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Régression robuste bayésienne à l'aide de distributions à ailes relevéesSchiller, Ian January 2008 (has links) (PDF)
Dans ce mémoire nous nous intéressons à des méthodes d'estimations robustes de la pente de la droite de régression linéaire simple ainsi que du paramètre d'échelle de la densité des erreurs en présence de valeurs aberrantes dans l'échantillon de données. Une revue des méthodes d'estimations des paramètres de la droite de régression est présentée. Nous y analysons numériquement les différentes méthodes afin de décrire le comportement des estimateurs en présence d'une valeur aberrante dans l'échantillon. Une méthode d'estimation bayésienne est présentée afin d'estimer la pente de la droite de régression lorsque le paramètre d'échelle est connu. Nous exprimons le problème d'estimation de la pente de la droite de régression en un problème d'estimation d'un paramètre
de position, ce qui nous permet d'utiliser les résultats de robustesse bayésienne pour un paramètre de position. Le comportement de cet estimateur est ensuite étudié numériquement lorsqu'il y a une valeur aberrante dans l'échantillon de données. Enfin, nous explorons une méthode bayésienne d'estimation simultanée du paramètre d'échelle et de la pente de la droite de régression. Nous exprimons le problème comme une estimation des paramètres de position et échelle même si les résultats de robustesse bayésienne pour ce cas ne sont pas encore publiés. Nous étudions tout de même le comportement des estimateurs de façon numérique. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Régression linéaire, Inférence bayésienne, Robustesse, Valeurs aberrantes, Densités à ailes relevées, Densités GEP (Generalized exponential power), P-credence.
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Perception de la douleur dans la schizophrénie : mécanismes excitateurs de la douleur / Pain perception in schizophrenia: pain excitatory mechanismsLévesque, Mylène January 2012 (has links)
Résumé : Depuis la caractérisation de la schizophrénie, les cliniciens ont noté une sensibilité anormale à la douleur chez leurs patients. D’un autre côté, la littérature publiée sur le sujet est plutôt inconsistante concernant la nature du changement de douleur rapportée. Dans un effort pour mieux caractériser le profil de réponse à la douleur dans la schizophrénie, nous avons donné des stimulations nociceptives aiguës et prolongées (à répétition rapide; sommation temporelle) à des patients souffrant de schizophrénie et à des sujets sains. En mesurant le score de douleur subjective et la réponse du réflexe de flexion nociceptif en réponse à des stimulations électriques transcutanées, il a été possible d’évaluer la contribution des circuits spinaux à la douleur chez les patients et les sujets sains. Les résultats révèlent une sensibilité augmentée à la douleur aiguë chez les patients atteints de schizophrénie (i.e., un seuil de détection de la douleur plus bas que les sujets sains) mais aussi une diminution de la sommation temporelle de la douleur quand les stimuli se répètent fréquemment. Les différences intergroupes dans l’expérience subjective à la douleur n’étaient pas accompagnées d’une différence dans l’amplitude du réflexe nociceptif, suggérant ainsi une origine supra-spinale du phénomène observé. Il est intéressant de noter que les symptômes positifs de la schizophrénie étaient corrélés négativement avec les scores de seuil de douleur chez les patients atteints de schizophrénie, suggérant que les distorsions de la pensée et des fonctions peuvent être reliées à une augmentation de la sensibilité à la douleur aiguë dans la schizophrénie. Ces résultats suggèrent la présence d’un profil de sensibilité à la douleur unique chez les patients atteints de schizophrénie ayant des répercussions importantes pour les pratiques cliniques. // Abstract : Ever since the characterization of schizophrenia, clinicians have noted abnormal pain sensitivity in their patients. The published literature, however, is inconsistent concerning the nature of the change reported. In an effort to better characterize the pain response profile of schizophrenia patients, we provided both acute and prolonged (i.e., rapidly-repeating: temporal summation) painful stimuli to schizophrenia patients and healthy controls. By measuring subjective pain ratings and nociceptive flexion reflexes in response to transcutaneous electrical stimulations of the sural nerve, it was possible to evaluate the contribution of spinal circuits to pain in patients and controls. Results revealed increased sensitivity to acute pain in schizophrenia patients (i.e., lower pain detection thresholds for schizophrenia patients than for controls), but decreased temporal summation of pain when painful stimuli repeated frquently. Group differences in subjective experience were not accompanied by group differences in nociceptive flexion reflex activity, suggesting supra-spinal origins to the change in pain experienced by patients. Interestingly, positive symptoms correlated negatively with pain threshold values among patients, suggesting that distortions of thought and function relate to pain sensitivity in schizophrenia. These results indicate the presence of a unique pain response profile for schizophrenia patients which have important implications for clinical practice.
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Associação entre Timp1, β1-integrinas e CD63 ao longo da gênese do melanoma / Association between Timp1, β1-integrin and CD63 during the genesis of melanomaPinto, Mariana Toricelli [UNIFESP] 24 November 2010 (has links) (PDF)
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Publico-393.pdf: 1637068 bytes, checksum: 4fe3757007f6a049eac930eb08b63c88 (MD5) / O melanoma é o tipo de câncer de pele menos frequente, mas que tem um grande poder de letalidade devido ao seu potencial de formar metástases. Para as células adquirirem a capacidade de formar metástases, estas precisam ter a característica de sobreviver independente de interações com a matriz extracelular e consequentemente apresentar resistência ao anoikis. Por isso, a importância de se estudar as alterações que ocorrem com células tumorais que adquirem essa capacidade. Em nosso laboratório foi desenvolvido um modelo que nos permite estudar diferentes etapas da gênese do melanoma. Melanócitos murinos melan-a que sobreviveram depois de 1, 2, 3 e 4 ciclos de impedimento de ancoragem por 96 horas apresentaram modificações na morfologia e crescimento independente de PMA, e foram denominadas 1C, 2C, 3C e 4C, respectivamente. Diferentes linhagens de melanoma (4C11-, 4C11+, Tm1, Tm5, etc) foram estabelecidas após submeter os esferóides sobreviventes da 4C à diluição limitante. Dados prévios de nosso laboratório mostraram aumento da expressão de Timp1 ao longo da transformação maligna de melanócitos e aumento da resistência ao anoikis. Melanócitos melan-a superexpressando o gene Timp1 adquirem fenótipo de resistência ao anoikis. No entanto, o mecanismo pelo qual Timp1 medeia essa sinalização de sobrevivência não é conhecido. Dados da literatura mostram interação entre CD63, Timp1 e 1-integrinas em células epiteliais de mama humana e que essa interação regula processos fisiológicos como apoptose. Além disso, a glicosilação aberrante em moléculas de adesão celular, como integrinas, pode conferir às células capacidade de sobreviver em condições independentes de ancoragem. O objetivo do presente estudo foi analisar a possível interação entre CD63, Timp1 e 1-integrinas ao longo da transformação maligna de melanócitos, a presença de N-glicosilação aberrante em β1-integrinas e o impacto da N-glicosilação aberrante na resistência ao anoikis. Observou-se interação entre CD63 e Timp1 e CD63 e 1-integrinas nas linhagens 4C, 4C11- e 4C11+, estabelecidas após ciclos de impedimento de ancoragem, já a interação entre Timp1 e 1-integrinas foi observada somente nas linhagens de melanoma 4C11- e 4C11+. A expressão de 1-integrinas na superfície celular está aumentada na linhagem de melanoma agressivo 4C11+, assim como a expressão de Mgat-V e N-glicosilação aberrante. Além disso, o perfil eletroforético da 1-integrina sugere que a mesma apresenta aumento de N-glicosilação aberrante na linhagem de melanoma metastático 4C11+. O tratamento de células de melanoma 4C11+ com o inibidor de N-glicosilação swainsonine resulta em menor capacidade destas células em resistir ao anoikis. Este parece ser o primeiro estudo descrevendo a interação entre Timp1, CD63 e 1-integrinas em células tumorais. Assim, o presente trabalho favorece o entendimento de como Timp1 regula resistência ao anoikis ao longo da transformação maligna de melanócitos. / Although malignant melanoma is the less frequently diagnosed skin cancer, it shows a poor prognosis due its chemoresistance and metastasis development. One of the adquired abilities of transformed cells is anoikis resistance and this property is closely related to metastasis formation. In our laboratory, we developed a model that allows us to study different steps of melanocyte malignant transformation. Melan-a melanocytes surviving after 1, 2, 3 and 4 deadhesion cycles showed modified morphology and independent PMA growth and have been named, 1C, 2C, 3C and 4C cells, respectively. Different melanoma cell lines were established after submitting 4C spheroids to limiting dilution. Previous results of our group showed increased expression of Timp1 along melanoma genesis and its correlation with anoikis resistance. However, the mechanism involved in this signaling is unknown. Published data demonstrated interaction between CD63, Timp1 and 1-integrins in human breast epithelial cells and its role in apoptosis. Furthermore, aberrant glycosylation in cell adhesion molecules such as integrins provides to cells the ability to survive under anchorage-independent conditions. The aim of this work was analyze the possible interaction among CD63, Timp1 and 1-integrins along melanocyte malignant transformation, possible aberrant N-glycosylation patterns of β1-integrins and their impact in anoikis resistance. Aberrant N-glycosylation patterns were observed in tumorigenic cells. We observed interaction between CD63 and Timp1 and between CD63 and 1-integrins in the melan-a-derived cells 4C, 4C11, and 4C11 +, and interaction between Timp1 and 1-integrins only in melanoma cell lines 4C11 - and 4C11 +. The presence of Timp1 in supernatant from 4C11+ conferred to melan-a cells anoikis resistance. The expression of 1-integrins in our study model is increased in aggressive melanoma lineage, 4C11+, as well as the expression of Mgat-V and aberrant N-glycosylation on cell surface. Moreover, the electrophoretic profile of  1-integrin suggests that melanoma metastatic 4C11+. Lineage present increased aberrant N-glycosylation in this molecule. Treatment of melanoma cells 4C11 + with the N-glycosylation inhibitor, swainsonine, resulted in reduced capacity of these cells to resist to anoikis. This seems to be the first study describing the interaction between Timp1, CD63 and 1-integrin in tumor cells and may contribute to a better understanding of how Timp1 regulates resistance to anoikis during the melanocyte malignant transformation. / TEDE / BV UNIFESP: Teses e dissertações
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Avaliação do padrão de metilação dos genes WT1 e RARß em metaplasia intestinal e associação com infecção pela Helicobacter pyloriSilva, Hector Matioli da [UNESP] 28 February 2008 (has links) (PDF)
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silva_hm_me_sjrp.pdf: 508031 bytes, checksum: 56b635113c96c5bc5c2ffa3a4cb5324a (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O câncer gástrico é a segunda causa de morte por câncer no mundo e o quinto tipo com maior prevalência no Brasil, sendo previstos 21.800 casos novos em 2008. Esta neoplasia apresenta etiologia bastante complexa, envolvendo fatores genéticos e ambientais. Os fatores etiológicos de maiores destaques incluem a infecção pela bactéria Helicobacter pylori, a ingestão de determinados alimentos, como defumados, enlatados e com elevada quantidade de sal, além do estilo de vida dos indivíduos, associado ao consumo de cigarro e álcool. Uma lesão pré-cancerosa importante no desenvolvimento da neoplasia gástrica é a metaplasia intestinal, podendo aumentar o seu risco em até 10 vezes. Atualmente é reconhecida a participação de alterações epigenéticas como metilação aberrante do DNA, que atua de forma igualmente relevante e complementar no processo de desenvolvimento e progressão do câncer. Vários genes com papel importante no controle do ciclo celular, reparo do DNA, apoptose, angiogênese e adesão celular podem apresentar expressão alterada devido metilação aberrante de sua região promotora, assim a investigação do padrão de metilação de genes envolvidos com o processo neoplásico pode ser uma estratégia interessante para a indicação de marcadores moleculares que possam auxiliar no diagnóstico precoce do câncer. Desta forma, no presente trabalho foi investigado o padrão de metilação dos genes WT1 e RARß em metaplasia intestinal (35 amostras) e suas respectivas mucosas gástricas normais, em comparação com o câncer gástrico (8 amostras) também com suas respectivas mucosas normais, através da técnica MS-PCR (Methylation Specific PCR). Devido à participação da infecção pela H. pylori na carcinogênese gástrica, foi investigada molecularmente a presença dessa bactéria nas amostras... / Worldwide, the gastric cancer is the second cause of death by cancer. In Brazil, it is the fifth type with more abundant, foreseen 21.800 new cases in 2008. This neoplasia presents very complex etiology involving genetic and environmental factors. The main etiologic factors include: infection by H. pylori, intake of specific foods such as curing food, canned food, and high consumption of salt wealthy food, besides people life style associated to alcohol and cigarette consumptions. An important previous-cankered lesion in development of gastric neoplasia is the intestinal metaplasia, what can increase your risk in ten times. At this moment, it is recognized the participation of epigenetic alterations like ADN aberrant methylation, which actuate in a same way considerable and complementary in development process and cancer evolution. Many genes with important role in control of cellular cycle, ADN repair, apoptosis, angiogenesis and cellular adhesion can present changed expression due aberrant metthylation of your promoter region. In this manner, the investigation of metithyation pattern of genes involved with the neoplasic process can be an interesting strategy for the indication of molecular markers that can help in cancer precocious diagnosis. Thus, in this present study were investigated the metthylation pattern of RARß and WT1genes (35 samples) and their respective normal mucous gastrics by technic MSPCR (Methylation Specific PCR). Due to participation of infection by H. pylori in gastric carcinogenesis, it was too molecular investigated the presence of this bacterium in the studied samples and the possible association with the metthylation pattern presented by both genes. The results showed high pattern of methylation in both valued lesions, that is, 97% and 100%, respectively of methylated samples in metaplasia group ...(Complete abstract click electronic access below)
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Élaboration d’un anticorps chimère anti-gp350 comme traitement prophylactique éventuel des syndromes lymphoprolifératifs B chez les greffésLeblond, Valérie 08 1900 (has links)
Le virus Epstein-Barr (VEB) est fortement associé au développement de syndromes
lymphoprolifératifs (SLP) en greffe pédiatrique. Ce virus a la capacité
d’immortaliser les lymphocytes B et de provoquer leur prolifération incontrôlée chez
l’hôte immunodéprimé. Plusieurs études démontrent que le cycle lytique du virus
jouerait un rôle primordial dans la genèse des SLP en produisant des particules
virales pouvant infecter les cellules B adjacentes. Chez un individu immunodéprimé,
ces cellules B nouvellement infectées peuvent donner naissance à une expansion
lymphocytaire. Le projet présenté dans ce mémoire fait partie d’un programme de
recherche visant à élucider le rôle de l’infection productive par le VEB dans le
développement des SLP. L’objectif précis de ce projet est de développer un anticorps
monoclonal chimère contre la glycoprotéine gp350 du VEB dans le but de neutraliser
le virus et d’ainsi prévenir son entrée dans les cellules B.
Notre laboratoire a construit une version chimère de l’anticorps monoclonal murin
72A1, lequel se lie à la gp350 et bloque l’infection. Les premiers essais ont révélé la présence de chaînes non fonctionnelles (aberrantes) dans l’hybridome produisant
l’anticorps 72A1. La construction de la chaîne légère authentique est maintenant
complète alors que celle de la chaîne lourde est toujours en cours. Le processus de
caractérisation de l’anticorps chimère inclura des essais de cytotoxicité à médiation cellulaire dépendante des anticorps (ADCC). Dans cette optique, une lignée cellulaire exprimant de façon stable la gp350 a été établie.
Notre anticorps chimère anti-gp350 pourrait éventuellement être utilisé comme thérapie préventive chez les greffés présentant un risque élevé de SLP en empêchant l’infection des cellules B adjacentes. / The Epstein-Barr virus (EBV) is associated with B-cell post-transplant
lymphoproliferative disease (PTLD). EBV has the unique property of immortalizing B lymphocytes, thereby causing their uncontrolled proliferation in an immunocompromised host. Certain evidence suggests that EBV productive infection
may play a primary role in the genesis of PTLD by generating virus particles which
can infect bystander B cells. In an immunocompromised individual, these infected B cells may then give rise to expanding B-cell clones. The project presented in this
thesis is part of a research program seeking to elucidate the role of EBV productive
infection in the genesis of PTLD. The specific aim of this work was to design a
chimeric monoclonal antibody against the EBV envelope glycoprotein gp350 in order to neutralize the virus, thereby preventing entry into B cells.
Our laboratory constructed a chimeric version of the murine monoclonal antibody,
72A1, which binds to gp350 and blocks infection. The initial cloning attempts
revealed the presence of nonfunctional (aberrant) transcripts in the hybridoma line
producing the 72A1 antibody. The chimeric version of the authentic light chain is
now completed while the chimeric heavy chain construction is ongoing. As part of the characterisation process for the chimeric antibody, a cell line stably expressing surface gp350 was generated. This gp350-expressing cell line will be used for
antibody dependent cellular cytotoxicity assays (ADCC).
This anti-gp350 chimeric antibody could be useful as a preventive therapy in transplant patients at high risk for PTLD by blocking the infection of bystander B cells.
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Structural-dependent effects of dietary fibers in colon cancer: Focus on dietary fiber naturally changed by the papaya ripening / Efeitos estrutura-dependente das fibras alimentares no câncer de cólon: foco na fibra alimentar naturalmente modificada durante o amadurecimento do mamão papaiaPrado, Samira Bernardino Ramos do 06 May 2019 (has links)
Dietary fiber (DF) consumption is related with several healthy benefits such as the decreasing risk of colon cancer development. The DF is not digested by the digestive enzymes and reach to colon where is fermented by the colonic microbiota. The fermentation process releases metabolites as short chain fatty acids (SCFA) such as butyrate, propionate and acetate. Besides the fermentation process, the DF can directly interact with intestinal epithelial cells inducing mechanism that can also be related with the associated DF consumption benefits. The lack of information regarding DF and colon cancer are due to the complexity of both the cancer and the DF structure. The papayas DF are derived from the fruit cell wall, and they are probably naturally modified during ripening through a massive polysaccharide hydrolysis, because papayas show a very fast pulp softening. Due to the lack of information about DF and their beneficial effects to human health as well as the possibility of the natural papaya ripening to modifying the DF presented in the fruit pulp, the present thesis had as the primary objectives: 1) to evaluate how the cell-wall degrading enzymes affect the fruit cell wall solubilization and molecular weight; 2) to investigate the direct effects of the papaya pectin derived from unripe to ripe papayas in cancer cell lines, in galectin-3 interaction and in HEK cells expressing pattern recognition receptors (PRR); 3) to evaluate the human colonic in vitro fermentation using DF from unripe and ripe papayas as substrates; 4) to conduct an in vivo experiment using rats with pre-neoplastic colon lesions while receiving a diet with DF from unripe and ripe papayas. The endopolygalacturonases were the main enzymes acting on the solubilizing papaya cell wall pectin affecting both the papaya firmness and pectin structure. Overall, the papayas DF showed a ripening dependent structureeffects. In the cancer cell lines experiments, the ripe papayas pectin showed a more pronounced effects in inducing cancer cell death, inhibiting cancer cells migration and aggregation, activating PRR as toll-like receptors and inhibiting the pro-metastatic protein galectin-3. The DF from papayas also showed different aspects in colonic in vitro fermentation regarding the DF utilization by the bacteria and the bacteria abundance profile. Lastly, the animals receiving the diet with the DF from ripe papayas had less aberrant crypt foci in colon than the animals that received the DF from unripe papayas or cellulose (AIN-93G DF). Therefore, the study of papaya DF was carried out both during papaya ripening and its biological effects in vitro and in vivo, generating unprecedented results relating the endogenous biochemical changes of the fruits during maturation with the possible beneficial effects of their ingestion for health human. / O consumo de fibras alimentares (FA) está relacionado com vários benefícios à saúde como a diminuição no risco do desenvolvimento de câncer de cólon. A FA não é digerida pelas enzimas digestivas do trato gastrointestinal sendo fermentada pela microbiota intestinal do cólon. Como subproduto do processo de fermentação há a liberação de ácidos graxos de cadeia curta (SCFA) - como o butirato, o propionato e o acetato. Além do processo de fermentação, a FA pode interagir diretamente com as células epiteliais do intestino, induzindo mecanismos que também podem estar relacionados com os benefícios associados ao consumo de FA. A falta de informação sobre a FA e o câncer de cólon é, em partes, devido à complexidade de ambos, tanto do câncer quanto da estrutura da FA. As FA do mamão papaia são derivadas da parede celular da fruta apresentando diferentes estruturas dependendo do ponto de amadurecimento do fruto. Esse fato ocorre, pois, durante o amadurecimento do mamão papaia, existe uma extensa hidrólise dos polissacarídeos presentes na parede celular, diminuindo rapidamente a firmeza da polpa do fruto. Devido à falta de informações sobre FA e seus efeitos benéficos à saúde humana que são dependentes da sua estrutura, bem como a possibilidade do amadurecimento do mamão papaia naturalmente modificar as FA presentes na polpa dos frutos, a presente tese teve como principais objetivos: 1) avaliar como as enzimas que degradam a parede celular do mamão papaia afetam a solubilização e o peso molecular da parede celular do fruto; 2) investigar os efeitos diretos da pectina derivada de mamões verdes e maduros em linhagens de células de câncer, na interação com a galectina-3, e em células do tipo HEK que expressam receptores de reconhecimento de padrões (RRP); 3) avaliar a fermentação colônica humana in vitro utilizando as FA de mamões verdes e maduros; 4) avaliar em ratos com lesões pré-neoplásicas no cólon o efeito do consumo de ração com ou sem FA de mamões papaias verdes e maduros. As endopoligalacturonases foram relacionadas como as principais enzimas que atuam solubilizando a pectina da parede celular do mamão, afetando tanto a firmeza da polpa do fruto quanto a solubilização da pectina durante o amadurecimento. De modo geral, as FA dos mamões exerceram um efeito estruturadependente de acordo com a maturação do fruto. Nos experimentos utilizando linhagens de células de câncer, a pectina do mamão papaia maduro apresentou efeitos mais pronunciados na indução da morte e na inibição da migração e da agregação das células, bem como ativando os RRP, como por exemplo, os receptores do tipo toll-like, além de inibir a proteína pró-metastática galectina-3. As FA dos mamões também apresentaram diferentes resultados na fermentação colônica in vitro quanto à utilização das FA pelas bactérias do intestino, e também no perfil de crescimento dessas bactérias. Por fim, os animais que receberam a dieta com as FA dos mamões maduros apresentaram menor incidência de focos de criptas aberrantes do que os animais que receberam as FA provenientes de mamões verdes ou de celulose (FA da ração AIN-93G). Portanto, o estudo das FA dos mamões foi efetuado tanto durante o amadurecimento dos mamões quanto dos seus efeitos biológicos in vitro e in vivo, tendo gerado resultados inéditos relacionando as alterações bioquímicas endógenas dos frutos durante o amadurecimento com os possíveis efeitos benéficos da sua ingestão para a saúde humana.
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Élaboration d’un anticorps chimère anti-gp350 comme traitement prophylactique éventuel des syndromes lymphoprolifératifs B chez les greffésLeblond, Valérie 08 1900 (has links)
Le virus Epstein-Barr (VEB) est fortement associé au développement de syndromes
lymphoprolifératifs (SLP) en greffe pédiatrique. Ce virus a la capacité
d’immortaliser les lymphocytes B et de provoquer leur prolifération incontrôlée chez
l’hôte immunodéprimé. Plusieurs études démontrent que le cycle lytique du virus
jouerait un rôle primordial dans la genèse des SLP en produisant des particules
virales pouvant infecter les cellules B adjacentes. Chez un individu immunodéprimé,
ces cellules B nouvellement infectées peuvent donner naissance à une expansion
lymphocytaire. Le projet présenté dans ce mémoire fait partie d’un programme de
recherche visant à élucider le rôle de l’infection productive par le VEB dans le
développement des SLP. L’objectif précis de ce projet est de développer un anticorps
monoclonal chimère contre la glycoprotéine gp350 du VEB dans le but de neutraliser
le virus et d’ainsi prévenir son entrée dans les cellules B.
Notre laboratoire a construit une version chimère de l’anticorps monoclonal murin
72A1, lequel se lie à la gp350 et bloque l’infection. Les premiers essais ont révélé la présence de chaînes non fonctionnelles (aberrantes) dans l’hybridome produisant
l’anticorps 72A1. La construction de la chaîne légère authentique est maintenant
complète alors que celle de la chaîne lourde est toujours en cours. Le processus de
caractérisation de l’anticorps chimère inclura des essais de cytotoxicité à médiation cellulaire dépendante des anticorps (ADCC). Dans cette optique, une lignée cellulaire exprimant de façon stable la gp350 a été établie.
Notre anticorps chimère anti-gp350 pourrait éventuellement être utilisé comme thérapie préventive chez les greffés présentant un risque élevé de SLP en empêchant l’infection des cellules B adjacentes. / The Epstein-Barr virus (EBV) is associated with B-cell post-transplant
lymphoproliferative disease (PTLD). EBV has the unique property of immortalizing B lymphocytes, thereby causing their uncontrolled proliferation in an immunocompromised host. Certain evidence suggests that EBV productive infection
may play a primary role in the genesis of PTLD by generating virus particles which
can infect bystander B cells. In an immunocompromised individual, these infected B cells may then give rise to expanding B-cell clones. The project presented in this
thesis is part of a research program seeking to elucidate the role of EBV productive
infection in the genesis of PTLD. The specific aim of this work was to design a
chimeric monoclonal antibody against the EBV envelope glycoprotein gp350 in order to neutralize the virus, thereby preventing entry into B cells.
Our laboratory constructed a chimeric version of the murine monoclonal antibody,
72A1, which binds to gp350 and blocks infection. The initial cloning attempts
revealed the presence of nonfunctional (aberrant) transcripts in the hybridoma line
producing the 72A1 antibody. The chimeric version of the authentic light chain is
now completed while the chimeric heavy chain construction is ongoing. As part of the characterisation process for the chimeric antibody, a cell line stably expressing surface gp350 was generated. This gp350-expressing cell line will be used for
antibody dependent cellular cytotoxicity assays (ADCC).
This anti-gp350 chimeric antibody could be useful as a preventive therapy in transplant patients at high risk for PTLD by blocking the infection of bystander B cells.
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