitrypsin). Maturation in vitro increased the accumulation of a1-antitrypsin by all of the monocyte subpopulations. In contrast, proinflammatory mediators up-regulated a1-antitrypsin accumulation by only the spontaneously adherent cells, probably by translational or post-translational mechanisms. In conclusion, these data indicate that monocytes are heterogeneous in their ability to accumulate at sites of infection and inflammation. In addition, the capacity of monocytes to adhere to fibronectin is related to monocyte functions that are of biological importance at sites of infection and inflammation. Furthermore, LPS released from foci of infection, may induce the accumulation of monocytes with an inflammatory effector phenotype, and may thereby promote resolution of tissue infection. Alternatively, LPS may promote the recruitment of monocytes with capacity to contribute to HLE-mediated tissue injury.
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Fairclough, Marianne Elizabeth. "Diversity among monocyte derived stromal cells." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/679/.
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Fibrocytes are monocyte-derived cells that morphologically look like fibroblasts, express both stromal and haematopoietic markers, and have been reported as being involved in wound healing and fibrosis. In-vitro derived fibrocytes can be differentiated in both serum-containing and serum-free environments and we wanted to study the relationship between these two fibrocytes; which potentially could be involved at different time points at a wound healing site. To investigate the relationship between serum-free and serum-containing derived fibrocytes monocytes were differentiated without serum. When these cells were placed in a serum-containing environment they became round, losing their fibroblast-like morphology. However when the reverse experiment was done on fibrocytes derived in a serum-containing environment there was no apparent effect on their morphology. The relationships between these two fibrocytes, as well as macrophages and fibroblasts was also examined using transcriptome analysis of 37000 genes, clustering the samples based on all the genes, and identifying those that were significantly different between the populations. This demonstrated that both fibrocyte populations are distinct from each other, as well as from both fibroblasts and macrophages. These data demonstrate that these two fibrocytes have different characteristics, suggesting that they may have different roles in the modulation of fibrosis in inflammation.
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Rodgers, Lewis Craig. "Metabolic control for inflammatory cascades in monocytes in response to chronic disease stimuli." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/30725/.
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Tissue microenvironments within chronic inflammatory disease sites, such as the synovial compartment within rheumatoid arthritis (RA) patients contains a plethora of factors to drive immune responses. However, one specific characteristic that is commonly found at these sites is the presence of tissue hypoxia. Therefore, both resident and infiltrating immune cells need to adapt to these microenvironments in order to survive and function to promote chronic inflammation. Adaptation to hypoxia requires a level of metabolic reprogramming for this purpose. Therefore, this thesis aimed to examine what the metabolic consequences were for human monocytes that were adapting into hypoxic sites and to interrogate what role these metabolic pathways had in driving specific functions in hypoxic conditions. Metabolomic analyses reveal that hypoxia induces metabolic alterations in human monocytes, including the decrease in abundance of carnitine metabolites, important for subsequent fatty acid oxidation (FAO), and increases in glycolytic metabolites. Furthermore, hypoxia exacerbated the release of pro- inflammatory mediators in LPS activated monocytes, such as CCL20 and IL-1β. Manipulation of carnitine metabolites identify a role for FAO in the production of CCL20, and in the regulation of IL-1β release. To mimic the RA synovial environment more thoroughly in vitro, human monocytes were cultured in cell culture medium containing RA synovial fluid (RA-SF) under hypoxic conditions. Further metabolomics analysis revealed that monocytes accumulate a number of metabolites in comparison to untreated and LPS activated cells, suggesting that monocytes may enter a stasis-like phase when challenged with RA-SF. This was reflected by low level release of pro-inflammatory mediators under these conditions. Nevertheless, media supplementation with carnitine increased CCL20 production under RA-SF treatment, highlighting FAO may have a role in CCL20 release in several inflammatory contexts. This body of work shows that distinct metabolic pathways regulated by the extracellular environment may act in conjunction for the production of pro- inflammatory mediators in chronic inflammatory disease. This thesis highlights the influencing nature of tissue microenvironments on the functional capacity of myeloid cells by harnessing its metabolic machinery.
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McCann, Katelyn J. "IFNγ Mediated Monocyte Metabolic Reprogramming." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1146.
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IFNγ is an essential and pleiotropic activator of monocytes, but little is known about the effects IFNγ on cellular metabolism. Therefore, we sought to characterize and elucidate the mechanisms by which IFNγ reprograms monocyte metabolism to support its immunologic activities. First, we identified a critical role for IFNγ in the induction of immunoresponsive gene 1 (IRG1) and its product, itaconate. The immunometabolite, itaconate, has been reported to have antibacterial, anti-inflammatory and antioxidant activity. Irg1-/- mice, lacking itaconate, are highly susceptible and phenotypically similar to IFNγ knock out (GKO) mice upon infection with Mycobacterium tuberculosis. Therefore, we assessed the role of IRG1/itaconate in the context of non-tuberculous mycobacterial (NTM) infection, the most common type of infection in patients with immunodeficiencies caused by defects in IFNγ signaling. Our data suggest that impaired induction of itaconate in the context of mycobacterial infection may contribute to mycobacterial susceptibility and immune dysregulation in patients with defects in IFNγ signaling. Next, we evaluated the metabolic phenotype of IFNγ-stimulated human monocytes and found that IFNγ increased oxygen consumption rates (OCR), indicative of reactive oxygen species generation by both mitochondria and NADPH oxidase. Transcriptional profiling of human macrophages revealed that this oxidative phenotype was dependent on IFNγ-induced, nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ salvage to generate NADH and NADPH for oxidation by mitochondrial complex I and NADPH oxidase, respectively. These data identify an IFNγ-induced, NAMPT-dependent, NAD+ salvage pathway that is critical for complete induction of the respiratory burst in IFNγ stimulated human monocytes.
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Barbosa, M. I. L. C. "The expression of surface antigens and phagocytic activity by human monocytes and alveolar macrophages." Thesis, Brunel University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234574.
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Saghafian, Hedengren Shanie. "Microbial and maternal influences on allergic sensitization during childhood: defining a role for monocytes." Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-27620.
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Allergic diseases are influenced by genetics and the environment. Maternal allergy appears to confer a higher risk for allergic sensitization than paternal allergy, suggesting an in utero influence. A decrease in particular infections or a lower exposure to microbial components during infancy is suggested to contribute to the high allergy prevalence in affluent societies. Toll-like receptors (TLR) 2 and 4 recognize peptidoglycan (PGN) and LPS respectively, are expressed on e.g. monocytes, and have been implicated in modulating the risk of IgE-sensitization. This thesis aimed to study the influence of maternal allergy and early microbial exposure on monocyte function and allergic sensitization during childhood. Blood samples from children participating in a prospective allergy cohort were used. Two-year old infants with allergic mothers had lower IL-6 production and reduced activation of the TLR-signalling intermediate p38-MAPK in response to PGN than children with non-allergic mothers. In 5-year old children, allergic disease and not maternal allergy influenced monocytic TLR2-regulation. Five-year olds who were seropositive for Epstein-Barr virus (EBV) at 2-years of age had a lower risk of persistent IgE-sensitization while EBV contraction after 2-years of age related to a higher risk of IgE-sensitization. Upon in vitro stimulation, NK cells from EBV+ 2-year olds produced lower IFN-g levels. EBV+ 2-year olds had also lower systemic IFN-g. In comparison to CD14++CD16- monocytes, CD14+CD16+ cells induced NK-cell IFN-g more potently in vitro, and EBV+ infants tended to have lower proportions of these CD14+CD16+ monocytes. This thesis highlights the importance of early-life microbial (EBV) exposure for a proper allergy-protective immunity. Also, maternal allergic heredity appears to influence monocytic microbial responses in early infancy. All these aspects relate to altered monocyte functionality, which suggest that they could have a role in allergic sensitization.
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Cole, Suzanne Lois. "Contribution of monocytes to immunopathology during influenza A virus infection." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:db927890-61de-405e-8681-8f5c33f08591.
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Liu, Xiao. "The role of monocytes in gouty arthritis : a thesis submitted to the Victoria University of Wellington in fulfilment of the requirements for the degree of Master of Science in Biomedical Science /." ResearchArchive@Victoria e-thesis, 2009. http://hdl.handle.net/10063/984.
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Christodoulopoulos, Pota. "Monocyte chemotactic proteins in allergen-induced rhinitis." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=21526.
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Allergen-induced rhinitis is associated with the recruitment and activation of inflammatory cells, particularly eosinophils and CD4 + T cells into the nasal mucosa. Monocyte chemotactic proteins (MCPs) have been shown to induce chemotactic activity in these particular cell types under in vitro assay conditions. To assess the contribution of MCPs in the recruitment of inflammatory cells in vivo, we investigated the allergen-induced late response in subjects with allergic rhinitis. Using immunocytochemistry and in situ hybridization, we demonstrated a constitutive expression of MCP-1, -3 and -4, of which MCP-3 and -4 were significantly increased in the nasal mucosa following allergen provocation. This upregulation of MCP-3 and 4 immunoreactivity in response to allergen, was reduced in patients pretreated with topical corticosteroids. Colocalization experiments revealed that the majority of MCP-positive cells were macrophages. The results of this study suggest that allergen-induced rhinitis is associated with an increased expression of MCP-3 and -4, which may be closely related to the influx of inflammatory cells and may thus contribute to the pathogenesis of allergic rhinitis.
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Shen, Yuenan. "Studies of blood monocytes from patients infected with the human immunodeficiency virus-1 (HIV-1)." Thesis, University of Ottawa (Canada), 1991. http://hdl.handle.net/10393/7771.
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To determine if blood monocytes from HIV-1 seropositive patients contain HIV-1 antigen and genome, we separated monocytes and T cell subsets using monoclonal antibodies (mAbs) conjugated to magnetic beads and by monocyte adherence to glass. We found: (1) Monocytes cultured without depletion of CD4$\sp+$ T cells (11 of 11 patients) were HIV-1 antigen positive and showed dramatically increased spontaneous formation of MGCs. (2) Monocytes cultured after depletion of CD4$\sp+$ T cells (3 experiments) were HIV-1 antigen negative and MGC formation was markedly decreased. (3) In 14 subsequent patients analyzed by PCR, all patients were positive for HIV-1 proviral DNA in cells enriched for CD4$\sp+$ T cells. In 11 of 14 patients (79%), the monocyte fractions were HIV-1 proviral DNA negative, while in the remaining 3 patients, the monocytes were positive for HIV-1 proviral DNA. In conclusion, the major reservoir for HIV-1 infection in human peripheral blood is CD4$\sp+$ T cells (14 of 14 cases). Fresh blood monocytes from HIV-1 seropositive patients were HIV-1 proviral DNA negative in 11 of 14 cases (79%). Blood monocyte-derived macrophages from HIV-1 seropositive patients may acquire HIV-1 infection in vitro from contaminating infected CD4$\sp+$ T cells. The pathogenic and clinical significance of HIV-1 infected monocytes (21% of patients) remains to be determined. (Abstract shortened by UMI.)
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Hespel, Cindy. "Régulation de la réponse immunitaire adaptative par les cellules dendritiques conventionnelles et inflammatoires." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209702.
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Les cellules dendritiques décrites depuis les années 60 ont instantanément capté l’intérêt des scientifiques qui ont pu mettre en évidence leur rôle indispensable dans l’initiation des réponses immunitaires adaptatives et leur ont attribué le surnom « d’adjuvant naturel ». De manière surprenante, les cellules dendritiques conventionnelles sont aussi indispensables dans le maintien de la tolérance et peuvent présenter naturellement ou acquérir une fonction suppressive. Parmi les mécanismes capables de contrôler les réponses de type Th1, l’enzyme indoléamine 2,3-dioxygénase (IDO) a particulièrement attiré notre attention. Cette enzyme initiant la première étape de dégradation du tryptophane et sa transformation en catabolites toxiques nommés kynurénines semble jouer un rôle primordial dans la tolérance envers les fœtus allogéniques et dans l’échappement des tumeurs à la réponse immunitaire. Nous avons donc évalué le rôle de l’IDO exprimé par les cellules dendritiques conventionnelles dans la régulation de la réponse adaptative. L’ensemble des résultats in vitro révèle que l’expression d’IDO par les cellules dendritiques conventionnelles au cours de leur maturation n’influence celle-ci ni au niveau de l’expression des molécules MHCII et CD86 ni au niveau de leur capacité à induire la différenciation des lymphocytes Th1. De plus, dans des modèles d’immunisation in vivo par transfert de cellules dendritiques conventionnelles, l’expression d’IDO par ces dernières ne semble pas leur permettre de contrôler les réponses T CD4+ ou T CD8+. Cependant, nous avons constaté qu’en absence de lymphocytes T régulateurs naturels l’expression d’IDO par les cellules de l’hôte constitue un mécanisme important limitant la réponse Th1.
En cas d’inflammation ou d’infection, de profonds changements affectent le compartiment des cellules dendritiques où émerge une nouvelle sous-population qui se différencie à partir des monocytes inflammatoires du sang et qui portent le nom de cellules dendritiques inflammatoires. Alors que les cellules dendritiques conventionnelles forment une population hétérogène où chaque sous-population semble se spécialiser dans la différenciation d’un type particulier de lymphocyte T auxiliaire ou « helper », la littérature met en évidence une incroyable plasticité phénotypique des cellules dendritiques inflammatoires qui les rend capables de s’adapter au type d’infection auquel l’hôte est confronté en intervenant directement au niveau de la réponse innée mais aussi en participant à l’initiation et la régulation de la réponse T la plus adaptée.
Le modèle d’immunisation in vivo par transfert de cellules dendritiques inflammatoires présentant l’antigène OVA nous a permis de démontrer la capacité de ces cellules à promouvoir spécifiquement la différenciation de lymphocytes de type Th17. Dans le cadre d’une immunisation classique par un adjuvant, le défaut dans le recrutement des cellules dendritiques inflammatoires dans les souris CCR2-/- nous a permis de mettre en évidence le rôle indispensable des cellules dendritiques inflammatoires pour l’induction des réponses Th1 et Th17. Finalement, envisageant la possibilité d’une collaboration entre DCs conventionnelles et inflammatoires pour l’induction des réponses de type Th17, nous avons constaté que le transfert de cellules dendritiques conventionnelles présentant l’antigène KLH provoque in vivo le recrutement de cellules dendritiques inflammatoires au sein des ganglions drainant le site d’injection et que ces cellules dendritiques inflammatoires semblent nécessaires pour la différenciation des lymphocytes de type Th17.
La collaboration entre cellules dendritiques via le transfert d’informations pourrait être un évènement fréquent permettant de réguler la réponse immunitaire adaptative à trois niveaux principaux :au niveau quantitatif, en augmentant le nombre de cellules dendritiques présentant l’antigène, au niveau de la durée, en transmettant l’information aux cellules dendritiques inflammatoires colonisant les tissus desquels les cellules dendritiques conventionnelles disparaissent après activation/maturation et au niveau qualitatif, en combinant les propriétés intrinsèques des différentes sous-populations de cellules dendritiques afin de réguler la différenciation des lymphocytes T helper.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished
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Hosker, Harold Stephen Ronald. "Alveolar macrophage and blood monocyte function in small cell lung cancer." Thesis, University of Newcastle Upon Tyne, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241364.
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劉恩梅 and Enmei Liu. "The development of cord blood monocyte-derived dendritic cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B3124340X.
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Creery, W. David. "Effects of immunoregulatory cytokines on B7-1 and B7-2 isoform expression on human monocytes and B cells." Thesis, University of Ottawa (Canada), 1996. http://hdl.handle.net/10393/10195.
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T cell activation and the generation of effective immune responses is critically dependent on APC-derived signalling. The relative expression of B7 isoforms on APC may be important in determining the nature and extent of the immune response, and immunoregulatory cytokines may mediate their effects through alterations in B7 isoform expression. The effects of a panel of cytokines on B7 isoform expression on resting and activated monocytes and B cells was evaluated. IL10 and IL4, which induce the development of Th2 type T cells, downregulated expression of B7-2 and modestly upregulated expression of B7-1 on unstimulated human monocytes. IFN$\gamma,$ a potent inducer of Th1 type T cells, upregulated both B7-1 and B7-2 expression. TNF$\alpha$ downregulated B7-2 expression, but did not alter B7-1 expression. Addition of anti-IL10 antibodies did not abrogate the effects of TNF$\alpha$ on B7-2 expression. LPS had effects on B7 isoform expression on purified monocytes similar to those of IL10 in PBMC, namely marked B7-2 downregulation and modest B7-1 upregulation. None of the cytokines influenced the levels of expression of B7 isoforms on either resting or activated B cells. Thus cytokines that influence development of T helper type immune responses have differential effects on expression of individual B7 isoform on monocytes but not on B cells. These findings may have important implications in activation and control of immune responses in infections, autoimmunity and malignancies.
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Wohleb, Eric S. "Stress-induced Monocyte Re-distribution and Microglia Activation Underlies Development and Recurrence of Anxiety." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1379520096.
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Barboza, Prado Lopes Erika. "Analysis of Ly-6Chigh CD1lb+ monocytes generated in vitro iniflammatory animal models / Análisis de monocitos Ly-6Chigh CD11b+ generados in vitro en modelos animales de inflamación." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/112024.
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a. Introduction
The immune system must detect a wide variety of agents, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. However, the immune system needs to be well regulated since a disorder in an immune response can result in autoimmune diseases, tissue destruction, inflammatory diseases and cancer.
Within the context of innate immunity, the mononuclear phagocyte system, cells comprising bone marrow progenitors, blood monocytes and tissue macrophages is acquiring great importance in the study of different pathologies and particularly the monocytes/macrophage functions. In this regard, recent studies demonstrate that monocytes present a heterogeneous population of innate cells.
Monocyte was found leading to distinct cell populations with various subtypes with distinct functions. Two types of monocytes were identified in mice. Resident monocytes, with a CD11b+CCR2lowLy-6ClowCX3CR1high phenotype, migrate to uninjured tissues after emigration from bone marrow and differentiate into resident macrophages and dendritic cells. In contrast, a distinct inflamed monocyte subset with a CD11b+CCR2highLy-6ChighCX3CR1low phenotype infiltrates infected tissue and contributes to the development of inflammation.
Currently, all studies performed with monocytes are done in transgenic models (i.e. CCR2-/-; GPF-CX3CR1 models) or with expensive techniques to study and acquire the maximum number of cell possible from mice blood. Monocytes constitute around 2% (100cells/μl) of the total peripheral blood leukocyte pool in mice, where only 1-5% are Ly-6Chigh monocytes. What makes difficult to study it.
b. Objective
1. Development of an in vitro model that allow the generation of large amounts of Ly-6Chigh monocytes from bone marrow from mice.
2. Characterization of the phenotype of Ly-6Chigh monocyte generated in vitro.
3. Analyze the activation function of Ly-6Chigh monocyte generated in vitro.
4. Study the migration of Ly-6Chigh monocytes in to two inflammation models:
- Skin (DNFB model)
- Muscle (Notexin muscle model)
5. Analyze the therapeutic effect of Ly-6ChighCD11b+ monocytes injection in the resolution of inflammation in two experimental models of inflammation.
c. Methodology and Results
To achieve the first aim of our work, bone marrow cells were cultured with different grows factors and FCS at 37ºC in a humidified 5% CO2 atmosphere for 7 days when the population of floating cells was obtained and stained with Ly-6C and CD11b markers. This population was sorted for the acquirement of the Ly-6ChighCD11b+ cells.
In order to characterize the phenotype of these cells we stained them with several markers. Our results demonstrated that this Ly-6Chigh enriched population is CD11b+CD62L+CCR2+ F4/80+CX3CR1low, presenting the same phenotype of the cells presents in the blood.
To study the functional heterogeneity of enriched Ly-6Chigh cells, these cells were incubated with IFN-γ as typical classical stimuli and IL-4 as an alternative pathway stimulus. Ly-6Chigh cells incubated with IFN induced the expression of TNF and NOS2 with a characterized kinetics similar to macrophages. However, these cells increased arginase-1 levels when were stimulated with IL-4. Thus, the in vitro results have shown the plasticity and heterogeneity of monocytes as previously described by macrophages and thus, suggests us that these cells can also adapt to changing microenvironments as previously described.
Further, to observe the migration capacity and functionality of these cells in vivo, we optimized two experimental model of inflammation. In the first model an ear skin irritation with 1%DNFB was induced. In the second model, muscle inflammation was developed by the injection of Notexin in the tibialis anterioris. In both models inflammation was induced and Ly-6Chigh enriched cells stained with an infrared fluorocrome were injected intravenous in mice and migration was observed by in vivo image at different days. Migratory capacity of Ly-6C cells to the inflamed tissues was appreciated in both models, corroborating with data previously described.
To analyze the therapeutic effect of Ly-6ChighCD11b+ monocytes injection in the resolution of inflammation, RNA and histology cuts were obtained from both models. The results showed that Ly-6Chigh-injected mice express higher levels of anti-inflammatory genes such as mannose receptor, which corroborate with the histological images where animals treated with Ly-6Chigh cells recover before of the inflammatory process that untreated animals.
d. Conclusion
1. We established a novel in vitro protocol to generate Ly-6ChighCD11b+ monocyte obtained from bone marrow of Balb/C mice.
2. The cells generated in vitro have the same phenotype of the Ly-6C from blood flow.
3. Cells Ly-6ChighCD11b+ monocyte present high plasticyty.
4. Ly-6ChighCD11b+ monocytes generated in vitro migrate in vivo.
5. Injection in acute and chronic in vivo inflammatory models of Ly-6ChighCD11b+ monocytes generated in vitro, display an improvement in the site of inflammation through the presentation of a more anti-inflammatory profile.Monocitos circulantes proporcionan una defensa contra las infecciones y también a enfermedades autoinmunes. Recientemente dos tipos de monocitos fueran identificaron en la sangre periférica de ratones. El monocito ¿residente¿ con fenotipo CD11b+CCR2lowLy-6ClowCX3CR1high, que migran a tejidos no lesionados y se diferencian en macrófagos residentes y células dendríticas (DC). En contraste, un subconjunto distinto conocido como monocitos ¿inflamatorios¿, con un fenotipo CD11b+CCR2highLy-6ChighCX3CR1low son células que migran al tejido infectado y en lo cual contribuye al desarrollo de la inflamación. Monocitos Ly-6Chigh, el objetivo de nuestro trabajo, representan un 2-5% de los monocitos del torrente sanguínea de los ratones. Dado que estas células son de difícil obtención y que la cantidad obtenida de la sangre de ratones es muy baja, nuestro grupo desarrolló un nuevo sistema para generar monocitos Ly-6Chigh in vitro a partir de médula ósea de ratón, con el objetivo de estudiar sus funciones in vivo en dos modelos animales de inflamación. Nuestro laboratorio ha optimizado dos modelos animales capaces de inducir inflamación local en ratones Balb/c, inmunocompetentes. En el primer modelo, 1-fluoro-2 ,4-dinitrobenceno (DNFB) se aplicó tópicamente en la oreja derecha para crear en la piel condiciones que inducen la migración de estas células para el sitio de la irritación (modelo DNFB). En este modelo de piel, la inflamación en la oreja fue calculada atreves del peso neto, donde el peso de la oreja izquierda es restado del peso de la oreja derecha después de 24h y 48h de la inyección intravenosa (iv) de los monocitos Ly-6ChighCD11b+ en los ratones. En el segundo modelo, la inflamación es inducida atreves de la aplicación de una inyección de Notexin en el tibial anterior (TA) de la pierna derecha del animal la cual induce una inflamación muscular (modelo Notexin). Finalmente en ambos modelos, monocitos Ly-6ChighCD11b+ generados in vitro pre-tratados in vitro con citocinas pro- o anti-inflamatoria (IFN-¿ o IL-4) o no tratados, fueran inyectados iv en la colas de los ratones. Por otra parte, expresión génica fue medida mediante PCR cuantitativa en tiempo real, la migración celular fue evaluada in vivo atreves de imágenes realizadas por el equipo de IVIS, estudios de citometría de flujo y ensayos de histología también fueran realizados para evaluar la función de las células Ly-6Chigh en el sitio de inflamación. El principal objetivo de nuestro estudio es: 1. Desarrollo de un modelo in vitro que permita generar grandes cantidades de monocitos Ly-6Chigh a partir de médula ósea de ratones. 2. Caracterización del fenotipo de los monocitos Ly-6Chigh generados in vitro. 3. Analizar funciones de los monocitos Ly-6Chigh generados in vitro tras su activación in vitro. 4. Estudio de la capacidad migratoria de los monocitos Ly-6Chigh generados in vitro en dos modelos de inflamación. - Piel (modelo de DNFB en oreja). - Músculo (modelo Notexin muscular). 5. Analizar el efecto terapéutico de la inyección de monocitos Ly-6Chigh generados in vitro en la resolución de la inflamación en dos modelos experimentales de inflamación. En ambos modelos animales la inflamación local aumentó en función del número de monocitos Ly-6Chigh inyectados. Migración celular fue analizada por imágenes in vivo en ambos modelos, donde células Ly-6Chigh generated in vitro fluorescentes estaban presentes apenas en el tejido inflamado. Análisis de hematoxilina y eosina en cortes histológicos demostraron una mejoría del tejido de los animales tratados con monocitos Ly6Chigh. En resumen, los resultados obtenidos en esta Tesis Doctoral revelar un nuevo método para generar in vitro Ly-6Chigh monocitos de médula ósea de ratones, con una mejora en la eficiencia de la producción celular, que facilitan el estudio de estas células in vitro e in vivo. Además, también han demostrado la capacidad de las células Ly-6Chigh para cambiar el fenotipo de la estimulación in vitro verdadera y la capacidad de migrar, así como la heterogeneidad funcional en dos modelos de inflamación in vivo, lo que indica que estas células accionar de la misma manera como se las células proveniente de la sangre periférica. Además, hemos demostrado que Ly-6Chigh monocitos pueden ser pre-tratados con citoquinas en orther para retrasar o aumentar la reparación de tejidos (IFN-¿ o IL-4), respectivamente Todos estos resultados juntos sugieren que los monocitos Ly-6Chigh generado por nosotros in vitro son células funcionales que se pueden utilizar como una herramienta terapéutica para tratar enfermedades inflamatorias.
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Morris, Matthew. "Molecular mechanisms responsible for the dynamic modulation of macrophage responses to varying dosages of lipopolysaccharide." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/64253.
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The innate immune system depends for its effectiveness on the function of specialized pattern recognition receptors which enable it to target pathogens for destruction on the basis of conserved molecular patterns such as flagellin or lipopolysaccharide (LPS). Specifically, LPS is recognized by the Toll-like receptor 4 (TLR4), activating a signaling pathway which triggers the production of both pro- and anti-inflammatory mediators. Very low doses of LPS, however, preferentially induce pro-inflammatory cytokines, which can lead to persistent low-grade inflammation, a contributing factor in a host of chronic diseases. The mild pro-inflammatory skewing induced by super-low-dose LPS also potentiates the inflammatory response to later challenge with a higher dose of LPS in a phenomenon known as the "Shwartzman reaction" or "endotoxin priming". We investigated the mechanisms involved in pro-inflammatory skewing by super-low-dose LPS in THP-1 cells and found it to be governed by a regulatory circuit of competitive inhibition between glycogen synthase kinase 3 (GSK3) and Akt, which promote the activity of the transcription factors FoxO1 and CREB, respectively. Super-low-dose LPS mildly activated FoxO1 and pro-inflammatory gene transcription without inducing anti-inflammatory genes or activating CREB, and this pro-inflammatory skewing could be abolished by inhibition of GSK3 or direct activation of CREB. We then examined the dynamics of the LPS response at various different dosages in murine bone-marrow-derived macrophages (BMDM). The pro-inflammatory cytokine IL-12 was most strongly induced by intermediate LPS dosages, with very low or high doses inducing less robust IL-12 production. Knockout of the inhibitory TLR4 pathway molecules Lyn or IRAK-M resulted in sustained induction of IL-12 by high doses of LPS. By activating CREB, we were able to reduce inflammation in WT BMDM, and saw that this corresponded with increased phosphorylation of CREB. Overall, we are confident that this subnetwork is an important switch regulating the resolution of inflammation in response to TLR4 stimulation. Furthermore, we propose that endotoxin priming is an example of the generalized capacity of all signaling networks to recall prior states, and that an appreciation for the history and context of exposure to stimuli is critical for the understanding of signaling behavior.Ph. D.
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Rahim, Rahimi Ali Akbar. "Molecular mechanisms for IL-10 induced CD14 expression in human monocytic cells." Thesis, University of Ottawa (Canada), 2004. http://hdl.handle.net/10393/26752.
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IL-10, an immunoregulatory cytokine with biological effects primarily on inhibition of inflammatory responses, has also been shown to stimulate a variety of functions including CD14 expression on human monocytic cells. CD14, a receptor for lipopolysaccharide (LPS), plays a critical role in the synthesis of proinflammatory cytokines by LPS-stimulated monocytic cells. Herein, I show that LPS-induced CD14 expression on monocytic cells may be mediated by endogenously produced IL-10. In this study, I have investigated the molecular mechanisms by which IL-10 enhances CD14 expression in normal human monocytes and a promyelocytic HL-60 cells as a model system. IL-10 induced the phosphorylation of PI3K and p42/44 extracellular signal-regulated kinase (ERK) MAPKs. By employing specific inhibitors for PI3K (LY294002) and ERK MAPKs (PD98059), I provide evidence that LY294002 either alone or in conjunction with PD98059 inhibited IL-10-induced phosphorylation of STAT1 and consequently CD14 expression. However; IL-10-induced STAT3 activation remained unaffected under these conditions. Furthermore, LY294002 and PD98059 inhibited the binding of STAT1 transcription factor to its binding site in the CD14 promoter. Finally, STAT1 siRNA inhibited IL-10-induced CD14 expression. Taken together, results show for the first time that IL-10-mediated CD14 upregulation may be mediated by STATI activation independently of STAT3. Furthermore, IL-10-activated STAT1 may be regulated through PI3K either alone or in concert with the ERK MAPKs.
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Niraula, Anzela. "Blood-borne factors regulate monocyte function during psychosocial stress: A case of corticosterone and IL6." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1521546421236938.
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Wagner, David H. "Role of the Cd40-cd40 Ligand Interaction in Cd4(+) T Cell Activation of Monocyte Interleukin-1 Synthesis." Digital Commons @ East Tennessee State University, 1994. https://dc.etsu.edu/etd/2816.
Full textAbstract:
Most studies of the induction of cytokine synthesis in monocytes have used an exogenous triggering agent such as Lipolpoysaccharide (LPS). However, during nonseptic chronic inflammatory responses (e.g., rheumatoid arthritis) monocyte activation occurs as a result of T cell generated signals. This report demonstrated that plasma membranes from anti-CD3 activated peripheral CD4$\sp{+}$ T cells (Tm$\sp{\rm A}$) but not from resting CD4$\sp{+}$ cells (Tm$\sp{\rm R}$) induced monocytes to synthesize IL-1 in the absence of costimulatory cytokines. The expression kinetics of the molecule(s) unique to activated T cells which interact with monocyte receptors to induce IL-1 demonstrated that optimal expression occurred at 6h post activation. This matched Lederman's, et al., (1992) previously reported kinetics of expression of CD40 ligand (CD40L) on activated peripheral T cells, implicating the CD40-CD40L interaction as a candidate for the initiator of IL-1 induction in monocytes. In this work, it was demonstrated that the signal could be reduced up to 85% by addition of 5c8, a monoclonal anti-CD40L antibody. In addition, a monoclonal anti-CD40 IgM (BL-C4) induced resting monocytes to synthesize IL-1. Experiments demonstrated that crosslinking the CD40 molecules on monocytes was critical for IL-1 induction. Tm$\sp{\rm A}$ but not Tm$\sp{\rm R}$ also up-regulated cell surface expression of adhesion/costimulatory molecules on monocytes including CD40, ICAM-1, and LFA-3. Anti-CD40 signaling up-regulated expression of ICAM-1 and LFA-3. Experiments suggested that signaling through CD40 may utilize a protein tyrosine kinase (PTK) mediated pathway but not a protein kinase C mediated pathway and studies using THP-1, a premonocytic cell line, indicated that the transcription factor, NF-$\kappa$B, was activated through anti-CD40 signaling. Since CD40 ligand-transfected cells alone did not induce IL-1 but Tm$\sp{\rm A}$ did, it was considered that an additional costimulatory cell surface molecule was required. Preliminary experiments suggested that CD69 may be required. In summary, these results indicate that contact-dependent T cell-monocyte interactions, alone, can activate inflammatory cytokine production by resting monocytes and that a critical component of this interaction is the CD40-CD40L signaling event.
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Braddock, Amber M. "Early Increase of CD11c in Human Monocyte-derived Dendritic Cells in the Presence of A/California/07/2009 (H1N1pdm)." Wright State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=wright1401451036.
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Paustian, Christopher Charles. "MULTIPLE DANGER SIGNALS AND THEIR EFFECT ON MONOCYTE DERIVED DENDRITIC CELL PHENOTYPE AND FUNCTION." Kent State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=kent1277947985.
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Chen, Miao. "Moraxella catarrhalis-induced innate immune responses in human pulmonary epithelial cells and monocytes." Toledo, Ohio : University of Toledo, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1260375737.
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Dissertation (Ph.D.)--University of Toledo, 2009.["In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences."] Title from title page of PDF document. Bibliography: p. 80-112.
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Graziani-Bowering, Gina M. "The expression and signal transduction of CD4, an HIV and interleukin-16 receptor, in monocytic cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0015/NQ57046.pdf.
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Williams, Marc Adrian. "A study of granulocyte-macrophage colony stimulating factor and the immunological function of the monocyte against malignancy and infection." Thesis, Queen Mary, University of London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367835.
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Poe, Jonathan C. "Cd40-mediated Signaling of Interleukin-1(beta) Synthesis and Rescue from Apoptosis in Monocytes: Modulation by Il-4 and Il-10." Digital Commons @ East Tennessee State University, 1997. https://dc.etsu.edu/etd/2959.
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To date, the cellular mechanisms involved in the progression of diseases characterized by chronic inflammation, such as rheumatoid arthritis (RA), remain largely unknown. However, cell-to-cell contact interactions between CD4+ helper T (Th) cells and monocytes have been implicated in the induction and maintenance of pro-inflammatory cytokine synthesis that is characteristic to the pathogenesis of RA. One such cytokine produced during monocyte-Th cell contact is interleukin (IL)-1 β, a mediator directly involved in the characteristic tissue destruction that occurs in the synovia of individuals with RA. Previous studies in our laboratories have shown that ligation of CD40 on monocytes with CD40 ligand (CD40L) present on activated Th cells induces monocyte IL-1β synthesis and rescues monocytes from apoptosis. These findings suggest a role for CD40 signaling of monocyte activation in the exacerbation and maintenance of chronic inflammatory responses. This dissertation represents efforts to elucidate components of the CD40 signaling pathway critical to monocyte activation and how CD40-mediated signaling events are modulated by the anti-inflammatory cytokines IL-4 and IL-10. Using either monocytes isolated from human peripheral blood or a monocytic cell line (THP-1), cellular kinases and transcription factors activated upon CD40 ligation were examined by western blot analyses and electrophoretic mobility shift assays (EMSA), respectively. CD40-dependent interleukin-1β synthesis in monocytes was abrogated by inhibitors of protein tyrosine kinase (PTK) activity but not by inhibitors of protein kinase C (PKC). The extracellular signal-regulated kinases 1 and 2 (Erk1/Erk2) mitogen-activated protein kinases (MAPK's) were specifically activated upon CD40 ligation, and specific inhibition of Erk1/Erk2 activation diminished IL-10 production in a dose-dependent manner. Both IL-4 and IL-10 reduced Erk1/Erk2 activation and synergized in this effect. Finally, STAT3, a member of the family of transcription factors involved in cytokine signaling, was highly phosphorylated in monocytes treated with IL-10 or with IL-10 and IL-4 in combination but not with IL-4 alone. Together these results suggest that in monocytes (1) CD40-mediated IL-1β synthesis and NF-κB activation require PTK activity, (2) CD40-mediated IL-1β production is critically dependent upon Erk1/Erk2 activity, (3) both IL-4 and IL-10 target the Erk1/Erk2 signaling cascade in the downregulation of IL-1β synthesis, (4) IL-4 and IL-10 have divergent effects on the CD40 signaling pathway in that these cytokines are synergistic with respect to their ability to inhibit CD40-mediated Erk1/Erk2 activation and IL-1β synthesis, and differ in their ability to block CD40-mediated rescue from apoptosis, and (5) STAT3 activation may be directly involved in the downregulatory effects of IL-10 on CD40 signaling. (Abstract shortened by UMI.)
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Seshadri, Sudarshan. "Role of IkappaBzeta and Pyrin as Modulators of Macrophage Innate Immune Function." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1211550109.
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Drouet, Christian. "Caractérisation structurale et fonctionnelle d'une lymphokine activatrice du monocyte humain." Grenoble 1, 1988. http://www.theses.fr/1988GRE10057.
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Mathisen, Stephanie Jane. "Mononuclear phagocytes in intestinal homeostasis and inflammation." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:dfa5b8b5-668f-45f8-8a3b-bf18a7b0703a.
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Changes to the composition and function of the gut mononuclear phagocyte (MNP) compartment are associated with the development of intestinal inflammation. Much work has focused on the role of MNPs in gut-associated lymphoid tissue in maintaining homeostasis, however little is known regarding the roles of MNPs during colitis. We have investigated MNPs in the large intestinal lamina propria during the steady state and inflammation. One of our primary aims was to determine the contribution of MNP subsets to intestinal pathology. For our studies of inflammation, we focused mainly on the Helicobacter hepaticus infection + anti-IL-10R model, which induces inflammation of the colon and caecum (typhlocolitis). We defined the composition of the MNP compartment alongside intestinal pathology scores throughout Hh + anti-IL-10R typhlocolitis. Peak pathology, 2-3 weeks after induction of colitis, coincided with peak frequencies of CX3CR1int Ly6C+ MNPs. Having observed the accumulation of CX3CR1int CD64+ monocyte/macrophage MNPs in the inflamed lamina propria, we conducted comparative whole genome microarray analysis of these cells isolated from the large intestine three weeks after Hh + anti-IL-10R treatment. CX3CR1int CD64+ MNPs selectively expressed a variety of pro- and anti-inflammatory genes, including a number of genes which individually can both promote and negatively regulate inflammation. IL-23 is essential for Hh + anti-IL-10R-induced intestinal pathology. We investigated the role of MNPs as a source of IL-23 which drives Hh + anti-IL-10R colitis. Unexpectedly, our results indicate that normally hyporesponsive CX3CR1hi macrophages may act as the initial source of IL-23, which induces development of colitis. Recruitment of Ly6C+ MHCII+ MNPs to the lamina propria was IL-23-dependent, and these cells also expressed IL-23, which may establish a positive feedback loop of immune cell recruitment, activation and IL-23 production. Finally, we also examined how MNPs might be recruited to the colonic lamina propria during inflammation. Our studies support the conclusion that CCR6 is not required for accumulation of monocyte-derived populations in the inflamed intestine. We cannot rule out a role for CCR2, however preliminary data from the Hh + anti-IL-10R colitis model suggest a potential role for CCR1 or its close relation CCRL2. Such pathways could represent new therapeutic targets in inflammatory bowel disease.
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Marti, Luciana Cavalheiro. "A influência do fator de crescimento endotelial vascular na maturação \"in vitro\" de células dendríticas derivadas de monócitos." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-12012009-124821/.
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Células dendríticas (DCs) são as responsáveis por orquestrar a resposta imunológica adaptativa através da estimulação de células T. Na imunoterapia do câncer, as DCs são um dos principais alvos de estimulação. Entretanto a maturação anormal destas pode interferir no resultado final da resposta imune. Neste estudo, analisaram-se os efeitos causados pelo fator de crescimento endotelial vascular (VEGF) na maturação de DCs. Nas DCs maturadas em presença de VEGF, utilizando-se citoquímica, constatou-se alterações morfológicas, como número reduzido de dendritos e citoplasma basofílico; a análise de expressão gênica global por microarranjos de DNA mostrou grande variação da expressão de genes relacionados com adesão celular e citoesqueleto. Na avaliação funcional verificou-se redução da capacidade das DCs de ativar linfócitos. Juntos esses resultados sugerem que células expostas ao VEGF seriam menos especializadas. A compreensão do impacto do VEGF em mecanismos de maturação celular contribui para o entendimento da supressão imunológica nos tumores que secretam VEGF.Dendritic cells (DCs) are in charge of orchestrating the adaptive immune response through T cells activation. DCs are the main target in cancer cell immunotherapy. However, DCs inadequate maturation interferes in the outcome of the immune response. In this study, were analyzed the effects of vascular endothelial growth factor (VEGF) on DCs maturation. DCs matured in the presence of VEGF, showed morphologic alterations such as reduced number of dendrites and basophilic cytoplasm by cytochemistry. Global gene expression assessed by DNA microarrays demonstrated broad variation in the expression of cell adhesion and cytoskeleton regulation-related genes. Functional studies detected the reduced capacity of VEGF-exposed DCs in the activation of lymphocytes. All together these results suggest that cells exposed to VEGF are less differentiated, a possible mechanism involved in the immune suppression caused by VEGF secreting tumors.
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Gillette, Devyn Dior. "Characterization of Inadequate Host Responses to Intracellular Gram-negative Bacterial Pathogens." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385465357.
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Parira, Tiyash. "Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-derived Dendritic Cells." FIU Digital Commons, 2018. https://digitalcommons.fiu.edu/etd/3890.
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The effects of alcohol abuse are multi-dimensional since alcohol is widely known to affect both the innate and adaptive immune systems. Recently, epigenetics has come into focus and has been implicated in many diseases as well as substance abuse disorders. Therefore, research efforts of understanding the epigenetic mechanisms underlying substance abuse effects including alcohol abuse have become more predominant.
In our laboratory, we have studied different epigenetic changes induced by alcohol exposure including regulation of histone deacetylases (HDACs), histone quantity, and histone modifications such as acetylation and deacetylation. We have observed differential effects of acute and chronic alcohol exposure in human monocyte-derived dendritic cells (MDDCs) wherein our laboratory previously found that HDACs were modulated in MDDCs treated acutely with alcohol in vitro, and in MDDCs from alcohol users. Our previous work has also demonstrated that alcohol consumption affects the dendritic cell function by modulating inflammatory markers and cannabinoid receptors such as CB2 and GPR55 through epigenetic modifications. For instance, chronic alcohol exposure upregulates histone (H) 4 acetylation at lysine 12 (H4k12ac) and acute alcohol effects on histone acetylation are associated with an increase in GPR55 expression.
The hypothesis of the study is that chronic alcohol modulates human MDDC function through epigenetic mechanisms. Therefore, the primary objective of this research project is to elucidate novel pathways involving histone post-translational modifications due to chronic alcohol exposure in human dendritic cells.
For this study, monocytes isolated from commercially available human buffy coats were differentiated into MDDCs, which were treated with chronic alcohol levels of 0.1 % (100mg/dL) and 0.2 % (200mg/dL) for 5 days in the presence or absence of the histone acetyltransferase inhibitor NU9056 (50nM) or the GPR55 antagonist CID16020046 (5µM). Results showed that chronic alcohol levels upregulated H4K12ac in MDDCs and this was associated with a concomitant increase in GPR55 gene and protein expression. Further, NU9056 and CID16020046 were able to reduce alcohol-induced inflammatory chemokine MCP-2 and reactive oxygen species production indicating that H4K12ac may be an inflammation and oxidative stress regulator. Additionally, NU9056 and CID16020046 could potentially reduce alcohol-induced inflammation and serve as potential therapeutic targets for alcohol use disorders.
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Milhorn, Denise M. "Role of Mitogen-activated Kinases in Cd40-mediated T Cell Activation of Monocyte/macrophage and Vascular Smooth Muscle Cell Cytokine/chemokine Production." Digital Commons @ East Tennessee State University, 1999. https://dc.etsu.edu/etd/2950.
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This dissertation represents efforts to determine the functional consequences acquired by vascular smooth muscle cells (SMC) in response to CD40 ligation by activated CD154+ T cells, and to elucidate components of the signaling pathway(s) activated in response to CD40 signaling in both monocytes and SMC. To study the consequences of CD40 stimulation, primary human monocytes and aortic SMC were treated with plasma membranes purified from CD154 + , CD4+ T cells. The results presented in this dissertation demonstrate that SMC, like monocytes/macrophages, are capable of interacting with T cells in a manner that results in reciprocal activation events. SMC were shown to present antigen to, and activate T cells. In turn T cell stimulus resulted in the activation of proinflammatory function in SMC initiated through the CD154:CD40 interaction. CD40 stimulation of SMC resulted in the production of the chemokines interleukin 8 (IL-8) and macrophage chemotactic protein-1 (MCP-1), and the upregulation of intercellular adhesion molecule (ICAM). Examination of the intracellular signaling pathways activated through CD40 signaling revealed the involvement of MAPKs in the pathway leading to induction of proinflammatory activity. Evaluation of CD40 signaling in monocytes demonstrated the activation of the MAPK family members ERK1/2, but not the MAPK family members p38 or c-jun-N-terminal kinase (JNK). In contrast, CD40 signaling in SMC was shown to result in ERK1/2 and p38 activation, and both of these kinases were shown to play a critical role in the induction of chemokine synthesis. An examination of the ability of anti-inflammatory cytokines to modulate CD40 signaling in monocytes and SMC demonstrated that the anti-inflammatory cytokines IL-4 and IL-10 abrogate CD40-mediated induction of inflammatory cytokine production by monocytes. This inhibition was shown to be a result of a negative influence of IL-4 and IL-10 on CD40 mediated ERK1/2, activation in monocytes. However, IL-4 and IL-10 did not inhibit SMC proinflammatory responses indicating a difference in the intracellular responses to these cytokines by the two cell types. (Abstract shortened by UMI.)
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Darlington, Donna. "Implications of Human Umbilical Cord Blood Cells: An Immunotherapeutic Strategy for Alzheimer's Disease." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5208.
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ABSTRACT
Alzheimer's disease (AD) is the most common progressive age related dementia and the fourth major cause of mortality in the elderly in the United States. AD is pathologically characterized by deposition of amyloid beta (Aβ) plaques in the brain parenchyma and neurofibrillary tangles (NFTs) within the neuronal soma. While pharmacological targets have been discovered, current strategies for the symptomatic or disease-modifying treatment of AD do not significantly slow or halt the underlying pathological progression of the disease. Consequently, more effective treatment is needed. One possibility for amelioration is using human umbilical cord blood cell (HUCBC) therapy. HUCBCs comprise a population of hematopoietic stem and progenitor cells. During recent years, functional recovery has been observed from the use of HUCBCs in pre-clinical animal models of brain and spinal cord injuries. Thus, modulation by cell therapy, specifically HUCBCs, may be a suitable treatment for AD and other models because of the observed cognitive and behavioral improvements. The studies presented in this dissertation centers on the suitability of using HUBCs as a potential treatment for AD. Expanding on this, the aims of the study sought to: (I) Investigate bio-distribution of HUCBC transplantation in PSAPP mice, (II) Characterize efficacy and determine therapeutic outcome of HUCBC following short and long term multi injections at early and late disease stages in PSAPP mice and (III) Determine AD-like pathological and cognitive changes associated with multiple HUCBC-derived monocyte (CD14) injections in PSAPP mice. Thus the findings of this work evolved from experiments that characterized the effects of low-dose infusions of HUCBC and HUCBC-derived monocytes into 6 month old Presenilin 1/Amyloid Precursor Protein (PSAPP) plaque-developing transgenic AD mice. Treated mice were studied using standard behavioral tests to determine the effects of infusion on the multiple cognitive domains affected by AD, followed by biochemical and histological analyses that included Aβ load and amyloid precursor protein (APP) processing. Specifically, PSAPP mice and their wild-type (WT) littermates were treated monthly with a peripheral HUCBC infusion over a period of 6 and 10 months, followed by cognitive and motor evaluation. Additionally, based on reports that tumor cells can originate from stem cells present in HUCB, we further examined whether monocytes purified from HUCBCs would have a similar significant effect on the reduction of AD-like pathology in PSAPP mice. HUCB cells homed into tissues including the brain. The principal finding was significant reduction in Aβ levels and β–amyloid plaques following low-dose infusions of both HUCBC– derived mononuclear cells as well as HUCBC-derived monocytes, with the monocytes providing a stronger effect. Results further demonstrated that HUCBC and HUCBC– derived monocyte infusion could improve memory function and locomotor ability in treated PSAPP mice. A possible reason for behavioral improvements in these animals may be the significant reduction in both Aβ levels and plaque load. This study also identified significant reduction in microglial activation and astrocytosis, both of which can contribute to AD pathology. In conclusion, our data suggest that it might be the HUCBC–derived monocytic population rather than stem cells that are responsible for the reduction in AD pathology.