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Reglier-Poupet, Hélène. "Etude des interactions entre les polynucléaires neutrophiles humains et l'interleukine-10." Paris 5, 1998. http://www.theses.fr/1998PA05P008.
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Mijatovic, Tatjana. "Régulation de l'expression du gène du TNF-alpha par les interleukines 4, 10 et 13." Doctoral thesis, Universite Libre de Bruxelles, 2001. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211683.
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Cottrez, Françoise. "Etude de la sous population T régulatrice Tr1 : rôle de l'IL-10 et du TGf. β dans l'autoimmunité." Paris, EPHE, 2000. http://www.theses.fr/2000EPHE3051.
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"Une des grandes questions encore en suspens en immunologie est liée à l'existence de cellules régulatrices ou suppressives. Si de nombreux travaux tendent à prouver l'existence et l'importance de ce type cellulaire dans la régulation des systèmes immunitaires, l'impossibilité de les cloner et de les caractériser in vitro a toujours empêché leur identification formelle. Les travaux de notre laboratoire ont montré que l'interleukine-10 pouvait induire une anergie de longue durée dans les cellules T CD4+ et CD8 et la différentiation d'une nouvelle sous-population de cellules T CD4+ présentant un profil de sécrétion de cytokines différent de celui des cellules ThO, Th1 et Th2. En effet ces cellules T regulatory cells 1 " (Tr1) ne sécrètent ni IL-2, ni IL-4, elles sécrètent par contre de l'IL-5 et de l'IFN-γ mais surtout de très grandes quantités d'IL-10. Ce profil de sécrétion de cytokines permet d'expliquer leur qualité et leur fonction. En effet, l'absence de sécrétion de facteurs de croissance explique leur faible capacité proliférante et la nécessité d'utiliser de fortes doses d'antigène pour induire leur prolifération. D'autre part la sécrétion de fortes quantités d'IL-10 explique leur capacité à inhiber la prolifération des cellules environnantes. Ces propriétés immunorégulatrices sont retrouvées in vivo après injection de clones Tr1 antigènes spécifiques. Ces cellules sont notamment capables d'inhiber la synthèse d'IgE induite par une vaccination en présence d'alumine, de prévenir et de guérir l'établissement d'une inflammation chronique du colon induite par des cellules T autoimmunes. Enfin la réalisation d'un modèle de souris transgéniques pour l'IL-10 nous a permis de mieux comprendre le rôle joué par cette cytokine dans les mécanismes de différenciation de ces cellules régulatrices in vivo. La possibilité de générer ces cellules régulatrices in vitro et in vito nous permet d'envisager de nombreuses utilisations thérapeutiques tant dans le cas des maladies autoimmunes que dans les greffes ou encore pour inhiber une réaction du greffon contre l'hôte. "
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Fluckiger, Anne-Catherine. "Rôle de l'IL-4 et de l'IL-10 dans la maturation in vitro des cellules B de leucémies lymphoïdes chroniques." Lyon 1, 1994. http://www.theses.fr/1994LYO1T037.
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Touitou, Robert. "Analyse de la transcription de l'interleukine 10 virale (bcrf1) codee par le virus epstein-barr : etude de l'expression des interleukines 10 virale et cellulaire dans les pathologies associees a ebv." Paris 11, 1996. http://www.theses.fr/1996PA11T016.
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Dohmen, Klaus Malte. "Die kritische Rolle von Interleukin-10 bei der Induktion nasaler Toleranz in der experimentellen Autoimmun-Myokarditis (EAM)." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-58242.
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Forrester, Megan Amy. "Identification of interleukin-10 producing cells specific for Epstein-Barr virus latent membrane protein 1 and the involvement of interleukin-27 in their induction." Thesis, University of Aberdeen, 2011. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=167956.
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During latent Epstein-Barr virus (EBV) infection, the T helper cell response to the EBV latent membrane protein (LMP)1 is dominated by the production of IL-10, but by IFN- γ during acute EBV infection. The purpose of this thesis was to develop methods for the enumeration and characterisation of the IL-10 producing CD4+ T cells that respond to peptides of the EBV protein LMP1, and to investigate the possible involvement of IL-27 in the development of these cells. It was found that some human donors have very high concentrations of IL-27 within serum, which is not dependent on EBV infection status but demonstrates relatively low heritability. The addition of IL-27 to cultures of human T cells did not induce IL-10 but the production of IL-17 was inhibited. To identify and characterise LMP1 responsive cells I used CD154 as a marker of activated T cells. Having optimised the methodology, 14 donors of known EBV serostatus were tested for activated IL-10 producing cells after culturing peripheral blood mononuclear cells with LMP1 peptides. However in most cases the frequency of CD4+ lymphocytes upregulating CD154 and IL-10 in response to LMP1 peptides was below the assay’s sensitivity. When the CD154+IL-10+ CD4+ cells were stained for T helper cell subset markers they were positive for every marker and isotype control, suggesting that the cells were non-specifically binding labelled antibody. Both single positive CD154+ and single positive IL-10+CD4+ cells were also present in response to LMP1, but again typically at frequencies below the level of sensitivity for this assay. The conclusions of the work are that IL-27 responses are heterogeneous, but unlikely to play an important role in the induction of IL-10+ T cells in EBV infection. The frequency of LMP1 responsive T cells is very low (<0.08%) in most donors.
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Asselineau, Delphine. "Le polymorphisme du promoteur de l'interleukine-10 et son rôle éventuel dans la maladie d'Alzheimer." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066089.
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La maladie d'Alzheimer (MA) est une maladie neurodégénérative irréversible et progressive entraînant des troubles cognitifs et comportementaux. L'inflammation est caractéristique de la MA. L'interleukine-10 (IL-10), une cytokine anti-inflammatoire a été associée à un risque plus faible de développer la MA. Cependant le lien entre l'IL-10 et la progression de la MA n'a jamais été étudié. Le but de cette thèse a été d'étudier le rôle de l'IL-10 dans le développement ainsi que dans la progression de la MA. Pour mener à bien cette étude, 31 sujets atteints par la MA et 20 sujets contrôles cognitivement intacts ont été recrutés. En fonction de la vitesse de diminution du test de Mini-Mental State Examination et de l’évolution des troubles cognitifs sur deux ans, les patients souffrant de la MA ont été divisés en deux sous-groupes: les patients avec une progression lente (MA lent) et ceux avec une progression rapide (MA rapide). Les analyses se sont portées sur la concentration d’IL-10 en périphérie (plasma, production par les cellules mononuclées du sang périphérique (PBMCs) après stimulation par les peptides Aβ) ainsi que le polymorphisme de son promoteur en position -592, -819 et -1082. En complément, d’autres cytokines impliquées dans l’inflammation ont été étudiées : l’IL-6 (sa concentration plasmatique, sa production par les PBMCs à la suite d’une stimulation par les peptides Aβ et son polymorphisme en position -174) et les polymorphismes du TGF-β1 (-10 et - 25), de l’IFN-γ (-874) et du TNF-α (-308) ainsi que le gène de l'apolipoprotéine E (ApoE). Une étude de la longueur des télomères, liée à l’inflammation, a été aussi réalisée. Les résultats ont montré une association entre le génotype AA et l’allèle A du polymorphisme de l’IFN-γ en position -874 avec la progression rapide de la MA. Une augmentation statistiquement significative de la production d'IL-10 après stimulation par les peptides Aβ a été montrée chez les patients atteints avec une progression lente (MA lent). Une longueur significativement plus courte des télomères a été aussi associée aux patients MA lent. L’ensemble de ces travaux suggère qu’un profil de forte production de l’IL-10 ainsi qu’un profil génétique d’IFN-γ (TT -874) pourrait ralentir la progression de la MA. Il est aussi apparu que la longueur des télomères pourrait être un marqueur du déficit cognitif. Il est clair que ces résultats préliminaires ont besoin d’être confirmés par une étude de plus grande envergure, avec un nombre de patients plus élevéAlzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder leading to cognitive and behavioral impairment. Inflammation is hallmark of AD although the exact mechanisms involved and the roles of the different inflammatory components are far less clear. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine and IL-10 -1082 A > G polymorphism has been associated with a lower risk of developing AD although the link between IL-10 and the AD progression have never been studied. The aim of this study is to study the role of IL-10 in the risk of developing AD and its role in AD progression. In order to complete successfully this study, 31 AD patients and 20 cognitively intact controls were recruited. Depending of the rate of decrease of mini-mental state test examination (MMSE) and evolution of cognitive disorders, AD patients were divided in two subgroups: patients with slow progression (AD slow) and those with fast progression (AD fast). Analysis were focused on periphery concentration of IL-10 (plasma and and its production by peripheral blood mononuclear cells (PBMCs) after Aβ peptides stimulation) as well as its promoter polymorphism in position -592, -819 and -1082. In addition, other cytokines involved in inflammation were studied: IL-6 (its plasma concentration, its production by PBMCs following stimulation with Aβ peptides and its polymorphism at position -174) and polymorphisms of TGF-β1 (-10 to - 25), IFN-γ (-874) and TNF-α (-308) as well as the gene polymorphisms of Apolipoprotein E (ApoE). A study of telomere length, link to inflammation, was also performed. Results showed IFNγ -874AA genotype and -874A allele was associated with AD fast progression. A statistically significant increase of IL-10 production by PBMCs stimulated with Aβ peptides was shown in AD slow patients. A significantly shorter telomere length was also associated with AD slow patients. All of this work suggests that a profile with high IL-10 production and high IFN-γ (-874 TT) genotype could confer a slower AD progression. It was also found that telomere length may be a marker of cognitive impairment. It is clear that these preliminary results need to be confirmed in a larger study with a larger number of patients
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Rees, Louisa Elizabeth Natasha. "The regulation of interleukin-10." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322627.
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Mahot, Ségolène. "Identification de nouvelles fonctions du facteur de transcription ZEBRA/EB1 du virus d'Epstein-Barr : induction d'interleukine-10 humaine et internalisation dans les lymphocytes B." Université Joseph Fourier (Grenoble), 2003. http://www.theses.fr/2003GRE19015.
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Le virus d'Epstein Barr (EBV) est un herpesvirus humain capable d'infecter et d'immortaliser les lymphocytes B. L'EBV est ainsi associé à des processus tumoraux chez le sujet sain ou immunodéprimé. Suite à une infection primaire évoluant sur un mode aigu, l'EBV va entrer en phase de latence et persiste chez le sujet infecté. La réactivation virale est sous la dépendance de l'expression de deux facteurs de transcription viraux, ZEBRA/EB1 (produit du gène BZLF1) et R (produit du gène BRLF1). La protéine ZEBRA/EB1 est impliquée dans la régulation de gènes viraux ainsi que dans la réplication virale. L'interleukine-10 humaine (hIL-10) est une cytokine produite par un certain nombre de cellules mononucléées (lymphocytes, monocytes) et est étroitement associée au cycle de l'EBV. Les résultats exposés montrent que la protéine virale ZEBRA/EB1 est suffisante pour induire l'expression de l'hIL-10. Ce facteur de transcription viral induit l'expression du gène cellulaire par fixation directe au niveau de son promoteur. Plusieurs sites de fixation de ZEBRA/EB1 ont été mis en évidence au niveau du promoteur minimum de l'hIL-10 (-315/+27). Parmi ceux-ci, deux sites participant à l'activation transcriptionnelle par ZEBRA/EB1, ont été localisés d'une part entre les positions -30 et -24 et d'autre part entre les positions -11 et -6. Nous montrons aussi, pour la première fois, que la protéine ZEBRA/EB1 est efficacement internalisée dans les cellules lymphoi͏̈des (lignée DG 75, Raji, MOLT-4), principales cibles de l'infection. Nos résultats montrent que cette internalisation requière les fonctions d'endocytose de la cellule. Nous démontrons ainsi, qu'à l'instar de certaines protéines (virales et non virales), ZEBRA/EB1 est capable de traverser les membranes cellulaires et ainsi être considérée comme une protéine "toxoi͏̈de"The Epstein-Barr virus (EBV) is a human herpesvirus that infects and immortalises B lymphocytes. EBV is associated with malignant diseases in the asymptomatic or the immunosuppressed carrier. Following a primary infection, EBV enters a latent phase and persists in the infected individual. Viral reactivation is dependent on the expression of two viral transcription factors, ZEBRA/EB1 (BZLF1 gene product) and R (BRLF1 gene product). The ZEBRA/EB1 protein is implicated in viral genes regulation and in viral replication. Human interleukin-10 (hIL-10) is a cytokine produced by various mononuclear cells (lymphocytes, monocytes) and is tightly associated with the EBV cycle. Results presented here demonstrate that the viral protein ZEBRA/EB1 is sufficient to induce hIL-10 expression. This viral transcription factor binds directly to the cellular gene promoter. Several sites specific for the ZEBRA/EB1 protein have been identified in the hIL-10 minimal promoter (-315/+27). Among them, two sites that are responsible for the ZEBRA/EB1 activation of transcription have been located between positions -30 and -24 and between positions -11 and -6. We also demonstrate, for the first time, that the ZEBRA/EB1 protein is efficiently internalized in lymphoi͏̈d cells (DG 75, Raji and MOLT-4 cell lines), major target of the viral infection. Our results show that this internalisation require the cell endocytic functions. By this way, we demonstrate that, as some proteins (viral and nonviral), ZEBRA/EB1 is able to translocate through cellular membranes and thus can be considered as a " toxoi͏̈d " protein
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Ramos, Rodrigo Nalio. "The immunosuppressive microenvironment in cancer : local and systemic effects on patients' monocytes." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10270.
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Chez les patients atteints de cancer, les cellules néoplasiques échappent au contrôle du système immunitaire en raison de leur faible immunogénicité et d'une capacité exacerbée à moduler le micro-environnement. Nous décrivons ici les effets de ce micro-environnement tumoral sur la différenciation locale et systémique des monocytes et l'impact de la présence de Macrophages-Associés aux Tumeurs (TAM) CD163+ sur la survie des patientes atteintes de cancer du sein. Par une analyse de cytométrie en flux, nous décrivons un composition hétérogène des sous-types de TAM CD163low et CD163high, où nous avons observé l'association entre une fréquence élevée de TAM CD163high et une faible infiltration des lymphocytes T CD3+. Par immunohistochimie sur une analyse rétrospective (±12 ans), nous avons démontré une forte corrélation entre la fréquence élevée de TAM CD163+ et un risque accru de progression pour les patientes (log-rank *p<0.05, n=238). In vitro, les monocytes CD14+ conditionnés par le micro-environnement tumoral présentent une différenciation biaisée en faveur des MΦ CD163highCD86lowIL-10high, que non seulement ne stimulent pas la prolifération des lymphocytes T CD4+ naïfs, mais inhibent fortement l'expansion et la production d'IFN-γ et de TNF-α par les lymphocytes T CD4+ préalablement activé. Cette différenciation de MΦ en M2-like (CD163highIL-10high) est associée à des quantités élevées de TGF-β, M-CSF et VEGF dans le micro-environnement tumoral. Par ailleurs, les monocytes circulants des patientes atteintes de cancer du sein présentent un profil cytokinique immunosuppresseur et sont biaisés vers une différenciation en MΦ et Mo-DCs qui présentant des capacités suppressivesIn cancer patients, the neoplastic cells escape from the immune control because of their low immunogenicity and their exacerbated capacity to modulate the microenvironment. Here we describe the local and systemic effects of the tumor microenvironment on monocyte differentiation and the impact of the presence of Tmor Associated Macrophages (TAM) CD163+ on the survival of breast cancer patients. By flow cytometry analysis, we describe a heterogeneous composition of CD163low and CD163high TAM subtypes, where we observed the association between high frequency of CD163high TAM infiltration and low CD3+ T lymphocytes presence. By immunohistochemistry on a retrospective analysis (±12 years), we have shown a strong correlation between high frequency CD163+ TAM and an increased risk of progression for patients (log-rank *p<0.05, n= 238). In vitro, CD14+ monocytes conditioned by tumor microenvironment exhibit a biased differentiation towards a CD163highCD86lowIL-10high macrophages (MΦ) phenotype, that not only failed to stimulate the proliferation of naive CD4+ T cells, but strongly inhibited the expansion and the production of IFN-γ and TNF-α by activated-CD4+ T cells. This differentiation into M2-like MΦ (CD163highIL-10high) is associated with high levels of TGF-β, M-CSF and VEGF found in the tumor microenvironment. Furthermore, circulating monocytes of breast cancer patients produced an immunosuppressive cytokine profile and are biased towards the differentiation into MΦ and Mo-DCs that show suppressive capacities
O desenvolvimento do câncer é normalmente associado a desvios no sistema imune, principalmente devido a sua falha em perceber, reconhecer e eliminar células neoplásicas de maneira eficiente. Nesse contexto, duas Células Apresentadoras de Antígenos (APCs), Células Dendríticas (DCs) e Macrófagos (MΦ), têm um papel crucial na identificação de alterações nos tecidos e na estimulação da imunidade adaptativa antitumoral. No entanto, fatores derivados de tumores modulam essas APCs, impedindo a iniciação das respostas imunes e culminando no estabelecimento do câncer. Investigamos aqui como o microambiente tumoral poderia modular a diferenciação de monócitos em APCs in vitro e de modo sistêmico. Nossos dados revelaram que em cânceres de mama e ovário, Macrófagos-Associados a Tumores (TAMs) são a subpopulação mais frequente em leucócitos CD45+MHCII+, e são encontrados em uma frequência variável de TAMs CD163low ou TAMs CD163high. O último, (TAMs CD163high) expressaram maiores níveis de PD-L1 e elevada produção de IL-10 sob a ativação de LPS. Além disso, a análise retrospectiva por imunohistoquímica revelou uma forte correlação entre a presença de TAMs CD163+ e uma baixa taxa de sobrevida em pacientes com câncer de mama. Ainda, a alta frequência de TAMs CD163high foi correlacionada com um baixo infiltrado de células T CD3+. Monócitos saudáveis condicionados por sobrenadantes de tumores de mama tiveram sua diferenciação in vitro direcionada para um fenótipo CD163highIL-10high, células capazes de suprimir a expansão de células T naive CD4+ e a produção de IFN- γ e TNF-α via IL-10. Esse fenótipo adquirido por monócitos condicionados foi associado à presença de altos níveis de CCL22, M-CSF, TGF-β1, TGF-β3, e VEGF no microambiente tumoral. Interessantemente, avaliando os efeitos sistêmicos dos tumores, monócitos circulantes de pacientes com câncer de mama falharam em diferenciar-se em M1- MΦ na presença de GM-CSF/IFN-γ e mantiveram um fenótipo alterado CD163+/-IL-10+TNF-α+
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Ben, Hadj Khalifa Sonia. "Interleukine-10 et régulation de l'activité procoagulante monocytaire. Intérêt dans le syndrome coronarien aigu." Thesis, Reims, 2011. http://www.theses.fr/2011REIMM201/document.
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Les monocytes jouent un rôle procoagulant majeur au cours du Syndrome Coronaire Aigu (SCA). Ils expriment à leur surface le Facteur Tissulaire (FT), initiateur majeur de la génération de la thrombine et sont à l’origine de la génération de icroparticules (MPs) procoagulantes exprimant également le FT. L’inhibition de la génération de thrombine et/ou de la génération des MPs monocytaires est ainsi d’un grand intérêt dans le contexte coronaire. Dans la première partie de ce travail, nous avons effectué une étude fondamentale évaluant, in vitro, l’effet d’anticoagulants utilisés dans le SCA, particulièrement le fondaparinux, ainsi que l’effet de l’interleukine-10 (IL-10), une cytokine anti-inflammatoire dotée des propriétés anti-athéromateuses. Ces deux types de molécules ont été analysées seules ou de façon combinée dans des modèles de génération de thrombine et de microvésiculation monocytaire. Ainsi, nous démontrons 1- que l’IL-10 inhibe lamicrovésiculation monocytaire, 2- que les molécules anticoagulantes inhibent d’avantage la génération de thrombine médiée par la MP monocytaire que celle médiée par le monocyte activé 3- que l’IL-10 potentialise l’effet anticoagulant du fondaparinux. Dans la mesure où la production de l’IL-10 est contrôlée génétiquement, nous avons évalué, dans la seconde partie de ce travail, l’association possible entre 5 polymorphismes génétiques de l’IL-10 et lerisque de pathologie coronaire aigue, et ce, dans une population tunisienne (291 patients/291témoins sains). Nous rapportons une association positive entre les variants polymorphes, IL-10 -592A (Odds ratio : 1,82) et IL-10R3 (Odds ratio : 1,46), et la pathologie coronaire. De façon intéressante, la littérature rapporte que ces deux variants polymorphes sont associés à une synthèse faible d’IL-10. En conclusion, nos résultats ne nous autorisent pas à proposer l’étude systématique des polymorphismes de l’IL-10 dans l’appréciation du risque coronaire aigu chez le patient. En revanche, nos résultats suggèrent que l’IL-10 pourrait constituer une molécule prometteuse dans l’arsenal des thérapeutiques anti-thrombotiquesProcoagulant monocytes play a major role in the pathogeny of the acute coronary syndrome(ACS). Indeed, they express Tissue Factor (TF), the main trigger of thrombin generation, and generate highly procoagulant TF-bearing microparticles (MPs). It is therefore a major issue to control MPassociated thrombin generation in SCA. This led us to evaluate, in the first part of this work, the effect of anticoagulant molecules used in the management of ACS (including fondaparinux) but also of IL-10, an anti-inflammatory cytokine, which can modulate the progression of atheroma. Both types of molecules were evaluated separately or incombination, in a in vitro model of thrombin generation and monocytic MP generation. Ours results show that: 1- IL-10 inhibits monocytic-MP generation; 2- anticoagulants inhibit more potently MP-induced thrombin generation than activated monocyte-induced thrombin generation; 3- IL-10 potentiates fondaparinux inhibitory effect on thrombin generation.As IL-10 production is genetically controlled, we evaluated the possible influence of 5 well-described IL- 10 polymorphisms on the risk of ACS among Tunisians (291 patients/291 healthy controls). Results show that two polymorphic variants of IL-10 i.e. SNP-592A (Odds ratio: 1,82) and microsatellite IL-10R3 Odds ratio: 1,46) are significantly associated with the risk of SCA. Interestingly, the literature reports that these two polymorphic variants are associated with low levels of IL-10 production. In conclusion: Our results do not allow us to recommend the analysis of IL-10 polymorphisms in the assessment of ACS risk. However, our data suggest that IL-10 is a promising antithrombotic pharmacological agent, in this clinical situation
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Kampshoff, Jörg. "Die Wirkung der Interleukine 4, 10 und 13 auf die Koinkubation von Endothelzellen und mononukleären Zellen, gemessen an der Freisetzung von PDGF, Interleukin-1-[beta] [Interleukin-1-beta] und Interleukin-6." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972057684.
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Powell, Mark Jason. "Gene regulation of murine interleukin -10." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299106.
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Crawley, Esther Madeleine. "Interleukin 10 in juvenile idiopathic arthritis." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249187.
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Schmid-Lossberg, Juliette. "Nachweis von Interleukin-1α, Interleukin-1ß, Interleukin-5 und Interleukin-10 im vaginalen Abstrich von gesunden Frauen." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-114787.
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Capper, Emma Rachel. "The human interleukin-10 and interleukin-10 receptor system : molecular & genetic analysis of SLE and recurrent miscarriage." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424695.
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Dokka, Sujatha. "IL-10 gene therapy for the treatment of pulmonary inflammation." Morgantown, W. Va. : [West Virginia University Libraries], 2000. http://etd.wvu.edu/templates/showETD.cfm?recnum=1421.
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Thesis (Ph. D.)--West Virginia University, 2000.Title from document title page. Document formatted into pages; contains ix, 132 p. : ill. (some col.) Vita. Includes abstract. Includes bibliographical references.
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Clarke, Christopher Jeremy Paul. "Molecular mechanisms of the anti-inflammatory cytokines interleukin-4 and interleukin-10." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285172.
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Degboé, Yannick. "Modulation thérapeutique du phénotype du macrophage dans la polyarthrite rhumatoïde." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30085/document.
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La polyarthrite rhumatoïde (PR) est le rhumatisme inflammatoire chronique le plus fréquent. Cette maladie est caractérisée par une auto-immunité et une synovite hypertrophique, responsables d'une destruction des articulations périphériques. Les macrophages contribuent aux phénomènes inflammatoires de la PR. Ces cellules peuvent présenter différents états d'activation ou " polarisation ", réversibles, dépendant de leur environnement, notamment cytokinique. Les biothérapies (bDMARDs) ont représenté une avancée majeure dans la prise en charge des manifestations inflammatoires des formes sévères de PR. Toutefois, peu d'études ont évalué si ce bénéfice était lié à une action spécifique sur le macrophage. L'objectif de ce travail de transversal était : (i) d'évaluer in vitro l'effet des principales biothérapies de la PR (anti-TNF : etanercept, adalimumab, certolizumab ; anti-IL- 6R : tocilizumab ; CTLA4-Ig : abatacept) sur la différenciation et l'activation de macrophages dérivés de monocytes issus de patients atteints de PR et de sujets sains, (ii) d'identifier des marqueurs de polarisation du macrophage, corrélés à l'activité de la maladie (DAS28). Parmi les bDMARDs évalués, seuls les anti-TNF ont montré une action sur la polarisation des macrophages. En contexte de différenciation avec M-CSF, les bDMARDs anti-TNF ont induit un biais vers une polarisation non inflammatoire dite alternative. En contexte d'activation inflammatoire, les bDMARDs anti-TNF ont induit une préservation sélective des marqueurs de polarisation liés à l'IL-10 (CD16, CD163, MerTK) et une inhibition des marqueurs inflammatoires (CD40, CD80). Nous avons montré que ce changement phénotypique s'accompagnait : (i) d'un changement fonctionnel concordant avec une polarisation induite par l'IL-10, (ii) d'une inhibition de la production des cytokines de l'inflammation (TNF, IL-6, IL-12), (iii) et d'une majoration de la phagocytose. Nous avons montré que ce mécanisme était dû à une production précoce d'IL-10 et dépendant de STAT3. De plus, nous avons pu montrer que le certolizumab, un anti-TNF, induisait une réponse anti-inflammatoire, impliquant le facteur de transcription NRF2 (nuclear factor erythroid-2-related factor 2), un régulateur central dans la réponse au stress oxydatif. Enfin, nous avons observé que l'expression de CD16, à la surface des macrophages non activés, était corrélée négativement à l'activité de la PR. Ces travaux concourent à montrer l'intérêt du ciblage du macrophage dans la PR et nous ont d'identifier de potentielles cibles théranostiques dans le traitement de la PR par anti-TNFRheumatoid arthritis (RA) is the most frequent chronic inflammatory rheumatism. This disease is characterized by an auto-immunity and a hyperplasic synovitis, both responsible for peripheral joints destruction. Macrophages contribute to inflammatory aspects of RA. This cell type can present various states of activation or "polarization", reversible and dependent on its environment, notably cytokines. Biologics (bDMARDs) represented a revolution in severe RA treatment. However, data regarding their specific action on macrophage are scarce. The aim of our translational work was: (i) to assess the in vitro effect of RA bDMARDs (anti-TNF: etanercept, adalimumab, certolizumab; anti-IL-6R: tocilizumab; CTLA4-Ig: abatacept) on the phenotype of monocytes-derived-macrophages from RA patients and healthy volunteers, during differentiation and activation phases, (ii) to identify polarization markers correlated with disease activity (DAS28). Among bDMARDs, only anti-TNF modulated macrophage polarization. During differentiation, anti-TNF bDMARDs induced a bias toward the so-called alternative non-inflammatory polarization. In inflammatory context, anti-TNF bDMARDs induced a selective preservation of markers associated with IL-10 (CD16, CD163, MerTK) and an inhibition of inflammatory markers (CD40, CD80). We showed that these changes in phenotype were associated with changes in functions consistent with: (i) a polarization induced by IL10, (ii) a decrease in inflammatory cytokines production (TNF, IL-6, IL-12), (iii) and an increase in phagocytosis. We showed that this mechanism was dependant on early IL-10 production and STAT3 signaling. Moreover, we have showed that certolizumab, an anti-TNF agent, induced an anti-inflammatory response, implicating the transcription factor NRF2 (nuclear factor erythroid-2- related factor 2), a central regulator of the response to oxidative stress. We observed that CD16 expression on non-activated macrophages was negatively correlated with RA activity. This work contributes to demonstrate the relevance of macrophage targeting in RA, and enabled us to identify theranostic targets for RA treatment with anti-TNF bDMARDs
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Schwarz, Annika. "Einfluss von Interleukin-10 auf die Differenzierung von Monozyten zu Dendritischen Zellen." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-148424.
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Interleukin-10 ist ein Paradebeispiel eines immunhemmenden Zytokins. Es konnte nachgewiesen werden, dass eine Reihe von Tumoren Interleukin-10 produziert, um einer Antitumor-Immunantwort zu entgehen. Viele Studien haben sich mit dem Einfluss von Interleukin-10 auf die antigenpräsentierenden Fähigkeiten der Dendritischen Zellen beschäftigt. Es gibt eindeutige Hinweise, dass der Effekt von tumorproduziertem Interleukin-10 nicht nur in einer hemmenden Wirkung auf die Ausreifung Dendritischer Zellen besteht, sondern dass Interleukin-10 zu einer Reduktion der Anzahl an Dendritischen Zellen führen kann. Ziel dieser Arbeit ist es daher, den Mechanismus für eine solche depletierende Wirkung auf die Dendritischen Zellen zu analysieren. Hierzu wurden die Effekte von Interleukin-10 auf die frühe Differenzierung von Dendritischen Zellen aus Monozyten untersucht.
Die Zugabe von Interleukin-10 zu einem Differenzierungscocktail aus Interleukin-4 und Granulozyten/Makrophagen-Kolonie-stimulierendem-Faktor führt zu einer nachhaltigen Hemmung des Differenzierungsprozesses von Monozyten zu Dendritischen Zellen. Bereits 48h nach Beginn der Zellkultur konnte mit Hilfe von cDNA-Microarray-Analysen gezeigt werden, dass Interleukin-10 nicht nur einen Differenzierungs-hemmenden Effekt ausübt, sondern auch die Entstehung aberranter Zellphänotypen bewirkt. In weiteren Experimenten konnte gezeigt werden, dass die Effekte des Interleukin-10 in der frühen Differenzierungsphase weitgehend irreversibel sind. Zusammenfassend können die Ergebnisse zur Erklärung beitragen, wie es bei Patienten mit Tumoren unter dem Einfluss von Interleukin-10 zu einer Reduktion der absoluten Zahl Dendritischer Zellen kommen kann.
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Walter, Claudia. "Bestimmung der Zytokine Interleukin-1ra, Interleukin-6, Interleukin-10 und Interleukin-12 im Vaginalsekret bei Frauen mit Bakterieller Vaginose." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-28461.
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Müller, Riccarda [Verfasser]. "Effekte einer Interleukin-10 Überexpression in humanen Gelenkchondrozyten und Interaktion von Interleukin-10 mit Tumor Nekrose Faktor-α / Riccarda Müller." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1027813623/34.
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Cochery-Nouvellon, Eva Nguyen Philippe Gris Jean-Christophe. "Régulation de la génération de thrombine par l'IL-10 ; polymorphisme de l'IL-10 et risque vasculair." S.n. : S.l, 2006. http://scdurca.univ-reims.fr/exl-doc/GED00000377.pdf.
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Cochery-Nouvellon, Éva. "Régulation de la génération de thrombine par l'IL-10 ; polymorphisme de l'IL-10 et risque vasculaire." Reims, 2006. http://theses.univ-reims.fr/exl-doc/GED00000377.pdf.
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L’@interleukine-10 (IL-10) est une cytokine jouant un rôle primordial dans la régulation des réactions immunitaires et inflammatoires. Bien que de nombreux arguments expérimentaux et des modèles animaux plaident en faveur d’un rôle de l’IL-10 dans la régulation de l’hémostase, l’implication de cette cytokine en pathologie vasculaire est peu appréhendée. Des polymorphismes génétiques situés sur le promoteur du gène de l’IL-10 ont été rapportés comme influençant son taux de sécrétion. Par ailleurs, certains polymorphismes sont associés à un risque de pathologie dysimmunitaire. Dans ce contexte, nous avons mis au point plusieurs modèles de culture cellulaire afin d’analyser la sécrétion d’IL-10 chez 20 volontaires sains, de génotype connu. L’IL-10 étant connue pour réguler l’expression du facteur tissulaire (FT), nous avons mis au point un modèle original d’étude de l’effet de l’IL-10 sur la cinétique de génération de thrombine induite par le monocyte activé. Nous avons ainsi montré le rôle modulateur de la sécrétion d’IL-10 endogène sur la génération de thrombine. En parallèle, deux études cliniques ont été menées. La première étude porte sur le risque de la maladie thromboembolique veineuse et montre que le polymorphisme IL-10 G13 est associé à un risque de thrombose veineuse (Thromb Haemost 2006 ;96 :24-8). La seconde étude concerne le risque de pathologie vasculo-placentaire. L’étude montre que le polymorphisme de substitution d’acide nucléique (-819T) est associé à la survenue de fausses couches précoces. Ces arguments plaident en faveur d’un rôle de l’IL-10 en pathologie vasculaire.
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Strong, Victoria. "Modulation of dendritic cell function by interleukin-10." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393790.
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Clutton, Genevieve Tyndale. "HIV-specific interleukin-10 responses and immune modulation." Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589623.
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Interleukin-l0 (IL-10) helps to limit the duration of potentially harmful inflammatory responses but has also been implicated in the persistence of a number of chronic viral infections. This thesis aimed to investigate the phenotype and function of mv -specific IL-l0-producing cells in chronic HIV-I infection, and the effect of IL-10 blockade on responses to candidate HIV -I vaccines. A cytokine capture assay was used to determine the HIV -specific cellular sources of IL- 10 in PBMC from 55 chronically infected individuals. A rare subset of CD8+ T cells was found to be the major HIV -I Gag-specific IL-10-producing population; these cells were restricted to ART-naive individuals and did not express the regulatory T cell markers CD25 or FoxP3 but could co-express IFN-y. A proportion of the population (median 48% and 9% respectively) expressed the P7 chain of the gut-homing integrin a4p7 and the chemokine receptor CXCR3, which mediates lymphocyte migration to sites of inflammation. Experimental depletion of Gag-specific IL-10+ CD8+ T cells did not affect T cell activation, or the production of cytokines such as IL-2 or IFN-y during short-term culture. However, depletion was associated with a significant increase in CD38 expression on CDI4+ monocytes, a trend towards increased HLA-DR expression on the same cells, and a significant increase in the concentration of the pro-inflammatory cytokine IL-6 in culture supernatants. There was also a significant increase in the number of HIV-infected (p24 antigen+) CD4+ T cells in cultures depleted of Gag- specific IL-10+ CD8+ T cells after 3 days, indicating that this population may contribute to control of viral replication. In order to determine the effect of IL-10 blockade on vaccine immunogenicity, IL-10R blocking antibody was administered to BALB/c mice prior to immunisation with two mV-I candidate vaccines, HIVA and HIVconsv. IL-10R blockade resulted in a trend towards increased IFN-y production by CD8+ T cells in response to the dominant H (Env) and P (Pol) epitopes of HIV A, and a significant increase in IFN-y ELISPOT responses to the subdominant Gl (Gag) epitope of HIV consv in vitro. Collectively, these data suggest that IL-10 producing cell populations may play critical but different roles in chronic infection and vaccination. Further research into how the timing of IL-10 responses affects disease outcome may allow IL-IO blockade to be explored as a therapeutic strategy in humans
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Rempel, Julia D. "Interleukin-12 and interleukin-10 regulation of antibody responses upon protein antigen immunization." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ41623.pdf.
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Alméras, Lionel. "Caractérisation de nouvelles cibles de la réponse immune dans la sclérose en plaques : des séquences rétrovirales endogènes aux auto-antigènes cérébraux." Lille 2, 2003. http://www.theses.fr/2003LIL2MT02.
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Santos, de Almeida Ana Margarida. "Molecular and cellular characterization of rhinoscleroma, a neglected disease caused by the bacterium Klebsiella rhinoscleromatis." Paris 6, 2012. http://www.theses.fr/2012PA066489.
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DESPRINGRE, JEAN-LUC. "Effets d'anticorps monoclonaux anti-interleukine 10 dans un modele de toxoplasmose experimentale murine." Université Louis Pasteur (Strasbourg) (1971-2008), 1993. http://www.theses.fr/1993STR1M155.
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Frellstedt, Linda. "Induction and characterization of endotoxin tolerance in equine peripheral blood mononuclear cells in vitro." Thesis, Virginia Tech, 2010. http://hdl.handle.net/10919/44307.
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Endotoxemia is responsible for severe illness in horses. Individuals can become unresponsive to the endotoxin molecule after an initial exposure; this phenomenon has been called developing a state of â endotoxin toleranceâ (ET). ET has been induced in horses in vivo; however, cytokine expression associated with ET has not been investigated. The purpose of this study was to develop and validate a method for inducing ET in equine peripheral blood mononuclear cells (PBMCs) in vitro, and to describe the cytokine profile which is associated with the ET. Blood was collected from 6 healthy horses and PBMCs were isolated. ET was induced by culturing cells with three concentrations of endotoxin given to induce ET, and evaluated after a second dose of endotoxin given to challenge the cells. The relative mRNA expression of IL-10 and IL-12 was measured by use of quantitative PCR.
ET was induced in all cells (n=6) exposed to the 2-step endotoxin challenge. In PBMCs treated with 1.0 ng/ml of endotoxin followed by challenge with 10 ng/ml of endotoxin, the relative mRNA expression of IL-10 in tolerized cells was not different from positive control cells. In contrast, the relative mRNA expression of IL-12 in tolerized cells was decreased by 15-fold after the second endotoxin challenge compared with positive control cells.
This experiment demonstrated a reliable method for the ex vivo induction of ET in equine PBMCs. A marked suppression of IL-12 production is associated with ET. The production of IL-10 was not altered in ET in our model.
Master of Science
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OBAFEMI, TOLULOPE FESAYO. "THE EFFECTS OF INTERLEUKIN 6 AND INTERLEUKIN 10 ON FRAILTY IN C57BL/6 MICE." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/613394.
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Studies have shown that pro-inflammatory IL-6 and anti-inflammatory IL-10 interleukins may correlate to frailty and aging. This frailty can be defined in the context of clinical symptoms which include sarcopenia and osteoporosis, decreased activity level; or in the context of increased susceptibility to adverse health outcomes from a deficient immune system. In this experiment we tested a cohort of conditionally regulated IL-6 and IL-10 mice with controls (IL-6tg+.rtTA(r/r) (n=8), IL-10(-/-). IL-10tg+ rtTA(r/r) (n=10) and rtTA(r/r) (n=5)) under frailty assessments and immunological cell analysis. We were unable to successfully induce expression in the conditionally regulated mice. Subsequently, there was no difference in the frailty scores, weight, or temperature fluctuation between all three genotypes. As a preliminary study, there arose essential learning points of improvement that can be applied to future experiments concerning frailty in transgenic mice.
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Schardt, Victor. "Vergleichende Untersuchungen zur Hefepilzbesiedelung von Mundhöhle und Vagina und Bestimmung von Interleukin-4, Interleukin-10 und Interleukin-12." Diss., lmu, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-155152.
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Leppert, Kyle McDonald McMurray Robert G. "The effect of glycogen depletion on responses of interleukin-1beta, interleukin-6, and interleukin-10 to maximal exercise." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2599.
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Thesis (M.A.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Oct. 5, 2009). "... in partial fulfillment of the requirement for the degree of Master of Arts in the Department of Exercise and Sport Science Exercise Physiology." Discipline: Exercise and Sports Science; Department/School: Exercise and Sport Science.
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Unterberger, Claudia. "Molekulare Mechanismen der Induktion von Interleukin-10 durch Glukokortikoide." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-74135.
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Chang, Wen-Lan William. "Genetic and functional dissection of rhesus cytomegalovirus interleukin-10 /." Connect to Digital dissertations. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.
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Karimi, Sepideh. "Expression of interleukin-10 in vitro and in vivo." Thesis, University of Ottawa (Canada), 1994. http://hdl.handle.net/10393/6527.
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Classification of cytokines into T helper type 1 (Th1) and T helper type 2 (Th2) has helped in the elucidation of the mechanisms of resistance or susceptibility to infections. HIV infection causes CD4$\sp+$ T cell dysfunction and depletion by indirect mechanisms; for example: inhibition of immunoregulatory cytokines. Interleukin (IL-10), the subject of this study, is secreted mostly by CD4$\sp+$ human Th2-like, but also by Th0,Th1-like, and by a proportion of CD8$\sp+$ T cell clones. HIV sero-positive patients exhibit depressed cell mediated immune responses, B cell hyperplasia, and hypergammaglobulinemia which may result from downregulation of Th1 and upregulation of Th2 class responses respectively. In this study, the expression of interferon$\gamma$ (IFN$\gamma$) and IL-10 which mediate Th1 and Th2 responses respectively, in unstimulated peripheral blood lymphocytes (PBLs) from HIV$\sp+$ patients were investigated. IL-10 expression as observed by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis was significantly upregulated in patients with less than 400 CD4$\sp+$ T cells in comparison with HIV$\sp+$ patients with more than 400 CD4$\sp+$ T cells and normal controls. A semi-quantitative RT-PCR analysis of unstimulated PBLs further demonstrated IL-10 upregulation was inversely associated with IFN$\gamma$ downregulation in the same individuals. Similar results were observed as determined by measuring IL-10 and IFN$\gamma$ production in the supernatants of unstimulated PBLs by employing enzyme immunoassay techniques. These results suggest that HIV infected individuals express predominately Th2 type cytokines in their PBLs.
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Blalock, Emily L. "Roles of TH2 and TH17 CD4+ T-Helper Cell Cytokines in the Pathogenesis of Experiemental Cytomegalovirus Retinitis." Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/biology_diss/122.
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Human cytomegalovirus (HCMV) is a betaherpesvirus that infects up to 80% of the population worldwide, and establishes latency in monocytes and bone marrow cells. Reactivated HCMV can become an opportunistic pathogen in individuals who are immunocompromised, such as those with acquired immunodeficiency syndrome (AIDS). HCMV infection of AIDS patients causes a sight-threatening retinitis that leads to vision loss and blindness in up to 46% of this population without antiretroviral treatment. Because untreated HIV-infected individuals exhibit the loss of cell-mediated immunity and alterations in CD4+ T-helper (Th) cell cytokines, including elevation of interleukin-4 (IL-4), IL-10, and IL-17, we sought to test the hypothesis that these cytokines play key roles in governing the susceptibility to AIDS-related HCMV retinitis. This hypothesis was tested utilizing a clinically relevant mouse model of experimental murine cytomegalovirus (MCMV) retinitis that occurs in C57BL/6 mice immunosuppressed by mouse retroviruses (MAIDS). Studies revealed that MAIDS progression was associated with increased levels of IL-4 and IL-10, cytokines whose production has been associated with diminished CD8+ T-cell-mediated immunity during HIV infection. However, MCMV–infected eyes of retinitis-susceptible IL-4-/- or IL-10-/- MAIDS mice exhibited frequency and severity of retinitis and viral titers equivalent to MCMV-infected eyes of wild-type MAIDS animals. These studies indicated that neither IL-4 nor IL-10 alone play key roles in increased susceptibility to MCMV retinitis. In comparison, IL-17, an inflammatory cytokine associated with the ocular autoimmune disease uveitis, was systemically increased during the progression of MAIDS, but MCMV-infected eyes of retinitis-susceptible MAIDS mice exhibited a significant reduction in IL-17. These findings suggested that IL-17 plays no direct role in the pathogenesis of experimental MCMV retinitis. However, these results also suggested the remarkable possibility that MCMV downregulates IL-17 production, a hypothesis supported by the observation that systemic MCMV infection of healthy and MAIDS mice resulted in the downregulation of IL-17. Mechanistic studies revealed that knockdown of IL-10 resulted in a partial recovery IL-17 levels during MCMV infection. We conclude that MCMV-induced IL-17 downregulation occurs via the stimulation of IL-10 and the suppressor of cytokine signaling (SOCS)-3. Taken together, our results add new information to the immunobiology of HCMV and to our basic understanding of the pathogenesis of AIDS-related HCMV retinitis.
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Frisch, Kristina. "Klonierung von IL-10 und IL-10-Homologen und Funktionsanalyse in einem Mausmodell der polymikrobiellen Sepsis." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973392185.
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Chong, Wai-po, and 莊偉波. "Association of interleukin 10 promoter polymorphisms with systemic lupus erythematosus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29295981.
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Gehrcke, Jan-Philip. "Investigation of the interleukin-10-GAG interaction using molecular simulation methods." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-163205.
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Glycosaminoglycans (GAGs) are linear polysaccharides, built of periodically occurring disaccharide units. GAGs are ubiquitous in the extracellular matrix (ECM), where they exhibit multifarious biological activities. This diversity arises from - among others - their ability to interact with and regulate a large number of proteins, such as cytokines, chemokines, and growth factors. As of the huge variety in their chemical configuration, GAGs are further sub-classified into different types (heparin, for instance, is one of these sub-classes). Hence, GAGs are a diverse class of molecules, which surely contributes to the broadness of their spectrum of biological functions. Through varying arrangements of sulfate groups and different types of saccharide units, individual GAG molecules can establish specific atomic contacts to proteins. One of the best-studied examples is antithrombin-heparin, whose biologically relevant interaction requires a specific pentasaccharide sequence. It is valid to assume, however, that various proteins are yet to be discovered whose biological functions are in some way affected by GAGs. In other cases, and this is true for the cytokine interleukin-10 (IL-10), there are already experimental indications for a biologically relevant protein-GAG interaction, but the details are still obscure and the fundamental molecular interaction mechanism has still not been clarified.
IL-10 has been shown to bind GAGs. So far, however, no structural detail about IL-10-GAG interaction is known. Function-wise, IL-10 is mainly considered to be immunosuppressive and therefore anti-inflammatory, but it in fact has the pleiotropic ability to influence the immune system in both directions, i.e. it constitutes a complex regulation system on its own. Therefore, the role of GAGs in this system is potentially substantial, but is yet to be clarified. In vitro experiments have yielded indications for GAGs being able to modulate IL-10\'s biological function, and obviously IL-10 and GAGs are simultaneously present in the ECM. This gives rise to the assumption that IL-10-GAG interaction is of biological significance, and that understanding the impact of GAGs on IL-10 biology is important - from the basic research point of view, but also for the development of therapies, potentially involving artificially designed ECMs.
A promising approach for obtaining knowledge about the nature of IL-10-GAG interaction is its investigation on the structural level, i.e. the identification and characterization of the molecular interaction mechanisms that govern the IL-10-GAG system. In this PhD project it was my goal to reveal structural and molecular details about IL-10-GAG interaction with theoretical and computational means, and with the help of experiments performed by collaborators in the framework of the Collaborative Research Centre DFG Transregio 67. For achieving this, I developed three methods for the in silico investigation of protein-GAG systems in general and subsequently applied them to the IL-10-GAG system. Parts of that work have been published in scientific journals, as outlined further below.
I proposed and validated a systematic approach for predicting GAG binding regions on a given protein, based on the numerical simulation and analysis of its Coulomb potential. One advantage of this method is its intrinsic ability to provide clues about the reliability of the resulting prediction. Application of this approach to IL-10 lead to the observation that its Coulomb attraction for GAGs is significantly weaker than in case of exemplary protein-GAG systems (such as FGF2-heparin). Still, a distinct IL-10-GAG binding region centered on the residues R102, R104, R106, R107 of the human IL-10 sequence was identified. This region can be assumed to play a major role in IL-10-GAG interaction, as described in chapter 3.
Molecular docking methods are used to generate binding mode predictions for a given receptor-ligand system. In chapter 4, I clarify the importance of data clustering as an essential step for post-processing docking results and present a clustering methodology optimized for GAG molecules. It allows for a reproducible analysis, enabling systematic comparisons among different docking studies. The approach has become standard procedure in our research group. It has been applied in a variety of studies, and served as an essential tool for studying IL-10-GAG interaction, as described in chapter 3.
Motivated by the shortcomings of classical docking approaches, especially with respect to protein-GAG systems, I worked on the development of a molecular dynamics-based docking method with less radical approximations than usually applied in classical docking. The goal was to make the computational model properly account for the special physical properties of GAGs, and to include the effects of receptor flexibility and solvation. The methodology was named Dynamic Molecular Docking (DMD) and published in the Journal of Chemical Information and Modeling-together with a validation study.
The subsequent application of DMD in a variety of studies required enormous amounts of computational resources. For tackling this challenge, I established a graphics processing unit-based high-performance computing environment in our research group and developed a software framework for reliably performing DMD studies on this hardware, as well as on other computing resources of the TU Dresden. The investigation of the IL-10-GAG system via DMD was focused on the IL-10-GAG binding region predicted earlier, and made heavy usage of the optimized clustering approach named above. An important result of this endeavor is that IL-10's amino acid residue R107 significantly stands out compared to all other residues and supposedly plays a particularly important role in IL-10-GAG recognition. The collaboration with the NMR laboratory of Prof. Daniel Huster at the Universität Leipzig was fruitful: I post-processed nuclear Overhauser effect data and obtained heparin structure models, which revealed that IL-10-heparin interaction has a measurable impact on the backbone structure of the heparin molecule. These results were published in Glycobiology. In chapter 8, I propose two different scenarios about how GAG-binding to IL-10 might affect its biological function, based on the findings made in this thesis project.
In conclusion, a set of methods has been developed, all of which are generically applicable for the investigation of protein-GAG systems. Regarding the IL-10-GAG system, valuable structural insights for increasing the understanding about its molecular mechanisms were derived. These observations pave the way towards unraveling GAG-mediated bioactivity of IL-10, which may then be specifically exploited, for instance in artificial ECMs for improved wound healing.
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VanDeusen, Jeffrey Bryan. "A role for stat-1 in regulating interleukin 10 production following LPS challenge." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1084860074.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains ix, 64 p.; also includes graphics (some col.). Includes bibliographical references (p. 54-64). Available online via OhioLINK's ETD Center.
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Wang, Allen Ping-Lun. "The effect of hypoxia on the production of interleukin-10 (IL-10) in human mononuclear cells." Thesis, University of Leicester, 2010. http://hdl.handle.net/2381/10228.
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Macrophages play an important role in both innate and adaptive immunity by engulfing intruding pathogens and damaged or infected cells, antigen presentation, and by secretion of immune mediators. Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine mainly produced by macrophages in response to cell activation, which serves to suppress immune reactions and inflammation. Hypoxia refers to oxygen deprivation. It is a common condition found in pathological tissues. The relationship between hypoxia and the production of IL-10 by macrophage is not yet thoroughly understood. In previous unpublished work by Staples and Burke et. al., it was found that both basal and LPS-induced IL-10 mRNA and protein are reduced in hypoxia. In the present study, it was shown that the transcription factor Hypoxia Inducible Factor 1 (HIF-1) appears to be involved in this reduction of IL-10 production in hypoxia. Although the regulatory elements on the IL-10 promoter responsible for this blockage effect were not definitively identified, our results indicated that the activity of a -4kb IL-10 luciferase reporter adenovirus was significantly reduced in cells treated with the HIF-1 inducing agents, cobalt chloride and desferrioxamine. The activity of a -195bp IL-10 luciferase reporter adenovirus was also decreased in the HIF-1inducing agent treated samples. These data imply that either by indirect interaction or physically binding to the IL-10 promoter or gene, HIF-1 does play a role in blocking IL-10 expression in hypoxia. Sequence and transcription factor analysis indicated the presence of a HIF-1 consensus sequence hypoxia responsive element (HRE) located in the -2,171bp to -2,187bp position on the IL-10 promoter. This result suggests that HIF-1 may affect IL-10 production, at least in part, by physically binding to its promoter. Lastly, we showed that the effect of hypoxia on IL-10 expression is observed with a range of different toll-like receptor ligands, and is not limited to induction by LPS.
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Williams, Lynn Michelle. "A comparison of interleukin-10 and lipopolysaccharide signalling in monocytes." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264968.
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Thompson, Kerry C. "The expression and function of interleukin-10 in liver injury." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285873.
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Madan, Rajat. "Novel insights into the in vivo biology of Interleukin-10." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1242133534.
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Dockstader, Kristy. "Role of interleukin-10 in lung repair during influenza infection." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/59050.
Full textAbstract:
The mammalian lung is intricately designed for effective gas exchange. However, infections such as influenza can damage the lung tissue and can cause a critical decrease in lung performance.
Influenza is a single stranded RNA virus from the Orthomyxoviridae family. Seasonal influenza outbreaks cause up to 600 deaths in Canada each year, with increased death tolls during years with pandemic strains. Influenza A virus primarily infects the epithelial cells of the respiratory system and leads to acute respiratory infections.
Tissue destruction occurs both as a result of viral-mediated apoptotic pathways, and as a consequence of the cytolytic immune response that is essential to bring the infection under control. The immune system attempts to minimize damage by producing key anti-inflammatory molecules, of which Interleukin-10 (IL-10) is a particularly potent example.
IL-10 is a pleotropic cytokine that not only functions as an anti-inflammatory cytokine, but has been shown to have a role in immune stimulation, increase cytoskeletal repair and aid in the recovery of epithelial integrity. We hypothesized that IL-10 may have an effect on the remodeling and repair of lung epithelium during and after influenza A virus infection. We determined that IL-10 is up-regulated in response to infection. The timing of increased IL-10 also coincided with the height of damage, inflammation and onset of repair during an influenza infection. We used a human bronchial epithelial cell line (16HBE) to develop a model to assess if IL-10 had a direct effect on epithelial repair. Preliminary data suggested that IL-10 may inhibit epithelial cell proliferation, but further research is required.
Our data suggest that IL-10 does not appear to have a role in direct epithelial proliferation but could still have a role in repair. A better understanding of the signals involved in epithelial cell repair could lead to the development of novel therapies that will minimize/mitigate lung damage caused by influenza, as well as other lung diseases.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
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Le, Moine Olivier. "Interleukin-10 in liver ischaemia-reperfusion injury and alcoholic cirrhosis." Doctoral thesis, Universite Libre de Bruxelles, 1996. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212296.
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Cavendish, Victoria Jane. "The regulation of tumour necrosis factor-alpha and interleukin-10 by interleukin-13 in monocytic cells." Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392976.
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