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1
Golbs, Sebastian. "Entzündungsparameter und Vorläufermarker bei der Coronaratherosklerose." Doctoral thesis, Universitätsbibliothek Leipzig, 2010. http://nbn-resolving.de/urn:nbn:de:bsz:15-20100407-135735-3.
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Atherosklerotische Arterien unterliegen strukturellem Umbau und chronischer Inflammation, die von einer dynamischen Entwicklung von Vasa vasorum (VV) begleitet wird. Die Beteiligung von Leukozyten und von vaskulären Vorläuferzellen an der Neovaskularisierung sowie die intimale Hyperplasie stehen im Zentrum der Atheroskleroseforschung. Damit verbundene Erkenntnisse könnten neue therapeutische Ansätze ermöglichen. Die vorliegende Arbeit befaßt sich mit der morphologischen Verteilung von Leukozyten (CD45, CD68, Mastzellen) und von Zellen mit Vorläufermarkern (CD34, CD117, VEGFR-2) in menschlichen Coronararterien mit verschiedenen atherosklerotischen Schweregraden. Mittels immunhistologischer Technik wurden Intima und Adventitia untersucht und die Ergebnisse zu den atherosklerotischen Schweregraden und der Neovaskularisierung korreliert. In Intima, Adventitia und dem perivaskulären Fettgewebe hat die Dichte der CD45+ Lymphozyten ihr Maximum im atherosklerotischen Grad 3. Dabei konnte sowohl in der Intima als auch in der Adventitia gezeigt werden, daß eine lineare Korrelation der CD45+ Lymphozyteninfiltration und VV-Dichte vorliegt. Es wurden zwei unterschiedliche Entzündungsmuster festgestellt. Beide zeigen in Grad 3 eine Zunahme der Zelldichten. In Grad 4-5 fällt die Dichte des einen Musters (CD45+, VEGFR-2+, VV) jedoch ab, während die Dichte des anderen Musters (CD34+, CD68+, Tryptase+, CD117+) in Grad 4-5 keine Veränderung aufweist. Die Ergebnisse deuten darauf hin, daß Leukozyten und vaskuläre Vorläuferzellen im Verlauf der Atherogenese wechselnde Funktionen wahrnehmen können. Sie nehmen offensichtlich VV als Eintrittspforte in die Gefäßwand.
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Barbosa, Maria Izabel Neves de Holanda. "Avaliação do PRA e CD30s no transplante renal intervivos. Acompanhamento no 1 ano e após 6 anos em pacientes do Hospital Federal de Bonsucesso (Rio de Janeiro, Brasil)." Universidade do Estado do Rio de Janeiro, 2013. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=5592.
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O CD30 solúvel (CD30s) é uma glicoproteína transmembrana da família do fator de necrose tumoral expressa na superfície das células T. Quando este marcador é clivado ele torna-se solúvel, sendo detectado na circulação. Atualmente, o valor de CD30s pré-transplante vem sido demonstrado como um bom preditor de rejeição aguda (RA) e perda do enxerto. Poucos estudos foram realizados para sua avaliação no pós-transplante e sua correlação com sobrevida e TFG. Avaliar a eficácia da determinação dos marcadores laboratoriais CD30 solúvel (CD30s) e anticorpos reativos contra painel HLA (PRA) em seis meses, um ano e seis anos pós-transplante renal em receptores de doadores vivos, correlacionando estes marcadores com episódios de rejeição aguda, eventos infecciosos no pós-transplante, perda do enxerto e óbito do paciente transplantado. E, avaliar a correlação destes marcadores com a sobrevida do enxerto renal nestes períodos. Os pacientes estudados foram transplantados
renais com doadores vivos no Hospital Federal de Bonsucesso (HFB) do Rio de Janeiro no ano de 2006 e do período de agosto de 2010 a maio de 2011, sendo uma extensão de um trabalho realizado previamente. CD30s e PRA foram analisados nas amostras coletadas no pré-transplante e com 7, 14, 21 dias, 1, 3, 6, 12 meses após o transplante e nos pacientes transplantados em 2006 amostras após 6 anos de transplante. A taxa de filtração glomerular (TFG) foi estimada
utilizando MDRD e CKD-epi e 6 meses, 1 ano e 6 anos após o transplante. Os pacientes foram agrupados em 5 grupos: sem eventos, com perda do enxerto, óbito, rejeição aguda e pacientes com quadros infecciosos. Estes grupos foram avaliados com relação ao CD30s, PRA I e II e comparados dois a dois. O teste qui quadrado foi utilizado. Quando necessário aplicou-se a correção de Yates, o teste de Fisher, o teste de Kruskal-wallis. Foi considerado estatisticamente
significante p<0,05. As análises foram feitas pelo programa EPI-Info (versão 3.5.3). Setenta e seis pacientes com doadores vivos foram incluídos no estudo 47 pacientes não tiveram nenhum evento (grupo 1), 7 pacientes perderam o enxerto (grupo 2), 3 pacientes faleceram (grupo 3), 11 pacientes ficaram no grupo de rejeição aguda (grupo 4) e oito pacientes tiveram infecção por CMV e herpes (grupo 5). Os pacientes do grupo de RA tiveram correlação positiva com os valores tanto de CD30s Pré-transplante (p=0,01), quanto do CD30s pós-transplante (p=0,002) e PRA I e II (p<0,001), respectivamente, quando comparados com pacientes sem eventos. A TFG tanto com MDRD e CKD-Epi não mostrou correlação com CD30s pré e pós-transplante e nem PRA I e II. A TFG com as duas fórmulas foi menor no grupo com RA comparado com o grupo sem evento após 6 anos de transplante (p=0,006). CD30s é um bom preditor de RA, assim como PRAI e II. E, também mais uma ferramenta que pode ser utilizada no acompanhamento pós-transplante Renal. A RA é um preditor isolado para diminuição de TFG no transplante.
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Fischer, Marie. "Mast cells in Hodgkin lymphoma : or 'What's a nice cell like you doing in a tumour like this?'." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4620.
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Bengtsson, Åsa. "The role of CD30 in atopic allergy /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4333-8/.
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Oberbarnscheidt, Martin. "Charakterisierung und Struktur des cd30-Gens." [S.l.] : [s.n.], 2001. http://www.diss.fu-berlin.de/2001/245/index.html.
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Hahn, Corinna. "Untersuchungen zur Apoptoseresistenz CD30-exprimierender Tumorzellen." [S.l.] : [s.n.], 2004. http://www.diss.fu-berlin.de/2004/258/index.html.
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Freitas, Helder Teixeira de. "Papel da sinalização da adenosina na geração de células T regulatórias a partir de células T naive de cordão umbilical e na imunomodulação por células-tronco estromais mesenquimais de medula óssea." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/17/17153/tde-19072018-135504/.
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As células T regulatórias (Tregs) são essenciais para a manutenção da tolerância periférica, prevenção de doenças autoimunes e limitantes nas doenças inflamatórias crônicas. Além disso, essas células exercem um papel fundamental no controle da rejeição de transplantes. Diferentes protocolos mostraram que é possível obter Tregs a partir de células T naive CD4+ in vitro. Para tal, é consenso que o TGF-? e a interleucina-2 (IL-2) são capazes de direcionar as células T naive CD4+ a se tornarem regulatórias após um estímulo antigênico (anti-CD3/CD28). Nosso grupo recentemente notou que, durante a imunomodulação de linfócitos T pelas células estromais mesenquimais (CTMs), estas eram capazes de produzir adenosina que, por sua vez, participa do processo de imunorregulação. Outros trabalhos indicam que as CTMs suprimem a proliferação dos linfócitos T pela geração de Tregs e que as CTMs induzem a geração de Tregs através da regulação negativa da via TCR e da via AKTmTOR. Evidências apontam que a adenosina pode atuar regulando negativamente a via mTOR. Portanto, acredita-se que a adenosina possa participar do processo de geração de Tregs através da modulação da via mTOR. Além disso, estudos recentes indicam que a ativação de receptores de adenosina, mais especificamente A2a, com agentes agonistas, leva ao aumento da produção de células Tregs, enquanto que a utilização de agentes antagonistas destes receptores leva à diminuição da diferenciação de Tregs. Porém, estes estudos mostram a geração de Tregs a partir de células T naive de camundongos. Visto a grande importância das Tregs no contexto imunológico, a produção eficiente de Tregs in vitro tem importância fundamental para o desenvolvimento de novos protocolos terapêuticos para o tratamento de doenças autoimunes e no combate à rejeição de transplantes. Assim, o objetivo central deste trabalho foi avaliar a participação de agonistas e antagonistas de receptores de adenosina na indução de células T regulatórias geradas in vitro (iTreg) pela ativação de células T CD4+ naive isoladas de sangue de cordão umbilical (SCU) humano. Para isso, células mononucleares foram isoladas de bolsas de SCU e as células T naive foram isoladas imunomagnéticamente. Essas células foram ativadas com beads ligadas a anticorpos anti-CD2/CD3/CD28 e cultivadas por cinco dias na presença de IL-2 e diferentes concentrações de drogas agonistas e antagonistas de receptores de adenosina. Em seguida, foram avaliados os principais marcadores de células T regulatorias por meio de citometria de fluxo e o meio de cultura foi coletado ao final da geração para quantificação de citocinas. Além disso, o RNA total foi extraído de todas as condições de cultivo para a análise da expressão de genes envolvidos na geração e desenvolvimento das Tregs, por PCR quantitativo. O potencial de supressão de células T efetoras também foi avaliado.Regulatory T cells (Tregs) are essential for the maintenance of peripheral tolerance, prevention of autoimmune and limiting diseases in chronic inflammatory diseases. In addition, these cells play a key role in the control of transplant rejection. Different protocols have shown that it is possible to obtain Tregs from naive CD4+ T cells in vitro. To this end, there is consensus that TGF-? and interleukin-2 (IL-2) are capable of directing the naive CD4 + T cells to become regulatory following an antigenic stimulus (anti-CD3/CD28).. Our group recently noted that during the immunomodulation of T lymphocytes by mesenchymal stromal cells (MSCs), they were able to produce adenosine which in turn participates in the immunoregulation process. Other studies indicate that MSCs suppress the proliferation of T lymphocytes by generation of Tregs and that MSCs induce generation of Tregs by downregulation of the TCR pathway and the AKT-mTOR pathway. Evidence indicates that adenosine may act by downregulating the mTOR pathway. Therefore, it is believed that adenosine may participate in the generation of Tregs by modulating the mTOR pathway. In addition, recent studies indicate that activation of adenosine receptors, more specifically A2a, with agonist agents, leads to increased production of Treg cells, whereas the use of antagonistic agents of these receptors leads to a decrease in Treg differentiation.. However, these studies show the generation of Tregs from naive T cells of mice. In view of the great importance of Tregs in the immunological context, the efficient production of Tregs in vitro is of fundamental importance for the development of new therapeutic protocols for the treatment of autoimmune diseases and in the fight against transplant rejection. Thus, the central objective of this study was to evaluate the participation of adenosine receptor agonists and antagonists in induction of regulatory T cells generated in vitro (iTreg) by the activation of naive CD4+ T cells isolated from human umbilical cord blood (SCU). For this, mononuclear cells were isolated from SCU and naive T cells were immunomagnetic isolated. These cells were activated with beads bound to anti-CD2/CD3/CD28 antibodies and cultured for five days in the presence of IL-2 and different concentrations of agonist drugs and antagonists of adenosine receptors. Next, the major regulatory T-cell markers were assessed by flow cytometry and the culture medium was collected at the end of the generation for quantification of cytokines. In addition, total RNA was extracted from all culture conditions for the analysis of the expression of genes involved in the generation and development of Tregs by quantitative PCR. The potential for suppression of effector T cells was also evaluated.
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Mac, Grogan Gaëtan. "Lymphomes cutanés à grandes cellules CD30 positives." Bordeaux 2, 1993. http://www.theses.fr/1993BOR23110.
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三井, 伸二, Masahide Takahashi, Masatoshi Ichihara, Sayaka Sobue, Kaori Ushida, Atsushi Enomoto, Masato Asai, et al. "Epidermal Hyperplasia and Appendage Abnormalities in Mice Lacking CD109." Thesis, Elsevier, 2012. http://hdl.handle.net/2237/17140.
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Brum, Liliani Mathias. "ATIVIDADE DA NTPDase DE LINFÓCITOS NA DERMATITE DE CONTATO ANTES E APÓS TRATAMENTO COM DEXAMETASONA NANOESTRUTURADA." Universidade Franciscana, 2008. http://tede.universidadefranciscana.edu.br:8080/handle/UFN-BDTD/235.
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Since the extracellular nucleotides represent an important means of modulating the activity of lymphocytes, it is essential the presence of an enzymatic mechanism to keep constant the concentration of those in the extracellular space. The activity of NTPDase has been recognized as a marker of activation necessary for the function of effector lymphocytes, participate in the processes of recognition of antigen. Contact dermatitis occurs in a delayed hypersensitivity reaction of type IV, mediated by cells through a mechanism that sensitizes the immune T lymphocyte to an antigen protein or a hapten linked to a protein. Among the mediators able to modulate the actions of lymphocytes stand out from the nucleoside and nucleotide adenine, in particular the extracellular ATP that is able to regulate the cell-cell interactions are important processes of activation, differentiation, development, proliferation, cell death and responses of effector lymphocytes. This study sought to determine first of the hydrolysis of adenine nucleotides, the NTPDase (EC 3.6.1.5, nucleoside triphosphate difosfoidrolase, CD39) in lymphocytes from mice with dermatitis induced by nickel sulphate to 5%, before and after treatment with dexamethasone and dexamethasone nanostructured free to try to check the possible changes in the activity of this enzyme front of an inflammatory reaction of type IV hypersensitivity and immunosuppressive therapy. Moreover, it was possible to verify the relationship of submission of the drug in the formulation free and nanostructures with the hydrolysis of adenine nucleotides. The average enzymatic activity of the group with contact dermatitis was significantly higher in the control group by the test of hypotheses to averages T. The results are in line with work done earlier that showed an increase of enzyme activity by the activation of lymphocytes. The hydrolysis of ATP and ADP in the group treated with dexamethasone free and in the group treated with dexamethasone nanostructured was significantly higher in the control group by analysis of variance for a way (ANOVA) followed by Kruskal-Wallis test (P < 0001). The results are in line with work done earlier that showed an increase of enzyme activity by the activation of lymphocytes. Was observed greater hydrolysis of ATP and ADP in the group treated with dexamethasone nanostructures in relation to the group treated with dexamethasone free. However, this difference was not statistically significant. Work previously shown an increase of enzyme activity during treatment with dexamethasone as a possible compensatory effect of the decrease in the number of lymphocytes. The results of this study suggest that dexamethasone nanostructures possess a immunosuppressive effects greatest, which may be the beginning of the evaluation of a more effective and safe treatment for contact dermatitis. From these results we can conclude that the determination of the activity of NTPDase in lymphocytes could be used as an indicator of the efficiency of the treatment of contact dermatitis
Uma vez que os nucleotídeos extracelulares representam uma importante via de modulação da atividade dos linfócitos, é indispensável a presença de um mecanismo enzimático capaz de manter constante a concentração desses no espaço extracelular. A atividade da NTPDase tem sido reconhecida como um marcador de ativação necessário para a função efetora dos linfócitos, participando também dos processos de reconhecimento do antígeno. Na dermatite de contato ocorre uma reação de hipersensibilidade retardada tipo IV, mediada por células, através de um mecanismo imunológico que sensibiliza os linfócitos T frente a um antígeno protéico ou a um hapteno ligado a uma proteína. Dentre os mediadores capazes de modular as ações dos linfócitos destacam-se os nucleosídeos e nucleotídeos da adenina, em especial o ATP extracelular que é capaz de regular as interações célula-célula sendo importante nos processos de ativação, diferenciação, desenvolvimento, proliferação, morte celular e respostas efetoras dos linfócitos. Este estudo procurou determinar primeiramente a hidrólise de nucleotídeos da adenina, pela NTPDase (EC 3.6.1.5, nucleosídeo trifosfato difosfoidrolase, CD39) em linfócitos de ratos com dermatite induzida por sulfato de níquel, antes e após tratamento com dexametasona livre e dexametasona nanoestruturada, para tentar verificar as possíveis alterações na atividade desta enzima frente a uma reação inflamatória de hipersensibilidade tipo IV e na terapia imunossupressora. Além disso, procurou-se verificar a possível relação da apresentação do fármaco na formulação livre e nanoestruturada com a hidrólise de nucleotídeos da adenina. A atividade enzimática média do grupo com dermatite de contato foi significativamente maior em relação ao grupo controle pelo teste de hipóteses para médias T. Os resultados encontrados estão de acordo com trabalhos realizados anteriormente que demonstram um aumento da atividade enzimática pela ativação dos linfócitos. A hidrólise do ATP e do ADP no grupo tratado com dexametasona livre e no grupo tratado com dexametasona nanoestruturada foi significativamente maior em relação ao grupo controle pelo teste de análise de variância de uma via (ANOVA) seguido pelo teste de Kruskal-Wallis (P< 0,001). Observou-se uma maior hidrólise de ADP e ATP, no grupo tratado com dexametasona nanoestruturada em relação ao grupo tratado com dexametasona livre. No entanto, esta diferença não foi estatisticamente significativa. Trabalhos anteriores já demonstraram um aumento de atividade enzimática durante tratamento com dexametasona como um possível efeito compensatório à diminuição do número de linfócitos. Os resultados deste estudo sugerem que a dexametasona nanoestruturada possui um efeito imunossupressor maior, o que pode ser o início da avaliação de um tratamento mais eficaz e seguro para a dermatite de contato. A partir destes resultados podemos concluir que a determinação da atividade da NTPDase em linfócitos poderia ser utilizada como um indicador da eficiência da terapêutica da dermatite de contato.
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Beylot-Barry, Marie. "Etude phénotypique et moléculaire des lymphoproliférations cutanées CD30 positives." Bordeaux 2, 1998. http://www.theses.fr/1998BOR28619.
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Bizet, Albane. "Mechanisms of action of CD109, a novel TGF-beta co-receptor." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104617.
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Transforming Growth Factor β (TGF-β) is a multifunctional cytokine that plays a critical role in cell growth, differentiation and extracellular matrix deposition. Dysregulation of its pathway has been implicated in tissue fibrosis and cancer. TGF-β signals via the type I (TGFBR1) and type II (TGFBR2) receptor complex, which phosphorylates their intracellular substrates, SMAD2 and SMAD3. The phosphorylated SMAD2/3 then forms a complex with SMAD4 and regulates target gene expression. Alternatively to the SMAD2/3 (canonical) pathway, TGF-β also elicits signalling via non-canonical pathways, such as the ERK and p38 MAPK pathways. TGF-β receptors internalize via the clathrin-coated pits route, which facilitates SMAD2/3 signalling, and via the caveolae route, which is associated with receptor degradation and with MAPK activation. Little is known regarding the factors regulating TGF-β receptor compartmentalization and turnover. Previously, CD109 was identified in our lab as a GPI-anchored protein that binds TGF-β and forms a heteromeric complex with the TGF-β receptors. The results presented here demonstrate that CD109 inhibits SMAD2/3-dependent signalling and responses, such as TGF-β-induced growth inhibition. Together, these results suggest that CD109 is a novel TGF-β co-receptor that negatively regulates TGF-β signalling. I then explored the mechanism by which CD109 regulates TGF-β action. My results indicate that CD109 increases TGF-β receptor internalization via the caveolar pathway and enhances TGF-β receptor degradation by the E3 ubiquitin ligase Smurf2, leading to inhibition of TGF-β signalling.Because TGF-β is a potent inducer of epithelial-mesenchymal transition (EMT), a process involved during cancer invasion and metastasis, I next investigated the role of CD109 in this process. CD109 inhibits TGF-β-induced EMT in both non-tumorigenic keratinocytes and squamous cell carcinoma cells via the SMAD and ERK and p38 MAPK pathways. Indeed, CD109 modulates TGF-β-induced MAPK activation, in a caveolin-1 dependent manner. Collectively, these data suggest that CD109 exerts its function by promoting TGF-β receptor localization to caveolae, thereby accelerating their degradation and modulating TGF-β canonical and non-canonical signalling. Thus, CD109 may play a critical role in pathologies where TGF-β signalling is dysregulated, such as cancer progression.Le TGF-β (facteur de croissance transformant β) est une cytokine multifonctionnelle jouant un rôle important dans la croissance, la différentiation cellulaire et la déposition de la matrice extracellulaire. La dérégulation de la cascade de signalisation du TGF-β peut engendrer la fibrose des tissus ou des cancers. Le TGF-β transmet son signal grâce aux récepteurs de type I (TGFBR1) et de type II (TGFBR2), qui phosphorylent leurs substrats intracellulaires, SMAD2 et SMAD3. Les SMAD2/3 phosphorylées s'associent à SMAD4 et régulent l'expression de gènes cibles. En plus de la voie canonique de SMAD2/3, le TGF-β transmet aussi son signal par des voies non-canoniques, telle les voies des MAPKs p38 et ERK. Les récepteurs du TGF-β sont internalisés dans des puits recouverts de clathrine (ce qui facilite la voie des SMAD2/3) et dans les cavéoles (ce qui entrainent la dégradation des récepteurs et l'activation des MAPKs). Peu de choses sont connues sur les facteurs régulant la compartimentalisation et la dégradation des récepteurs du TGF-β. CD109 a été identifié précédemment dans notre laboratoire en tant que protéine à ancre GPI capable de se lier au TGF-β et de former un complexe avec les récepteurs du TGF-β. Les résultats présentés ici démontrent que CD109 inhibe la voie des SMAD2/3 et leurs réponses associées, telles l'arrêt de la croissance cellulaire. Tout ceci suggère que CD109 est un nouveau co-récepteur du TGF-β régulant de manière négative le signal du TGF-β. J'ai ensuite exploré les mécanismes par lesquels CD109 régule l'action du TGF-β. Mes résultats indiquent que CD109 augmente l'internalisation dans les cavéoles des récepteurs du TGF-β et leur dégradation par l'E3-ubiquitine ligase Smurf2, conduisant ainsi à l'inhibition du signal du TGF-β.Comme le TGF-β induit l'EMT (transition épithélium-mésenchyme), j'ai examiné le rôle de CD109 dans ce processus impliqué dans les métastases cancéreuses. CD109 inhibe l'EMT dans les keratinocytes non tumorigéniques et dans les cellules de carcinomes squameux, via les voies des SMADs et des MAPKs p38 et ERK. CD109 régule l'activation des MAPKs, par un processus qui dépend de la cavéoline-1. L'ensemble de ces données suggèrent que CD109 exerce ses fonctions en facilitant la localisation des récepteurs dans les cavéoles, accélérant ainsi leur dégradation et modulant les voies canoniques et non canoniques du TGF-β. CD109 pourrait donc jouer un rôle crucial dans les pathologies où l'action du TGF-β est dérégulée, comme la progression des cancers.
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Lighter, Melani. "Regulation of matrix metalloproteinase-13 expression by CD109 in skin cells." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106468.
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Our group has identified CD109 as a novel TGF-β co-receptor that inhibits TGF-β signaling in skin cells. To study the role of CD109 in skin in vivo, our group has developed transgenic (TG) mice that overexpress CD109 in the epidermis. Previous results have shown that these mice display enhanced wound healing and improved scarring as compared to wild-type (WT) littermates. The aim of this study was to determine the effect of CD109 on the regulation of gene expression in the skin by using a genome microarray. Total RNA isolated from TG and WT mouse keratinocytes was subjected to microarray analysis using Illumina Bead Chip technology. The raw data from the microarray was analyzed using the FlexArray program and 300 genes were found to have differential gene expression in the TG compared to WT keratinocytes; 168 of these genes were up-regulated in the TG keratinocytes and 132 genes down-regulated in the TG keratinocytes. These 300 genes were then analyzed using the Ingenuity program, which implicated them in dermatological diseases and cell interaction. Matrix metalloproteinase-13 (MMP-13) gene expression was found to be up-regulated by 8.4-fold in the TG mouse keratinocytes compared to the WT. MMP-13 is of particular interest due to its ability to breakdown extracellular matrix (ECM) and its important role in wound healing and fibrotic processes. As TIMPs are MMP inhibitors, TIMP-2 was also investigated and found to be up-regulated by 3.03-fold. CXCL1 and αSMA were also studied as they were found to be highly down-regulated in TG compared to the WT mouse keratinocytes. The results obtained from the microarray were confirmed by qRT-PCR and showed an increase at the gene expression level of MMP-13 and TIMP-2 in the TG keratinocytes and a decrease in the gene expression levels of CXCL1 and αSMA. In order to study MMP-13 further a western blot analysis was performed to look at its protein level. Results showed an increase at the protein level of MMP-13 in the TG keratinocytes although the results were not statistically significant. To investigate MMP-13 in vivo, immunohistochemisty was performed and MMP-13 expression was found to be increased in the TG compared to the WT mouse tissue. This study demonstrates increased expression of MMP-13 in TG keratinocytes suggesting that CD109 may modulate wound healing by increasing MMP-13 expression in keratinocytes.Notre groupe a identifié un nouveau co-recepteur du TGF-β, CD109, qui inhibe la cascade de signalisation du TGF-β. Pour étudier le rôle de CD109 in vivo, nous avons développé des souris transgéniques (TG) qui surexpriment CD109 dans l'épiderme. Les précédents résultats du laboratoire indiquent que les souris TG CD109 cicatrisent mieux que les souris sauvages (WT) de la même portée. Pour déterminer les effets de CD109 au niveau moléculaire, j'ai effectué une étude du génome par puce à ADN. Les ARNs totaux extraits de kératinocytes de souris TG et WT ont été préparés et soumis à une analyse par puce à ADN (Illumina). Les résultats ont été analysés à l'aide des programmes FlexArray et Ingenuity et 300 gènes ont une expression différentielle; 168 de ces gènes ont montré une régulation à la hausse dans les kératinocytes TG et 132 gènes ont montré une régulation à la baisse dans les kératinocytes TG. L'analyse par puce à ADN révèle une forte hausse de MMP-13 (métalloprotéinase matricielle-13) dans les kératinocytes TG, comparée aux keratinocytes WT. Les résultats de cette analyse montrent que, parmi les nombreux gènes surexprimés dans les kératinocytes TG, comparés aux kératinocytes WT, MMP-13 est augmentée de 8,4 fois. MMP-13 est d'un intérêt particulier puisque sa capacité à dégrader la matrice extracellulaire joue un rôle majeur dans les processus de cicatrisation et de fibrose. Comme TIMPs sont des inhibiteurs de MMPs, TIMP-2 a également été étudié et a montré une régulation à la hausse de 3,03 fois. CXCL1 et αSMA ont également été étudiés car ils ont montrés une régulation à la baisse des TG par rapport aux kératinocytes de souris WT. Ces résultats ont été confirmés par qRT-PCR, indiquant que l'expression de l'ARNm de MMP-13 et TIMP-2 est augmentée dans les kératinocytes TG et une baisse dans les niveaux d'expression des gènes et de CXCL1 αSMA. De plus, afin d'étudier MMP-13, une analyse Western blot a été réalisée pour examiner sa teneur en protéines. Les résultats ont montré une augmentation au niveau des protéines de MMP-13 dans les kératinocytes TG bien que les résultats n'étaient pas statistiquement significatifs. Pour étudier MMP-13 in vivo, l'immunohistochimie a été réalisée pour examiner l'expression de MMP-13 et on a trouvé une augmentation dans les TG par rapport au tissu de souris WT. MMP-13 est un important facteur impliqué dans la guérison des plaies cutanées, grâce à sa capacité de dégrader les protéines de la matrice extracellulaire. Cette étude démontre que l'expression de MMP-13 est augmentée dans les keratinocytes TG, suggérant que CD109 pourrait moduler les processus de cicatrisation en induisant une surexpression de MMP-13 dans les kératinocytes.
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Vorstenbosch, Joshua. "Overexpression of CD109 in the epidermis reduces skin fibrosis and inflammation." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116840.
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Transforming growth factor-beta (TGF-ß) is a multifunctional growth factor involved in a variety of cellular processes including wound healing, extracellular matrix deposition, inflammation, and fibrosis. Excessive TGF-ß signaling during wound healing causes sustained inflammation and elevated expression of extracellular matrix proteins, which have both been associated with fibrosis and scarring. Therefore, inhibition of TGF-ß during wound healing is an attractive target to reduce fibrotic skin disorders. Our lab is interested in CD109, a 150 kDa GPI-anchored protein which has been shown to bind TGF-ß in its soluble form and to inhibit TGF-ß signaling in keratinocytes and fibroblasts in vitro. The TGF-ß antagonist properties of CD109 suggest that modulation of its expression in vivo might ameliorate fibrosis and scarring, perhaps via differential activation of keratinocytes and fibroblasts. To investigate the role of CD109 in the skin, we generated transgenic mice overexpressing CD109 in the epidermis.To explore the role of CD109 during wound healing, I conducted incisional and excisional wound healing studies using CD109 transgenic mice and wild-type littermate controls. These studies demonstrate improved scarring parameters including reduced myofibroblast differentiation, reduced granulation tissue, and improved extracellular matrix architecture in the CD109 transgenic mice. Additionally, the data in this thesis show that overexpression of CD109 in the epidermis inhibits immune cell recruitment, and is associated with a reduction in expression of the proinflammatory cytokines IL-1 and MCP-1. I correlated these data with immunohistochemical analysis of Smad2/3 phosphorylation, and show that CD109 overexpression is associated with a reduction in TGF-ß signaling. Collectively, these data suggest that overexpression of CD109 in the epidermis inhibits fibrosis during wound healing in a TGF-ß dependent manner.To better understand the role of CD109 in fibrosis, I employed a murine bleomycin-induced model of fibrosis, which exhibits similarities to scleroderma, in CD109 transgenic mice and wild-type littermates. This study shows that CD109 transgenic mice express reduced levels of the extracellular matrix proteins fibronectin and collagen I, as well as Smad2/3 phosphorylation, and also display improved extracellular matrix architecture and reduced dermal thickness. Collectively, these data suggest that CD109 resists bleomycin-induced fibrosis, and could thus be an attractive target for therapeutic treatment of fibrotic skin disorders.To better understand how CD109 modulates TGF-ß in vivo, I analyzed the TGF-ß signaling molecules in skin, primary keratinocytes, and primary fibroblasts harvested from CD109 transgenic mice and wild-type littermates. Here, I show that CD109 transgenic mice express less collagen I and fibronectin, and display elevated ALK1 expression and signaling through the Smad1/5/8 pathway while wild-type mice express elevated ALK5 and preferentially signal through the Smad2/3 pathway. Investigation of cultured keratinocytes showed a similar expression pattern, with the only difference existing in the expression of ALK1 and ALK5 which were both increased in the CD109 transgenic keratinocytes, and fibroblasts from both genotypes showed similar expression patterns. In both cultured keratinocytes and whole skin extracts, the CD109 transgenic tissue expressed less TGF-ß than their wild-type counterparts. The differential TGF-ß signaling described here could underscore our previous observations indicating that overexpression of CD109 inhibits scarring and fibrosis in vivo.Collectively, the data presented here demonstrate that CD109 potently alters physiological processes in the skin in vivo. The capacity for CD109 to reduce scarring, fibrosis, and inflammation in vivo makes it an attractive target for treating fibrotic skin disorders.Le facteur de croissance transformant bêta (TGF-ß), est un facteur de croissance multifonctionnel impliqué dans une multitude de processus cellulaires tel que la cicatrisation, la déposition de matrice extracellulaire, l'inflammation et la fibrose. Ainsi, l'inhibition de TGF-ß semble être une cible de choix pour réduire les désordres fibrotiques de la peau. Notre laboratoire a identifié CD109, une proteine de 180 kDa ancrée à un glycosylphosphatidylinositol agissant comme co-récepteur cellulaire de TGF-ß. Ce nouveau récepteur, auquel TGF- ß s'ancre avec très haute affinité, aurait pour propriété d'inhiber la signalisation intra-cellulaire de TGF-ß. Les propriétés antagonistes de CD109 suggèrent que la modulation de son expression in vivo dans la peau pourrait améliorer la cicatrisation et la fibrose cutanée. Pour investiguer le role de CD109 dans la peau, nous avons généré une souris transgénique en clonant CD109 en aval du promoteur de keratin-14, limitant ainsi la surexpression de CD109 à l'épiderme.Afin d'explorer le rôle de CD109 au sein de la guérison des plaies, nous avons conduit des études de ce processus où nous avons pu observer une amélioration des paramètres de cicatrisation tels que la réduction de la différentiation des myofibroblastes, la réduction du tissu de granulation et une amélioration de l'architecture de la matrice extracellulaire chez les souris transgénique CD109 comparées au souris de génotype sauvage pour la même portée. De plus, la surexpression de CD109 dans l'épiderme inhibe le recrutement de cellules immunitaires au site de la plaie et est associé avec une réduction de la signalisation de TGF-ß ainsi que l'expression des cytokines pro-inflammatoire IL-1 et MCP-1. Toutes ces données, suggèrent que la surexpression de CD109 dans l'épiderme inhibe la fibrose cutanée lors de la guérison des plaies.Nous avons ensuite examiné le rôle de CD109 lors de la fibrose en utilisant un model de sclérodermie murine induit par bleomycine. La souris transgénique CD109 exprime des niveaux réduits des protéines fibronectine et collagène 1 dans la matrice extracellulaire, ainsi que des niveaux réduits de phosphorylation de Smad2/3. Elle démontre aussi une meilleure architecture de la matrice extracellulaire et une réduction de l'épaisseur de la couche dermique. Toutes ces données suggèrent que CD109 résiste à la fibrose induite par bleomycine. Cela pourrait donc en faire une cible attrayante pour traitement thérapeutique des désordres fibrotiques de la peau.Pour mieux comprendre comment CD109 modifie l'action de TGF-ß in vivo, nous avons analysé les molécules de signalisation de TGF-ß dans la peau, les keratinocytes primaires et les fibroblastes primaires récoltés des souris transgéniques et de leur sœurs de portée du génotype sauvage. Les souris transgéniques CD109 expriment substantiellement moins de collagène I, de fibronectine et démontre une expression élevée de ALK1 et une activation élevée de la voie Smad1/5/8. Les études utilisant des keratinocytes cultivés démontrent une phosphorylation de Smad et une expression des gènes de la matrice extracellulaire similaire; l'expression de ALK1 et ALK5 étant toutefois plus élevée dans les keratinocytes transgéniques CD109 comparé à ceux du génotype sauvage. Les fibroblastes des deux génotypes démontrent des profils d'expression similaires. La signalisation différentielle de TGF-ß pourrait rehausser nos observations précédente et ainsi renforcer l'idée que la surexpression de CD109 inhibe la cicatrisation et la fibrose cutanée in vivo.Ainsi, les données présentée démontrent que CD109 est un puissant altérateur des processus physiologiques de guérison des plaies, cicatrisation, fibrose et inflammation dans la peau in vivo. La capacité pour CD109 de réduire la cicatrisation, la fibrose et l'inflammation dans la peau in vivo en font une cible attrayante pour traiter les désordres fibrotiques de la peau.
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Bernhard, Oliver Karl. "Proteomic Investigation of the HIV Receptors CD4 and DC-Sign/CD209." University of Sydney. Medicine, 2004. http://hdl.handle.net/2123/585.
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HIV infection and disease is a multistage process that involves a variety of cell types as the virus spreads through the body. Initially, dendritic cells (DCs) present at the mucosal site of infection bind and internalise HIV for degradation and presentation to T cells. As the DCs migrate to lymph nodes and mature, part of the internalised virions remains infective inside endosomal compartments. During formation of the immunological synapse between CD4 T cells and DCs, infective virions from dendritic cells are transferred to CD4 T cells leading to a strong infection of those cells allowing rapid virus dissemination throughout the body and establishment of the typical HIV infection. Various membrane receptors are involved in this process. Initial HIV binding to DCs is mediated by C-type lectin receptors such as the mannose receptor or DC-SIGN (DC specific intracellular adhesion molecule 3 grabbing non integrin) which is followed by virus internalisation and lysis albeit virus induced changes in endocytic routing prevents a proportion from degradation. Productive infection of DCs has also been observed allowing trans infection of CD4 T cells through a different mechanism. HIV infection of CD4 T cells, DCs and other cells is a multistep process initiated by binding of HIV envelope gp120 to the CD4 receptor, a 55 kDa transmembrane glycoprotein. Subsequent conformational changes in gp120 allow binding to a chemokine receptor, either CCR5 or CXCR4, followed by membrane fusion and infection. The aim of this thesis was to investigate protein associations with the HIV receptors DC-SIGN and CD4 in order to elucidate the mechanism of complex formation, virus entry and/or defining target sites for antiretroviral drugs. This thesis used a proteomic approach for studying the receptors with mass spectrometry-based protein identification as its core technology. A range of different approaches were developed and compared for identification of protein interactions and characterisation of the identified protein associations. An affinity purification of the CD4 receptor complex from lymphoid cells was used as the basis for detecting novel CD4-binding proteins. For this approach a strategy based on mass spectrometry identification of CD4 associating proteins using affinity chromatography and affinity-tag mediated purification of tryptic peptides was developed. This method proved successful for the identification of CD4 interacting proteins such as the strongly associated kinase p56lck, however a limited number of non-specifically bound proteins were also identified along the receptor complex. Using one-dimensional SDS-polyacrylamide gel electrophoresis followed by in-gel digests and mass spectrometry analysis, a large number of non-specifically binding proteins were identified along the CD4/lck complex. Evaluation of different lysis buffers in several independent experiments demonstrated that there was a large and inconsistent array of proteins that were obviously non-specifically bound to the receptor. No further specific binding partners were detected. These data suggested that protein interactions of CD4 on this cell type are of weak and/or transient nature. It also demonstrated a need for careful interpretation of proteomic data in the light of the propensity of non-specific binding under these conditions. To overcome dissociation of weak protein interactions, a method was developed using chemical cross-linking to preserve weak protein interactions on lymphoid cells. Affinity purification was used to purify CD4 along with cross-linked associated proteins and mass spectrometry analysis identified an interaction with the transferrin receptor CD71 and the tyrosine phosphatase CD45. The CD45-CD4 interaction is well known. The CD4-CD71 interaction was demonstrated to be a result from colocalization of the two molecules during formation of endocytic vesicles. Flow cytometry-based fluorescence resonance energy transfer (FRET) measurements were applied to confirm colocalization. A similar interaction was suspected for CD4 and DC-SIGN on the plasma membrane of DCs as cis infection of DCs has been demonstrated i.e. initial binding to DC-SIGN then to CD4/CCR5 on the same cell. Therefore, protein associations of DC-SIGN were investigated using the developed techniques. Using cross-linking, DC-SIGN was shown to assemble in large complexes on the surface of immature monocyte-derived DCs. Mass spectrometry analysis of the purified complexes identified them as homo-oligomers of DC-SIGN. The absence of CD4 suggested that the fraction interacting with CD4 at any one time must be small. The complexes of DC-SIGN were further characterised to be tetramers and successfully co-immunoprecipitated with HIV gp120 and mannan. DC-SIGN monomers were not evident demonstrating that the assembly of DC-SIGN into tetramers is required for high affinity binding of its natural and viral ligands. Thus potential antiviral agents aimed at blocking the early stage of HIV binding to DCs must simulate tetramers in order to neutralise the virus efficiently. Overall the thesis provides new information on protein interactions of CD4 and DC-SIGN, a careful investigation of "proteomics" techniques for identifying the proteins in affinity-purified samples and demonstrates the need for multifaceted analytical approaches to probe complex cellular systems.
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Lima, Nathália Ferreira. "Mansonella ozzardi: uma filaria negligenciada que pode modular a resposta imune." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-12032018-143909/.
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As infecções humanas com a filaria Mansonella ozzardi ocorrem em focos situados em regiões tropicais e subtropicais da América Central e do Sul e frequentemente coexistem com outras doenças endêmicas tropicais. Na Amazônia brasileira, as infecções são geralmente assintomáticas e a maior parte delas, consequentemente, deixam de ser diagnosticada. As filarioses crônicas, geralmente não tratadas, podem criar um ambiente imunorregulador, caracterizado pela expansão de linfócitos T produtores de IL-10, que mediam a supressão de respostas proliferativas de células T frente a antígenos específicos bem como a antígenos não-relacionados. Neste trabalho, utilizamos marcadores de ativação celular (CD69 e HLA-DR) e de atividade reguladora (CD39, CTLA-4, OX40, GITR, LAG3, PD-1, LAP-TGF-β e TNFRII) para caracterizar populações de células mononucleares de sangue periférico (PBMCs) em indivíduos infectados por M. ozzardi bem como em controles saudáveis de uma área endêmica deste parasito na Amazônia Brasileira. A análise de PBMCs, por citometria de fluxo multiparamétrica de 49 pacientes infectados por M. ozzardi, mostrou que pacientes e controles apresentam proporções similares de Treg clássicas circulantes, no entanto, indivíduos infectados apresentam um aumento da proporção de células CD4+ e células T reguladoras (Tregs) que expressam a molécula CD39. Células Treg CD39+ parecem definir uma população distinta entre as Treg, pois ao compararmos os marcadores de regulação e ativação entre Tregs CD39+ e CD39- encontramos proporções aumentas destes marcadores nas Treg CD39+. O bloqueio dessa molécula em condições de reestimulo celular aumenta a produção de citocinas inflamatórias e diminui a produção de IL-10 confirmando seu papel regulador.Human infections with the filarial parasite Mansonella ozzardi are common in areas of tropical and subtropical Central and South America and often coexist with other endemic tropical diseases, such as malaria. In the Amazonian Basin of Brazil, infections are typically asymptomatic; most of them will remain undiagnosed. These chronic, untreated filarial infections are potentially associated with a regulatory immune environment, dominated by IL-10-producing T-cells, which mediate the suppression of T-cell proliferation in response to filarial and non-related antigens. Here, we used markers of cell activation (CD69 and HLA-DR) and regulatory activity (CD39, CTLA-4, OX40, GITR, and TNFRII) to characterize peripheral-blood mononuclear cell (PBMCs) subpopulations in individuals infected with |M. ozzardi and in healthy controls living in an area of M. ozzardi endemicity in the Brazilian Amazon. Multiparameter flow cytometry analysis of PBMCs from 49 malaria patients showed that patients and controls have similar proportions of classic circulating Tregs, however, the proportion of CD4 + cells and Tregs expressing the CD39 (an ectonucleotidase that regulates the balance of immune responses through Phosphohydrolysis of ATP, an inflammatory molecule in adenosine, an anti-inflammatory molecule), is increased in infected patients. CD39+Treg cells seem to define a distinct population among Tregs, compare activation and regulatory markers between CD39+ and CD39- Tregs - we found increased proportions of these markers in the CD39+ Tregs. Blocking this molecule under cellular restimulation conditions increases production of inflammatory cytokines and decreases IL-10 production, improving its regulatory role.
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Eichenauer, Dennis Alexander. "ADAM10 als CD30-Sheddase und immuntherapeutische Möglichkeitenn durch ihre Inhibition /." Köln, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000252839.
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Xu, Meishu. "Association of DC-SIGN (CD209) gene polymorphisms with severe acute respiratory syndrome (SARS)." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B3723125X.
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Xu, Meishu, and 徐美術. "Association of DC-SIGN (CD209) gene polymorphisms with severe acute respiratory syndrome (SARS)." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B38616142.
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Ho, Desiree Shulin. "Transcriptional regulation of the human CD30 gene through an intronic enhancer." University of Western Australia. Biochemistry and Molecular Biology Discipline Group, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0026.
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Lymphomas are neoplasms of the human immune system and can be divided into two categories, Hodgkins lymphoma (HL) and non-Hodgkin lymphoma (NHL). Anaplastic large cell lymphoma (ALCL) is a form of NHL that shares a common distinctive feature with HL, the overexpression CD30. The expression of cytokine receptor CD30 is restricted to proliferating B and T lymphocytes in healthy individuals while its overexpression is associated with several lymphoproliferative diseases such as ALCL and HL. The activation of CD30 via ligand or antibodies triggers various cellular responses ranging from apoptosis to cell proliferation and it is thought that the variable cellular response to CD30 activation may be due to cell surface levels of CD30. The human CD30 gene is regulated at the transcriptional level and previous studies characterising its promoter have identified several factors that regulate the expression this gene. However none of these identified factors explain for the high levels of CD30 observed in HL and ALCL. Therefore this study focused on the identification and functional analysis of transcriptionally active regions located up or downstream of the CD30 promoter region. The first aim for this study was to identify and characterise regions within the human CD30 gene that are involved in its transcriptional regulation. Phylogenetic footprinting identified several regions downstream of the CD30 promoter that displayed high levels of sequence homology indicating potential functional significance. Validation of these regions through two in vivo approaches, DNase 1 hypersensitivity assay and chromatin accessibility studies localised potential transcriptionally active regions to intron 1 of the CD30 gene.
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Younas, Mehwish. "Modulation de l’effet suppresseur des cellules T régulatrices chez l’Homme en physiologie et au cours de l’infection par le VIH." Thesis, Paris Est, 2013. http://www.theses.fr/2013PEST0068.
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Les cellules T régulatrices (Treg) jouent un rôle important dans différentes infections chroniques comme le VIH. Lors de l’infection chronique par le VIH, une augmentation du nombre de ces cellules limite la réponse des cellules T effectrices spécifiques du virus mais permet également le contrôle de la très forte activation du système immunitaire. La régulation de l’activité suppressive des Treg constitue une voie importante pour le développement d’un vaccin, l’efficacité de la surveillance tumorale et l’auto-immunité. Dans ce travail, nous avons étudié différents mécanismes de régulation des Treg chez les patients infectés par le VIH et sujets sains. Le but de mon travail a été d’étudier les mécanismes impliqués dans les fonctions suppressives des Treg et de leur régulation. Nous nous sommes particulièrement intéressés au rôle de Notch sur la sensibilité des cellules T effectrices à la fonction suppressive des Treg, en montrant que l’activation de Notch rendait les cellules T effectrices plus sensibles à l’action suppressive des Treg, et ceci même en présence d’un très faible nombre de Treg. Nous avons démontré que certains ligands de Notch, tels que DL-4 et Jagged-1 mais non DL-1, régulent l’effet inhibiteur des Treg sur les cellules T effectrices par une surexpression de TGFβ-RII et à la phosphorylation de Smad3. Le rôle important de l’enzyme CD39 dans la fonction suppressive des Treg a été décrit, mais peu d’études ont démontré son rôle dans l’infection par le VIH. Nous avons montré que les Treg de patients infectés par le VIH experiment plus fortement le CD39, et que leur effet suppresseur était inhibé en utilisant un anticorps monoclonal anti-CD39 et maintenu en utilisant un agoniste de l’adénosine. Nous avons également montré que le polymorphisme du gène CD39, associé à une plus faible expression de CD39, était corrélé à une plus lente progression de la maladie. Nos résultats montrent non seulement les mécanismes impliqués dans l’activité suppressive des Treg lors de l’infection par le VIH, mais constituent une approche intéressante pour en modifier les fonctions. Enfin, nous avons recherché l’effet de l’IL-7 sur le phénotype des Treg et l’expression de molécules impliquées dans leur fonction suppressive. Nos résultats montrent deux effets synergique de l’IL-7 sur les Treg mémoires: diminution de l’expression de CD39 à leur surface induisant une diminution de leur fonction suppressive, et surexpression du récepteur à l’ATP induisant un phénotype Th17. L’administration d’IL-7 in vivo chez des patients infectés par le VIH a confirmé la modification de phénotype des Treg en Th17 et notamment une surexpression du facteur de transcription spécifique des Th17, RORγt. En conclusion, notre travail apporte de nouvelles connaissances sur les mécanismes impliqués dans les fonctions inhibitrices des Treg et comment moduler ces fonctions. Ceci pourrait avoir un impact clinique direct, soit dans le traitement de maladies associées à un dysfonctionnement des Treg (infections chroniques virales, sclérose multiple, diabète de type 1, arthrite rhumatoide et lupus érythémateux), soit dans les stratégies vaccinalesT regulatory cells (Treg cells) play an important role during various chronic infections like HIV. Increase in Treg cell number during chronic phase limit the HIV specific T effector cell response but may control exaggerated activation of the immune system. Modulation of regulatory T cell (Treg cells) suppression has important implications for vaccine development, the effectiveness of tumor surveillance, and the emergence of autoimmunity. Here we studied various mechanisms of Treg cells modulation in HIV+ patients and healthy subjects. The aim of my work was to decipher some aspects of the mechanisms involved in Treg cell mediated suppressive effects and the modulation of Treg cell suppressive effects in healthy subjects and HIV- infected patients.We have extended knowledge on the role of Notch in Treg/Effectors T cells cross talk. Here we focused our interest on the role of Notch pathway on the sensitivity of effectors T cells to Treg cell-mediated suppression, showing that Notch activation may significantly increase the sensitivity of effector cells to Treg cells even at a low ratio. We demonstrated that Notch ligands DL-4 and Jagged-1, but not DL-1 modulate significantly the suppressive effect of Treg cells on effectors T cells through an up regulation of TGF-RII expression and the phosphorylated form of Smad3 protein.A critical role of CD39 has been described for Treg cells in general but only a few studies have analyzed its role in HIV infection. We showed an increase in CD39 expression on Treg cells in a cohort of HIV- infected patients. Treg cells inhibitory effects were relieved by CD39 down modulation using an antiCD39 monoclonal antibody and this suppressive effect was reproduced on effector CD8+ T cells by an adenosine agonist. We found that CD39 gene polymorphism associated with a lower CD39 expression correlated with slower progression to AIDS. Our results shows not only the mechanism by which Treg cell suppression occurs during HIV infection but also provide an attractive approach to modify Treg cell functions.Finally, we have investigated the role of IL-7 on the phenotype of Treg cells and expression of molecules involved in the suppressive functions of these cells. Our results show that IL-7 exerts two synergistic effects on memory Treg cells. It decreases their suppressive effect by decreasing CD39 expression and increases ATP receptor leading to a switch towards a Th17 phenotype. In vivo administration of IL-7 tipped the balance towards a higher expression of RORγT in PBMCs from HIV infected patients.In conclusion our study bring new findings in the mechanisms involved in Treg cell mediated suppression and the way to modulate these cells which could have direct clinical impact either in the treatment of diseases associated with Treg cell dysregulation (chronic viral infections, autoimmune disorders like multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and systemic lupus erthematosus) or during vaccination
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D'Almeida, Sénan. "Rôle de l’éctonucléotidase CD39 dans l’acquisition d’un phénotype immunorégulateur par les macrophages associés aux tumeurs." Thesis, Angers, 2015. http://www.theses.fr/2015ANGE0006/document.
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Les macrophages associés aux tumeurs (TAM) sont des cellules immunorégulatrices qui s’accumulent massivement dans le microenvironnement (ME) tumoral. Chez les patients atteints de cancer de l’ovaire (CO) ou de mésothéliome pleural malin (MPM), leur densité est associé à un mauvais pronostic. Le projet est porté sur la caractérisation des mécanismes impliqués dans leur recrutement et leur polarisation. L’éctonucléotidase CD39 hydrolyse l’ATP enadénosine extracellulaire, présentant des propriétés immunosuppressives. Nous avons montré que les TAMCD14+CD163+ isolés de CO et les M générés in vitro en présence de M-CSF, expriment un niveau élevé de CD39membranaire comparativement aux M immunostimulants. L’inhibition de CD39 diminue les fonctions immunorégulatrices des M CD163+CD39+high (i.e. IL-10 etPD-L1). Nous avons identifié la cytokine IL-27, sécrétée parles neutrophiles infiltrants la tumeur, comme rhéostat de l’expression de CD39. En conséquence, neutraliser l’IL-27pendant la différenciation des M en présence de M-CSF diminue l’expression de CD39 et PD-L1 ainsi que la sécrétiond’IL-10 par ces M . Parallèlement, nous avons montré que les effusions pleurales du MPM induisent la migration des monocytes via CCL2, polarisent les monocytes en MCD163+ et protègent des cellules tumorales de l’effet des agents cytotoxiques. L’ensemble de ces résultats suggère que le ciblage du recrutement (CCL2) et des molécules impliquées dans la polarisation des TAM (ligands du MCSFR,IL-27, CD39) représentent de nouvelles pistes thérapeutiques dans le traitement de certaines tumeurs solidesTumor-associated macrophages (TAM) are immunosuppressive cells that can massively accumulate in the tumor microenvironment (ME). In patients with ovarian cancer (OC) and malignant pleural mesothelioma (MPM), their density is correlated with poor prognosis. Targeting mediators that control the recruitment or the polarization of immunoregulatory macrophages (M ) represents therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties. We report here thatCD14+CD163+ TAM isolated from OC patients and Mgenerated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated M . CD39 blockade diminished some of the immunosuppressive functions ofCD163+CD39hugh, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumorin-filtrating neutrophils, located close to infiltratingCD163+ M , as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 down-regulatedCD39, PD-L1 expression as well as IL-10 secretion byM-CSF-M . In parallel, we showed that pleural effusion of MPM induced monocytes migration via CCL2, the polarization of monocytes into CD163+ and induced protection to tumor cell death after chemotherapeutic treatments. Collectively, these data suggest that targeting the recruitment (CCL2) or molecules that maintain the immunosuppressive phenotype of TAM(CD39, drived by IL-27 and M-CSFR ligands) could give substantial benefit to the treatment of some solid tumors
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Anastasi, Cyril. "De la maturation des collagènes à la régulation de la signalisation TGF-ß : nouveaux rôles moléculaires et cellulaires de la métalloprotéase BMP-1." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1097.
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La Bone Morphogenetic Protein-1 (BMP-1) est une métalloprotéase impliquée dans la maturation et l'activation de nombreuses molécules extracellulaires. Parmi celles-ci, on trouve notamment les collagènes fibrillaires, les protéines les plus abondante chez l'Homme, ainsi que les facteurs de croissance de la superfamille du TGF-ß, des protéines pléiotropes. Au travers de ses fonctions, BMP-1 joue un rôle crucial au cours du développement embryonnaire mais également durant les processus physiologiques et pathologiques de remodelage tissulaire (cicatrisation, fibroses, croissance osseuse, cancers...).Le projet présenté dans ce manuscrit a consisté à étudier plusieurs fonctions importantes de BMP-1 au niveau moléculaire et à caractériser les conséquences de ces activités au niveau de plusieurs types cellulaires.Dans un premier temps, un test quantitatif a été mis au point afin de pouvoir étudier en temps réel l'effet de BMP-1 sur les collagènes fibrillaires ainsi que les mécanismes de sa régulation. Par la suite, de nouveaux substrats de BMP-1 ont été mis en évidence, parmi lesquels des co-récepteurs du TGF-ß (Bétaglycan, CD109) ainsi qu'une protéine matricellulaire (TSP-1). L'étude de ces activités a permis de caractériser les multiples voies par lesquelles BMP-1 est capable de réguler l'activité du facteur de croissance TGF-ß.De plus, nous avons mis en évidence que le clivage de ces différents substrats entraine une modulation importante du phénotype de plusieurs lignées cellulaires (HT1080, HEK-293T) avec des effets au niveau de l'adhésion, la prolifération et la migration cellulaire. En conclusion, ce travail révèle que les activités de BMP-1 s'étendent bien au-delà de ce qui est actuellement décritBone Morphogenetic Protein (BMP-1) is a metalloprotease known to be involved in the maturation and activation of several important extracellular proteins, including fibrillar collagens and growth factors of the TGF-beta superfamily. As a consequence, it is essential for embryonic development and tissue remodeling and has been clearly involved in lethal diseases such as fibrosis and cancer.This thesis project focused on the major molecular functions of BMP-1 and their implications for the phenotype of several cell types. First, a quantitative and real-time assay was developed to study the effect of BMP-1 and associated regulatory proteins on fibrillar collagens. Then, new BMP-1 substrates, such as TGF-ß co-receptors (Betaglycan and CD109) and matricellular proteins (TSP-1) were characterized in detail. Especially, we evidenced that these activities played a major role in the regulation of the TGF-ß pathway.Furthermore, we shown that these BMP-1 activities induce major phenotype changes (adhesion, proliferation, migration) in several cell lines including HT1080 and HEK-293T. Altogether, this work reveals that BMP-1 substrates extend far beyond what is presently described and open several perspectives for future studies
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Kočár, Darius. "Tříosé ovládání tiskového stroje." Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2010. http://www.nusl.cz/ntk/nusl-237210.
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This thesis is about creating library for control of the 3D printing machine. Printer active axes are realized by stepper motors from Microcon Corporation connected with CD30x control unit. Communication between application and control units is via RS232 serial link. Part of this work is dedicated to application showing typical usage of this library.
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Bernhard, Oliver. "Proteomic investigation of the HIV receptors CD4 and DC-SIGN/CD209 membrane protein interactions." Saarbrücken VDM Verlag Dr. Müller, 2004. http://d-nb.info/989278026/04.
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Loreau, Emilie. "Identification de gènes impliqués dans le développement des lymphones cutanés primitifs CD30+." Phd thesis, Université Victor Segalen - Bordeaux II, 2003. http://tel.archives-ouvertes.fr/tel-00011307.
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Le lymphome cutané primitif (LCP) CD30+ est une lymphoprolifération maligne de phénotype T. Son oncogenèse reste à ce jour inconnue. Le but de ma thèse est d'identifier des gènes exprimés spécifiquement dans les LCP CD30+ afin de comprendre les mécanismes d'oncogenèse et également d'identifier des marqueurs diagnostics ou thérapeutiques. Des banques d'ADNc soustraites sont réalisées par SSH « Suppressive Subtractive Hybridisation » entre des LCP CD30+ et des lymphocytes sanguins. Ces banques sont ensuite criblées par des techniques de Dot Blot avec des sondes radiomarquées spécifiques des échantillons étudiés. Les clones sélectionnés sont enfin validés par PCR en temps réel. Nous avons ainsi mis en évidence cinq gènes surexprimés dans les LCP CD30+ : THW, p120caténine, SPARC, PTTG1, CD30 et cinq gènes sousexprimés : humanine, CIN85, Bcl11B, CD30 L et CD30s. Il reste à vérifier si ces gènes sont responsables de l'oncogenèse ou s'ils sont uniquement des phénotypes des LCP CD30+.
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Perks, Kerry Louise. "An investigation on roles of OX40 and CD30 in B cell differentiation." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3500/.
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TNF receptor/ligand superfamily members signal through pathways giving rise to proteins that regulate lymphocyte proliferation, activation, differentiation and survival. Absence of TNF ligands OX40L and CD30L impairs survival of GC T cells and affinity maturation of antibody responses. Direct effects of these molecules on B cells in antibody responses are not characterised. I dissected roles of OX40 and CD30 for B cells using T-independent type II (TI-II) antigen NP-Ficoll. Humoral immunity is impaired in OX40 deficiency. Defects in class switched and non-class switched antibody production are due to reduced development of antigen-specific switched and non-switched plasma cells. CD30 has an opposing role, deficiency results in similar or higher switched and non-switched antibody titres and higher numbers of antigen-specific plasma cells that develop rapidly. This may explain why in OX40/CD30 double deficiency, there is a less pronounced defect than in OX40 single deficiency. B cell intrinsic roles are revealed for OX40 and CD30 that suggest OX40 on B cells is critical for TI-II plasmablast differentiation or survival and B cell CD30 inhibits onset of plasmablast differentiation.
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Bajracharya, Bijay. "Adenosine production via CD39/CD73 pathway promotes Leishmania amazonensis survival in macrophages." reponame:Repositório Institucional da UFOP, 2014. http://www.repositorio.ufop.br/handle/123456789/3697.
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A leishmaniose cutânea (CL), causada por L. amazonensis, é caracterizada por uma intensa imuno- supressão e multiplicação descontrolada do parasito em modelos experimentais e é geralmente grave em humanos, variando desde a forma cutânea até a cutâneo-difusa. Não existem mecanismos precisos conhecidos sobre como L. amazonensis modula a resposta imunológica para que os macrófagos (MФ) infectados com L. amazonensis se tornem refratários à ativação por células T efetoras. Aqui, nós investigamos o possível mecanismo regulador que Leishmania provavelmente pode induzir em MФ residentes durante a interação precoce, de modo a impedir ativação das células. Neste estudo, analisou-se a expressão de CD39 e CD73, por citometria de fluxo, em MФ peritoneais murinos infectados com promastigotas metacíclicas de L. amazonensis e também a porcentagem dessas células que expressam a CD39 e CD73 foi avaliada. Nossos resultados mostraram que em 72hrs inativos os MФ tiveram baixa expressão de CD73. Curiosamente, no entanto, ao contrário de MФ tratados com LPS os infectados com L. amazonensis expressaram altos níveis de CD73. Esta informação foi posteriormente validada pelos resultados de estudos no contexto ex-vivo que mostrou igualmente que MФ infectados são predominantemente CD73+. Quando as atividades enzimáticas de CD39 e CD73 foram bloqueadas, tal como pelo uso de DIDS e MAD αβ, tanto a infecção quanto o número de amastigotas diminuiu significativamente após 48 horas de incubação. Da mesma forma, a inibição dos receptores de adenosina A2a e A2b de ZM241385 e MRS1754 também apresentou os mesmos efeitos sobre a sobrevivência do parasito e infectividade. Em estudo posterior, em busca de um possível papel da HIF- 1α na infecção por Leishmania, investigamos os efeitos da FM19G11, inibidor do HIF- 1α, na expressão de CD39 e CD73, bem como na infecção parasitária . Observou-se que, apesar de HIF - 1α poder influenciar na sobrevivência do parasito, os seus efeitos sobre a expressão de CD39 e CD73 não eram visíveis. Também foi avaliada, por PCR em tempo real, a expressão de receptores de adenosina em populações infectadas, nas quais não se observou nenhuma mudança significativa na expressão após 24 horas de infecção. Além disso, também foi avaliada a produção de citocinas, tais como TNF- α e IL-10 a partir da produção de NO nos grupos tratados. Surpreendentemente, não houve variação nos níveis destes mediadores, sugerindo a existência de outros mecanismos independentes da mediação por citocina para produção de Óxido Nítrico, tais como a produção de ROS ou efeitos leishmanacidas independentes do triptofano. Concluindo, nossos dados mostram que a infecção por L. amazonensis regula a expressão CD73 durante 24 horas de infecção e sua sobrevivência depende de atividades enzimáticas, bem como de receptores A2a e A2b. __________________________________________________________________________________________
ABSTRACT:Cutaneous leishmaniasis (CL) caused by L. amazonensis is characterized by intense immune-suppression and uncontrolled parasite multiplication in experimental models and is usually severe in humans ranging from cutaneous to diffuse cutaneous leishmaniasis. There are no precise mechanisms known how L. amazonensis modulates immune response so that macrophages (MФ) infected with L. amazonensis are refractory to activation by effector T cells. Here, we investigated the possible regulatory mechanism that Leishmania can likely induce in host MФ during early interaction so as to prevent their host cells from activation. In this study, we analyzed the expression of CD39 and CD73, by flow cytometry, in murine peritoneal MФ infected with metacyclic promastigotes of L. amazonensis and percentage of those cells expressing CD39 and CD73 was evaluated. Our results showed that 72hrs rested MФ down regulated CD73 expression. Interestingly, however, unlike LPS treated MФ, L. amazonensis infected MФ up regulated CD73 expression. This data was further validated by the findings from in ex-vivo studies which equally support that infected MФ are predominantly CD73 positive. When CD39 and CD73 enzymatic activities were blocked such as by the use of DIDS and αβ MAD, both infection and amastigote number decreased significantly within 48hrs of incubation. Similarly, inhibition of adenosine receptors A2a and A2b by ZM241385 and MRS1754 also had the same effects on the parasite survival and infection. In another study, in search of a possible role of HIF-1α in Leishmania infection, we investigated the effects of FM19G11, inhibitor of HIF-1α, on expression of CD39 and CD73 as well as parasitic infection. We observed that although HIF-1α can influence in the parasite survival, their effects on CD39 and CD73 expression were not visible. We also evaluated the expression of adenosine receptors in infected population by real time PCR in which we observed no significant change in the expression after 24hrs of infection. Moreover, we also evaluated cytokine production such as TNF-alpha, IL-10 and NO production from the treated groups. Surprisingly, there was no alternation in the levels of these mediators suggesting other mechanisms, independent of cytokine mediated nitric oxide production such as ROS production or tryptophan independent oxygen anti-leishmanacidal effects, involved in it. In conclusion, our data show that L. amazonensis infected up regulates CD73 expression during 24hrs of infection and its survival is dependent on enzyme activities as well as A2a and A2b receptors.
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Loreau, Emilie. "Identification de gènes impliqués dans le développement des Lymphomes Cutanés Primitifs CD30+." Bordeaux 2, 2003. http://www.theses.fr/2003BOR21017.
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Le lymphome cutané primitif (LCP) CD30+ est une lymphoprolifération maligne de phénotype T. Son oncogenèse reste à ce jour inconnue. Le but de ma thèse est d'identifier des gènes exprimés spécifiquement dans les LCP CD30+ afin de comprendre les mécanismes d'oncogenèse et également d'identifier des marqueurs diagnostics ou thérapeutiques. Des banques d'ADNc soustraites par SSH (Soustractive Suppressive Hybrididation) entre des LCP CD30+ et des lymphocytes sanguins. Ces banques sont ensuite criblées par des techniqes de Dot Blot avec des sondes radiomarquées spécifiques des échantillons étudiés. Les clones sélectionnés sont enfin validés par PCR en temps réel. Nous avons ainsi mis en évidence cinq gènes surexprimés dans les LCP CD30+ : THW,p120caténine, SPARC, PTTG1, CD30 et cinq gènes sousexprimés : humanine, CIN85, Bcl11B, CD30 L et CD30s. Il reste à vérifier si ces gènes sont responsables de l'oncogenèse ou s'ils sont uniquement des phénotypes des LCP CD30+The CD30+ Primary Cutaneous Lymphoma (PCL) is a malignant T-cells lymphoproliferation. Its oncogenesis remains currently unknown. The aim of my thesis is to identify genes expressed specifically in CD30+ PCL in order to understand the mechanisms of oncogenesis and also to identify diagnostic or therapeutics markers. The substracted libraries of cDNA are obtained by SSH (suppressive substractive hybridisation) between CD30+ PCL and blood lymphocytes. These libraries are then screened by dot blot techniques with specific radiolabelled probes of the studied samples. The selected clones are finally validated by real time PCR. We have thus found five genes over expressed in CD30+ PCL : THW, p120catenin, SPARC, PTTG1, and CD30 and five genes under expressed : humanin, CIN85, Bcl11B, CD30L and CD30s. It remains to be checked if these genes are responsible for oncogenesis or if they are uniquely phenotypes of CD30+PCL
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Bossennec, Marion. "Caractérisation et régulation des lymphocytes T CD4+CD73+ en contextes physiologique et pathologique." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1159.
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L'étude des populations de lymphocytes T CD4+ effecteurs (Teff) chez l'Homme présente un intérêt croissant dans les enjeux actuels que constitue l'élaboration de nouvelles immunothérapies. Ces travaux détaillent la caractérisation et la régulation d'une population de Teff exprimant l'ecto-nucléotidase CD73 ayant pour fonction de dégrader l'AMP extracellulaire en adénosine (Ado) immunosuppresseur. Cette population, enrichie en lymphocytes T helper de type Th1.17, est très polyfonctionelle et pro-inflammatoire. Les Teff CD73+ expriment peu de points de contrôles immunitaires inhibiteurs mais sont régulés par leur production autocrine d'Ado qui limite leurs fonctions effectrices et leurs capacités prolifératives. Les Teff CD73+ expriment par ailleurs fortement le transporteur ABC multidrug-resistance 1 (MDR1), responsable de l'exclusion de nombreuses drogues du cytoplasme des cellules. L'étude de cette population dans différents contextes pathologiques a permis de détailler le fonctionnement de cette population. J'ai pu mettre en évidence que l'expression de CD73 est en effet dynamique. Elle est notamment diminuée dans des pathologies arthritiques auto-immunitaires (la polyarthrite rhumatoïde et le rhumatisme psoriasique) dans lesquelles les Th17 et les Th1.17 sont fortement activés. La diminution d'expression de CD73 sur ces cellules constitue la levée d'un frein qui leur permet de contribuer pleinement à l'inflammation chronique caractérisant ces pathologies. Les Teff CD73+, présents dans les tumeurs solides humaines de sein et d'ovaire, pourraient en revanche présenter un avantage sélectif en contexte tumoral de par leur expression de MDR1 leur permettant de résister aux traitements de chimiothérapie. Ces traitements substrats de MDR1, combinés à des thérapies inhibant la fonction enzymatique de CD73, pourrait permettre la restauration d'une réponse immunitaire anti-tumorale efficace médiée par cette population pro-inflammatoireRequirement for CD4+ effector T lymphocytes (Teff) comprehensive study in human is increasing since it can contribute to the emergence of new immunotherapy strategies. This work brings up important information concerning the characterization and regulation of a Teff population expressing the CD73 ecto-nucleotidase, which is able to degrade extracellular AMP into immunosuppressive adenosine (Ado). This population, highly polyfunctional and pro-inflammatory, is enriched in Th1.17 cells. CD73+ Teff express low levels of inhibitory immune checkpoints but are negatively regulated by the autocrine Ado production that limits their pro-inflammatory function and proliferative capacities. In addition, CD73+ Teff express high levels of the ABC transporter multi-drug resistance 1 (MDR1), responsible for the exclusion of cells’ cytoplasm of many drugs. The study of this population in different pathological contexts enabled to decipher its functions. I could evidence that CD73 expression is dynamic. CD73 is notably decreased in autoimmune arthritic pathologies (rheumatoid arthritis (RA) and psoriatic arthritis (PsA)) in which Th1.17 and Th17 are highly activated. CD73 decreased expression by these cells is a mechanism that alleviates self-inhibition by autocrine Ado production and enables them to fully contribute to chronic inflammation characterizing these pathologies. In tumor context, CD73+ Teff present in breast and ovarian tumors could on the contrary bear a selective advantage due to their high MDR1 expression enabling them to resist MDR1 substrates-based chemotherapy treatments. These chemotherapy treatments combined to therapies blocking CD73 enzymatic function could allow the restauration of an efficient anti-tumor immune response
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Melo, Juliana. "Avaliação da influência das moléculas PD-1, CD39 e CD73 na imunomodulação induzida pela infecção com a bactéria Brucella Abortus." Universidade Federal de Juiz de Fora (UFJF), 2017. https://repositorio.ufjf.br/jspui/handle/ufjf/6030.
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A brucelose é uma doença infectocontagiosa causada por bactérias do gênero Brucella que acometem o homem e uma grande variedade de animais domésticos, resultando em prejuízos econômicos significativos aos sistemas de produção. Em humanos essa infecção pode causar febre ondulante, endocardite, artrite, osteomielite e complicações neurológicas enquanto em animais leva ao aborto e infertilidade. Sabe-se que a resposta imunológica a bactérias intracelulares como a Brucella ocorre essencialmente através da imunidade mediada por células, sendo macrófagos especialmente importantes no combate à infecção. Entretanto, apesar da efetividade da resposta, a B. abortus conta com diversos mecanismos de evasão, o que garante a sua sobrevivência no organismo hospedeiro. Dentre estes mecanismos, a modulação de células apresentadoras de antígenos tem sido apontada como um dos mais relevantes. Recentemente, diversos trabalhos têm evidenciado a importância das NTPDases e da molécula PD-1 na modulação da resposta imune. As NTPDases estão envolidas com a produção de adenosina que apresenta relevante caráter imunomodulador. Já a molécula PD-1 está associada a indução de um perfil anti-inflamatório com diminuição de IL-12 e aumento de IL-10. Neste contexto, o objetivo deste estudo foi determinar se a infecção com B. abortus é capaz de alterar a expressão destas moléculas e assim limitar a ação do sistema imune, favorecendo a sobrevivência do patógeno. Para isso, células RAW 264.7 foram infectadas com B.abortus e a modulação das moléculas CD80, CD86, CD40, MHCII, foi avaliada por citometria de fluxo. Em seguida, a expressão de CD39 também foi determinada por citometria de fluxo e por Western Blot. Por fim analisamos possíveis alterações na expressão da molécula PD-1 induzidas pela bactéria. Como resultados, foi confirmado que a infecção é capaz de inibir a expressão de CD80, CD86 e CD40, embora o mesmo não tenha sido observado com o MHCII. Além disso, a expressão de CD40 se mostrou diminuída mesmo após o estímulo com LPS. De forma surpreendente, foi observada uma diminuição na expressão das moléculas CD39 e PD-1, o que pode ser explicado pela menor ativação celular induzida pela infecção. Assim, os dados obtidos até o momento demonstram que as moléculas CD39 e PD-1 não são utilizadas pela Brucella para modular as APCs, mas são influenciados pela menor ativação celular induzida pelo patógeno.
Brucellosis is an infectious disease caused by bacteria of the genus Brucella that affect humans and a wide variety of domestic animals, resulting in significant economic losses to production systems. In humans the infection can cause undulant fever, endocarditis, arthritis, osteomyelitis and neurological complications while in animals leads to abortion and infertility. It is known that the immune response to intracellular bacteria such as Brucella occurs primarily by cell-mediated immunity, macrophage being especially important in fighting infection. However, despite the effectiveness of the response, B. abortus has several avoidance schemes, which ensures their survival in the host organism. Among these mechanisms, modulation of antigen-presenting cells has been identified as one of the most relevant. Recently, several studies have shown the importance NTPDase and PD-1 molecule to modulate the immune response. The NTPDase are envolidas with the production of adenosine which presents immunomodulatory relevant character. Since PD-1 molecule is associated with induction of an anti-inflammatory profile with decreased IL-12 and IL-10 increase. In this context, the aim of this study was to determine whether infection with B. abortus is able to alter the expression of these molecules and thus limit the action of the immune system, favoring the survival of the pathogen. To this end, RAW 264.7 cells were infected with B.abortus and modulation of CD80 molecules, CD86, CD40, MHCII, was evaluated by flow cytometry. Then the CD39 expression was also determined by flow cytometry and Western blot. Finally, we analyze possible changes in PD-1 molecule expression induced by bacteria. As a result, it was confirmed that the infection is capable of inhibiting expression of CD80, CD86 and CD40, although this has not been observed with MHCII. Additionally, CD40 expression showed decreased even after the stimulation with LPS. Surprisingly, it was observed a decrease in the expression of CD39 and PD-1 molecules, which can be explained by the lower cellular activation induced by the infection. Thus, the data obtained so far show that the PD-1 and CD39 molecules are not used by Brucella Modular APCs but are less influenced by cellular activation induced by the pathogen.
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Peres, Raphael Sanches. "A sinalização de TGF-β envolvida na expressão de CD39 em células T reguladoras está associada com a eficácia terapêutica do metotrexato na artrite reumatóide." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-06012017-163133/.
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A Artrite Reumatóide (AR) é uma artropatia autoimune multifatorial com etiologia desconhecida que afeta aproximadamente 1% da população adulta. A estratégia padrão para o tratamento da AR consiste na administração de baixas doses de Metotrexato (MTX), cujo efeito anti-inflamatório está relacionado com a manutenção dos níveis elevados de adenosina (ADO) extracelular. No entanto, uma parte considerável dos pacientes com AR é refratária ao tratamento com MTX e o mecanismo pelo qual este fenômeno ocorre ainda não está totalmente esclarecido. Neste contexto, o presente estudo descreveu que a eficácia terapêutica ao MTX está associada com a expressão em células Tregs da ectoenzima CD39, cuja função biológica é a geração de ADO extracelular via metabolização do ATP. Especificamente, através da realização de um estudo longitudinal, observamos que pacientes respondedores ao MTX (R-MTX) apresentam uma expansão de células Tregs circulantes expressando CD39 após o tratamento com MTX. Por outro lado, identificamos que pacientes não respondedores ao MTX (UR-MTX) possuem uma redução da expressão de CD39 em células Tregs, o que culmina em um comprometimento das suas funções supressoras. Ainda, demonstramos que a expressão de CD39 em células Tregs é um biomarcador apto em predizer a resposta terapêutica ao MTX, visto que pacientes UR-MTX apresentam uma expressão reduzida de CD39 em Tregs mesmo antes do início do tratamento com MTX. Posteriormente, nós investigamos as bases moleculares que acarretam na expressão reduzida de CD39 observada em células Tregs de pacientes URMTX. Demonstramos que a estimulação com TGF-? tanto em células Tregs isoladas quanto diferenciadas in vitro aumenta a expressão de CD39 através da ativação sequencial da seguinte plataforma molecular: receptores de TGF-? (TGFBRII e TGFBRI), transdutor de sinal SMAD2, fator de transcrição CREB, de modo dependente da atividade de p38. Uma vez identificada a via envolvida com a indução da expressão de CD39, demonstramos que células Tregs diferenciadas de indivíduos que apresentam uma expressão reduzida de CD39 são incapazes de induzir a expressão desta ectoenzima através da estimulação com TGF-?. Por fim, transpondo nossos achados para pacientes com AR, observamos que pacientes UR-MTX apresentam uma redução nos níveis de RNAm para TGFBRII e CREB bem como também uma redução das proteínas fosforiladas SMAD2 e CREB em células CD4+ e Tregs, sugerindo que o comprometimento na cascata de sinalização de TGF-?, envolvida com a indução da expressão de CD39 em células Tregs, está associado com a resistência ao MTX.Rheumatoid arthritis (RA) is an autoimmune multifactorial arthropathy with unknown etiology that affects approximately 1% of the adult population. The standard strategy for RA treatment comprises the administration of low doses of methotrexate (MTX), whose antiinflammatory effects are associated with maintenance of high levels of extracellular adenosine (ADO). However, a considerable proportion of RA patients is resistant to MTX treatment and the mechanisms underlying this phenomenon occurs is poorly understood. Within this context, the present study showed that therapeutic efficacy of MTX is associated with expression on Treg cells of the ectoenzyme CD39, whose function is related to the generation of extracellular ADO by ATP metabolism. Specifically, we conducted a longitudinal study and observed that responsive patients to MTX (R-MTX) exhibit an increase in the frequency of circulating Treg cells expressing CD39 after MTX treatment. On the other hand, we found that non-responsive patients to MTX (UR-MTX) have a reduction of CD39 expression on Treg cells, which culminates in an impairment of Treg function. Furthermore, these findings indicate that CD39 expression on Treg cells is a biomarker for therapeutic response to MTX, since UR-MTX patients had a depressed CD39 expression on Treg cells even before MTX treatment. Subsequently, the present study investigated the molecular mechanisms that would cause the reduction of CD39 expression on Treg cells from UR-MTX patients. For this, we demonstrated that TGF-? stimulation increases CD39 expression in isolated and in vitro differentiated Treg cells through participation/activation of the following molecules: receptors of TGF-?, TGFBRII and TGFBRI, signal transducer SMAD2 and transcription factor CREB, through p38 activity dependent-manner. Once identified these molecules involved with CD39 induction, we demonstrated that differentiated Treg cells from healthy individuals with an intrinsic reduction of CD39 expression on circulating Treg cells are unable to increase CD39 expression by TGF-? stimulation. Transposing our findings to RA patients, we found that UR-MTX patients exhibit a reduction of mRNA for TGFBRII and CREB as well as reduction on levels of phospho-SMAD2 and phospho-CREB in CD4+ and Treg cells, suggesting that an impairment in TGF-? signaling pathway, related to induction of CD39 expression on Treg cells, is associated with MTX resistance.
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Duarte, Marta Maria Medeiros Frescura. "Hidrólise de nucleotídeos de adenina em plaquetas de pacientes com diferentes níveis de colesterol e sua relação com o processo inflamatório." Universidade Federal de Santa Maria, 2006. http://repositorio.ufsm.br/handle/1/11120.
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The activity of NTPDase (EC 3.6.1.5, apyrase, CD39) was verified in platelets from patients with increasing cholesterol levels. A possible association between cholesterol levels and inflammatory markers, such as oxidized low density lipoprotein (oxLDL), highly sensitive C-reactive protein (hsCRP) and oxLDL autoantibodies was also investigated. The following groups were studied: group I (< 150 mg/dl), group II (151 to 200 mg/dl); group III: (201 to 250 mg/dl); group IV (> 251 mg/dl) of cholesterol. The results demonstrated that both ATP and ADP hydrolysis were enhanced as a function of cholesterol levels. The LDL levels increased concomitantly with total cholesterol levels. The triglyceride levels were increased in the group with total cholesterol above 251 mg/dl. oxLDL levels were elevated in groups II, III and IV. hsCRP was elevated in the group with cholesterol higher than 251 mg/dl. oxLDL autoantibodies were elevated in groups III and IV. TBARS content was enhanced as a function of cholesterol levels. In summary, hypercholesterolemia is associated with an enhanced of inflammatory response and ATP and ADP hydrolysis. The increase in NTPDase activity is possibly related to a compensatory response to the
inflammatory and pro-oxidative state associated with hypercholesterolemia.A atividade da NTPDase (EC 3.6.1.5, apyrase, CD39) foi verificada em plaquetas de pacientes com diferentes níveis de colesterol. Uma possível associação entre os níveis de colesterol e os marcadores inflamatórios como LDL oxidado (oxLDL), proteína C reativa ultrasensível (hsCRP) e anticopos anti-LDL oxidado (Anti-oxLDL) foi investigado. Os seguintes grupos foram estudados: grupo I (< 150 mg/dl), grupo II (151 a 200 mg/dl); grupo III: (201 a 250 mg/dl); grupo IV (> 251 mg/dl) de colesterol. Os resultados demonstraram que a hidrólise dos nucleotídeos (ATP e ADP) aumentou em função dos níveis de colesterol. Os níveis de LDL aumentaram concomitantemente com os níveis de colesterol total. Os níveis de triglicerídeos foram elevados no grupo com colesterol total acima de 251 mg/dl. Os níveis de oxLDL foram elevados nos grupos II, III and IV. A hsCRP foi elevada no grupo com cholesterol maior que 251 mg/dl. Os Anti-oxLDL foram elevados nos grupos III e IV. O conteúdo de TBARS foi aumentando em função dos níveis de colesterol. Em resumo, a hipercolesterolemia está associada com o aumento da resposta inflamatória e hidrólise de ATP e ADP. O aumento da atividade da NTPDase está possivelmente relacionado com uma resposta compensatória ao estado inflamatório e pró-oxidativo associado com a hipercolesterolemia.
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Eckert, Marion. "Zur Rolle des CD30 Liganden bei der Induktion einer spezifischen Immunantwort gegen Melanomzellen." Diss., lmu, 2002. http://nbn-resolving.de/urn:nbn:de:bvb:19-5672.
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Prinz, Vincent Matthias [Verfasser]. "Neuroprotektion nach Schlaganfall : die Rolle intravenöser Statine, PACAP und CD39 / Vincent Matthias Prinz." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2010. http://d-nb.info/1024054772/34.
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Recke, Andreas [Verfasser]. "Bedeutung struktureller Elemente des CD30 für die Abspaltung durch membranständige Metalloproteasen / Andreas Recke." Aachen : Shaker, 2003. http://d-nb.info/1179034171/34.
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Georgieva, Petya [Verfasser]. "Microglial purinergic signaling in mouse models of CD39 deficiency and schizophrenia / Petya Georgieva." Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1069290173/34.
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Pierre-Hellier, Isabelle. "Lymphomes anaplasiques à grandes cellules CD30 positifs cutané : rôle du virus d'Epstein-Barr." Montpellier 1, 1997. http://www.theses.fr/1997MON11150.
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Huang, Huang. "The Role of CD39 in Modulating Effector Immune Responses in Inflammatory Bowel Disease." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295870.
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Inflammatory bowel disease is associated with excessive inflammation of the bowel and intestinal tissues in genetically susceptible individuals. IBD can manifest in two major forms, ulcerative colitis and Crohn’s disease. T helper type 17 cells (Th17) are effector lymphocytes that have been linked to intestinal inflammation in both mice and humans. Effector Th17 cells and regulatory T cells (Treg) – a subset pivotal to immune-tolerance maintenance – derive from the same CD4 progenitors. Our investigation demonstrates that Th17 cells with suppressor activity (supTh17) can be generated upon induced regulatory T cell (iTreg) exposure to Th17 polarizing conditions. With immune suppressive function that differentiates it from Th17, suppressor Th17 (supTh17) expresses high levels of CD39, a membrane-bound protein that catalyzes conversion of pro-inflammatory extracellular nucleotides into nucleosides, such as adenosine. Interestingly, though supTh17 is detected in the peripheral circulation and lamina propria of healthy subjects, it is diminished in patients with Crohn’s disease. This finding has important clinical implications for the development of innovative therapeutic techniques for targeting inflammation in autoimmune diseases, such as IBD.
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Winocour, Sebastian. "Effect of CD109, a novel TGF-beta antagonist, in a skin flap-induced hypoxic wound model." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96688.
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Background: Our group has identified CD109 as a novel TGF-beta antagonist which inhibits TGF-beta signaling and extracellular matrix (ECM) protein production in vitro and fibrotic responses in vivo. Since some fibrotic skin disorders such as hypertrophic scarring and scleroderma are associated with hypoxia, we examined whether CD109 is able to regulate ECM deposition under low oxygen tension in vivo.Objectives: (1) To validate a bipedicle skin flap-induced hypoxic wound model in mice and (2) to determine the role of CD109, a TGF-beta antagonist, in hypoxic wound healing using transgenic mice overexpressing CD109 in the skin.Method: Transgenic mice and wild-type littermates were used to generate a hypoxic wound model (previously validated in rats) by creating dorsal bipedicle skin flaps with centrally located excisional wounds. Excisional wounds were made in mice from each experimental group, namely (i) without skin flaps, (ii) with skin flaps but no underlying silicone sheet, and (iii) with skin flaps having an underlying silicone sheet. Excisional wounds lateral to the dorsal skin flaps served as internal controls in group (iii). Mice were sacrificed at day 7 or 14 after surgery, and tissues were harvested for analysis. Histological changes were analyzed by H&E and Masson's Trichrome staining, degrees of hypoxia were evaluated by immunohistochemistry (IHC) and alterations in TGF-beta signaling pathway components were determined by Western blot.Results: Both transgenic and wild-type mice sacrificed at day 7 and 14 post-wounding showed evidence of hypoxia by IHC within flap wounds with underlying silicone, validating this animal model in mice. Importantly, transgenic mice sacrificed at day 7 post-wounding demonstrated decreased collagen I and fibronectin deposition (ECM proteins) in the hypoxic wounds as compared to hypoxic wounds in their wild-type counterparts, and to non-hypoxic internal control wounds. This correlated with decreased dermal thickness in these mice. Secondly, transgenic mice showed no detectable difference in angiogenesis in hypoxic or non-hypoxic control wounds as compared to wild-type counterparts. Finally, CD109 expression decreased with increasing degrees of hypoxia found in excisional wounds.Conclusions: Bipedicle skin flap-induced hypoxic wounds in CD109 transgenic mice display decreased collagen I and fibronectin content and decreased dermal thickness during excisional wound healing. These data suggest that CD109 regulates hypoxic wound healing by decreasing the production of ECM components. In addition, CD109 expression inversely correlates with the degree of hypoxia found in excisional wounds. As a result, manipulating this molecule may have potential therapeutic value for the treatment of fibrotic and hypoxic skin disorders caused by diseases such as scleroderma and diabetes.Contexte: Notre groupe a identifié CD109 en tant que nouvel antagoniste du TGF-beta capable d'inhiber la production de protéines de la matrice extracellulaire (MEC) in vitro. Puisque certains désordres fibrotiques de la peau, tels que les cicatrices hypertrophiques et la sclerodermie, sont associés à l'hypoxie, nous avons examiné si CD109 est capable de réguler le dépot de la MEC dans des conditions hypoxiques in vivo.Objectifs: (1) Valider un modèle murin de plaie ischémique réalisée par lambeaux bi-pédiculés, et (2) déterminer le rôle de CD109, un antagonsite du TGF-beta, dans les blessures hypoxiques, en utilisant des souris transgéniques surexprimant CD109 dans la peau.Méthodes: Des souris transgéniques et des animaux sauvages de la même portée ont été utilisées pour générer un modèle de blessure hypoxique (précédemment valider chez le rat), en créant sur leur dos un lambeau de peau bi-pédiculé avec en son centre une plaie excisionnelle. Les plaies excisionnelles ont été réalisées dans des souris de chaque groupe expérimental: (i) sans lambeau, (ii) avec lambeau, mais sans feuille de silicone en dessous, et (iii) avec une feuille de silicone en dessous du lambeau. Des plaies excisionnelles latérales aux lambeaux ont servis de contrôle interne. Les souris ont été sacrifiées 7 ou 14 jours après chirurgie, et les tissus ont été collectés pour analyse. Les changements histologiques ont été analysés par coloration aux H&E et Masson's Trichrome, le degré d'hypoxie a été évalué par immunohistochimie (IHC) et les modifications des composants de la voie du TGF-beta ont été déterminés par Western blot.Résultats: 7 et 14 jours après leur création, les plaies excisionnelles réalisées sur les lambeaux de peau montrent des signes d'hypoxie par IHC aussi bien chez les souris transgéniques que sauvages, validant ainsi ce modèle chez la souris. De plus, une baisse de la déposition du collagène I et de la fibronectine (deux protéines de la matrice extracellulaire) est observée dans les blessures ischémiques des souris transgéniques sacrifiées 7 jours après chirurgie, comparées aux blessures hypoxiques des animaux sauvages et aux blessures non-hypoxiques des contrôles internes. Ceci corrèle avec une diminution de l'épaisseur du derme chez ces souris. En outre, les animaux transgéniques ne présentent pas d'augmentation de l'angiogénèse dans les blessures ischémiques et non ischémiques, comparés aux souris sauvages. Finalement, l'expression de CD109 est inversement proportionnelle au degré d'hypoxie des plaies excisionnelles.Conclusions: Les plaies hypoxiques réalisées par lambeaux bi-pédiculés des souris transgéniques pour CD109 ont une diminution du collagène I et de la fibronectine et montrent une réduction de l'épaisseur du derme lors de la cicatrisation des plaies excisionnelles. Ces résultats suggèrent que CD109 régule la cicatrisation des blessures hypoxiques en réduisant la production de composants de la matrice extracellulaire. De plus, l'expression de CD109 est inversement proportionnelle au degré d'hypoxie des plaies excisionnelles. Donc, manipuler cette molécule pourrait avoir un bienfait thérapeutique pour le traitement de désordres fibrotiques et hypoxiques de la peau causés par des maladies telles que la sclérodermie et le diabète.
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Tresckow, Bastian von. "Die proteolytische Freisetzung von löslichem CD30 in Abhängigkeit vom zellulären Cholesteringehalt und lipid rafts /." Inhaltsverzeichnis, 2005. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014185017&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Gehring, Marina Petersen. "Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta ? radioterapia em gliomas." Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2016. http://tede2.pucrs.br/tede2/handle/tede/6652.
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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES
Gliomas represent the most common class of malignant tumors of the central nervous system being the most aggressive, and lethal brain tumors in primary brain tumors. Among the treatments, radiation is one of the most used therapies, but the intrinsic radioresistance of these tumors remains a critical problem in the management of these patients. Currently it is known that the effect of radiation extends beyond the directly cytotoxicity caused in tumor cells. Radiation therapy appears to induce an immunogenic cell death that among the features is ATP release. The ATP can cause cytotoxicity via P2X7 receptor and also acts as a sign of damage activating the immune system. The ATP can be hydrolyzed by enzymes of the purinergic system, among them the ectonucleotidase CD39, to adenosine, which has an opposite effect to ATP, causing immunosuppression. The radiation-induced ATP release and the ability of this nucleotide in modulate immune responses raised the hypothesis about the purinergic signaling participation in the tumor and immune cells response to radiation. Therefore, this study investigated: i) the role of ectonucleotidase CD39/NTPDase1 in the radiation-induced immune response in gliomas, ii) the importance of ATP-P2X7 receptor in the gliomas response to radiotherapy. Using knockout mice for CD39/NTPDase1, we observed that the deletion of this enzyme combined with radiotherapy significantly reduced the immunosuppressive cells Tregs in the tumor and spleen, attenuated the infiltration of myeloid derived suppressor cells caused by radiation and increased CCR7 expression in splenic dendritic cells and macrophages, indicating the presence of freshly mobilized antigen presenting cells available to differentiate in immune-effector cells that sustain a more prolonged antigen-specific T-cell?mediated immune response. Thereby, showing that blocking the activity of CD39/NTPDase1 can control immunosuppressive mechanisms generated by the tumor and promises to improve the radiotherapy response. Furthermore, in this study we observed that radiation actives the P2X7 receptor and by silencing this receptor on the GL261 glioma cell line, we have shown that radiotherapy is less efficient in vivo when compared with mice injected with GL261 WT cells, which constitutively express the P2X7 receptor. We also showed that patients with glioma that overexpress the P2X7 receptor, showed a better response to radiotherapy, revealing the importance of the expression of this receptor on glioma cells as a useful marker to analyze the tumor sensitivity to radiation and a successful radiotherapy response. In summary, our data shed light on the purinergic signaling for modulating the radiotherapy response in gliomas.
Os gliomas representam a classe mais comum de tumores malignos do sistema nervoso central, sendo o tumor cerebral mais agressivo e letal entre os tumores cerebrais prim?rios. Dentre os tratamentos, a radia??o ? uma das terapias mais utilizadas, por?m a radiorresist?ncia intr?nseca destes tumores continua a ser um problema cr?tico na gest?o de destes pacientes. Atualmente, sabe-se que o efeito da radia??o se estende al?m da citotoxicidade direta causada nas c?lulas tumorais. A radioterapia parece induzir uma morte celular imunog?nica, que entre as caracter?sticas est? a libera??o de ATP. O ATP pode causar citotoxicidade atrav?s do receptor P2X7 e tamb?m atua como um sinal de dano celular ativando o sistema imune. O ATP pode ser hidrolisado por enzimas do sistema purin?rgico, dentre elas a ectonucleotidase CD39/NTPDase1, ? adenosina, que tem um efeito aposto ao ATP, causando imunossupress?o. A secre??o de ATP induzida pela radioterapia e a capacidade deste nucleot?deo em modular a resposta imune, levantou a hip?tese da participa??o da sinaliza??o purin?rgica na resposta de c?lulas tumorais ? radia??o e na resposta imune induzida pela radioterapia. Portanto, neste estudo visou-se investigar: i) o papel da ectonucleotidase CD39/NTPDase1 na resposta imune induzida pela radioterapia em gliomas, ii) a import?ncia da via ATP-receptor P2X7 na resposta de gliomas ? radioterapia. Atrav?s de camundongos knockout para a enzima CD39/NTPDase1, observamos que a dele??o desta enzima combinada com a radioterapia reduziu significativamente as c?lulas imunossupressoras Tregs no tumor e no ba?o, atenuou a infiltra??o de c?lulas mieloides supressoras causada pela radia??o, e aumentou a express?o de CCR7 em c?lulas dentr?ticas e macr?fagos localizados no ba?o, indicando a presen?a c?lulas apresentadoras de ant?geno rec?mmobilizadas e dispon?veis para se diferenciarem em c?lulas imunes efetoras que sustentam uma resposta imune mais prolongada mediada por c?lulas T ant?geno espec?ficas. Deste modo, mostrou-se que o bloqueio da atividade da CD39/NTPDase1 pode controlar mecanismos imunossupressores gerados pelo tumor e promete melhorar a resposta ? radioterapia. Al?m disso, neste estudo observou-se que a radioterapia ativa o receptor P2X7 e atrav?s do silenciamento deste receptor na linhagem de glioma GL261, demonstramos que a radioterapia foi pouco eficiente in vivo, quando comparado com camundongos injetados com a GL261 WT, que expressa constitutivamente o receptor P2X7. Tamb?m demonstramos que pacientes com glioma que expressaram mais o receptor P2X7, apresentaram uma melhor resposta a radioterapia, revelando a import?ncia da express?o deste receptor em c?lulas de glioma como um marcador ?til para analisar a sensibilidade tumoral ? radioterapia e para uma resposta bem-sucedida ? radioterapia. Em suma, nossos dados lan?am luz sobre a sinaliza??o purin?rgica para a modula??o da resposta ? radioterapia em gliomas.
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Bussara, Tirakalyanapan Sittipong Dilokwanich. "The cooperation between government agency and environmental NGOS : a case study on convention on international trade in endangered species of wild fauna nad flora /." Abstract, 2005. http://mulinet3.li.mahidol.ac.th/thesis/2548/cd379/4537409.pdf.
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Carrara, Verena Ilona Pratap Singhasivanon. "Epidemiological impact of the large scale deployment of early diagnosis and combination treatment of falciparum Malaria on the Northwestern border of Thailand; the Tak Malaria initiative /." Abstract, 2006. http://mulinet3.li.mahidol.ac.th/thesis/2549/cd390/4437564.pdf.
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Rajitphan, Jantarach Yupin Lawanprasert. "Intention to buy OTOP food products among consumers in Nonthaburi Province /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd399/4937999.pdf.
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Siswanto, Eddy Bhuiyan Shafi Ullah. "Knowledge and perception of pneumonia disease among mothers of children under five years attending Nakhon Pathom General Hospital, Thailand /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd399/4937989.pdf.
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Ahmed, Fayyaz Shaikh Teera Ramasoota. "Factors affecting nutritional status of five years old children in Islamabad, Pakistan /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd399/4937997.pdf.
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Bui, Thi Bich Hang Manop Suphantharika. "Development of a monoclonal antibody assay for Infectious Hypodermal and Hematopoietic Necrois Virus (IHHINV) of shrimp /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd399/4837387.pdf.
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Hien, Nguyen Mannee Chaiteeranuwatsiri. "Teacher's and administrator' perception of Asean cooperation in tourism training case studies of Thailand and Vietnam /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd399/4836019.pdf.
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Amin, Khan Mandokhail Boonyong Keiwkarnka. "Patient satisfaction towards outpatient department services of medicine in banphaeo autonomous hospital Samut Sakhon Province, Thailand /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd399/4937996.pdf.
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