Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Caractérisée par la présence de la mutation JAK2 V617F, la polyglobulie primitive voit son développement contenu par des saignées mais est associée à une incidence plus élevée de cancers. Une exploration globale de l'immunité des patients a été réalisée par la quantification des sous populations lymphocytaires de l'immunité innée et adaptative. Ceci a permis la mise en évidence d'une diminution des lymphocytes B et d'une augmentation des cellules NK. Les cellules NK sont réputées pour leurs propriétés antitumorales mais elles ne sont pourtant pas capables d'éradiquer la PV, posant la question de leurs capacités fonctionnelles. Si les cellules NK des patients présentent une activité cytotoxique basale inférieure aux témoins, elles ne présentent pas d'anomalies de l'expression de leurs récepteurs, de la production de molécules cytolytiques ou de prolifération. Par contre, les cellules NK d'un patient ayant développé une érythroleucémie ou des cellules NK de sujets âgés par rapport à des témoins plus jeunes présentent des anomalies d'expression des récepteurs. L'augmentation des cellules NK pourrait être liée à la mutation JAK2 V617F. Si cette mutation est présente dans les lymphocytes de tous les patients, il existe des arguments pour sa présence dans les cellules NK de certains patients. Enfin, une analyse transcriptomique a permis de définir un profil d'expression propre aux cellules NK des patients. / Characterized by the presence of the JAK2 V617F mutation, polycythemia vera's development is content by phlebotomy but is associated with a higher incidence of cancer. A global exploration of the immunity of patients was performed by quantification of lymphocyte subpopulations of innate and adaptive immunity. This allowed the detection of a decrease in B cells and an increase in NK cells. NK cells are known for their antitumor properties but they are not yet able to eradicate PV, raising the question of their functional abilities. If NK cells of patients have a lower basal cytotoxic activity than healthy donors, they do not show abnormal expression of their receptors, the production of cytolytic molecules or proliferation. On the contrary, NK cells from a patient who developed erythroleukemia or NK cells from elderly healthy donors compared with younger healthy donors exhibit abnormalities of receptors expression. The increase in NK cells could be related to the JAK2 V617F mutation. If the mutation is present in cells of all patients, there are arguments for its presence in the NK cells of some patients. Finally, transcriptome analysis has identified an expression profile specific to NK cells of patients.

No description available.

The British Museum holds one of the largest and most important collections of Late Antique gold glasses in the world, numbering over fifty pieces. However, the collection has never been fully examined or analysed and the standard reference works on the medium are well over 100 years old. This thesis uses the British Museum collection to offer a new and in-depth case study of gold glass which reconsiders the traditional but untested set of interpretations that have been in circulation since the mid-nineteenth century and before. Chapter One examines the history of gold glass scholarship from the late sixteenth century up until the present day. This serves to demonstrate where many of the frequently repeated assumptions regarding gold glass have their roots. Chapter Two gives a brief account of scholarship focusing on the British Museum collection. It then moves on to examine in detail the formation of the collection itself in the context of changing nineteenth-century attitudes to Late Antique art. Chapter Three for the first time defines the various sub-types of gold glass identifiable in the British Museum collection and incorporates a discussion of the first significant program of scientific analysis to be carried out on the medium. Chapter Four concentrates on the manufacture of gold glass and includes a detailed program of experimental reproduction. Chapters Five to Eight discuss in detail the range of iconography appearing on the gold glasses in the British Museum collection, reflective of the medium as a whole. Lastly, after examining the pattern of gold glass distribution and context, Chapter Nine draws together the preceding analysis to explore the possible workshop identity and chronology. The final Chapter concludes as to the function of gold glass in Late Antiquity.

No description available.

CD20 is a 35kDa surface antigen expressed on B cells from the early pre-B stage through the mature B stage. Moreover, the CD20 antigen is found on a majority of B cell malignancies. Rituximab is a chimeric anti-CD20 monoclonal antibody which has been extensively used alone or in combination in the treatment of CD20+ B cell malignancies including acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphomas (NHL) and chronic lymphocytic leukemia (CLL), as well as in the treatment of numerous autoimmune disorders. Despite its emerging use in the clinic, 30% to 50% of patients with low-grade NHL exhibit no clinical response to Rituximab. Previous work to elucidate the mechanisms of Rituximab resistance has established that antibody dependent cellular cytotoxicity (ADCC) is important as a predominant mechanism of lymphoma cell clearance and that Fcγ receptors (FcγRs) are critical for the in vivo actions of Rituximab in NHL. Natural killer group 2D, NKG2D is a major activating receptor on T lymphocytes and natural killer cells. The NKG2D–ligand (NKG2D-L) interaction triggers an activating signal which results in cytotoxic lysis of the cell expressing the ligand. One potential ligand for murine NKG2D is the retinoic acid early 1β (Rae-1β) protein which is expressed during cellular stress and has a high affinity for the NKG2D receptor in mice. We have recently shown that an anti-HER2-IgG3 fused to murine NKG2D Ligand, Rae1β inhibited HER2+ tumor growth significantly more than Herceptin alone. Similarly, our objective is to enhance the performance of anti-CD20 directed therapy through activation of NK cells by an anti-CD20 antibody encoding the same NK activation ligand. Previous results with anti-HER2-IgG3-Raelβ led us to hypothesize that a CD20 specific fusion protein will bind to CD20 expressing tumor cells and deliver an activation signal to local NKG2D receptors on effector cells triggering a non-FcγR dependent anti-tumor response. Here we show that anti-CD20-NKG2D-L can be synthesized and tested for its ability to bind human CD20 and activate NK cells through the NKG2D receptor in vitro.

Τα φυσικά φονικά κύτταρα (NK) αποτελούν περίπου το 10% των κυκλοφορούντων λεμφοκυττάρων και παίζουν σημαντικό ρόλο στην πρώτη γραμμή άμυνας του ανοσοποιητικού συστήματος. Έχουν την ικανότητα να αναγνωρίζουν καρκινικά και μολυσμένα κύτταρα, τα οποία μπορούν να θανατώνουν απελευθερώνοντας κυτταροτοξικά κοκκία και κυτταροκίνες. Σκοπός της παρούσας εργασίας ήταν η μελέτη της έκκριση IFN-γ και TNF-α, από τα περιφερικά μονοπύρηνα (PBMCs) και ΝΚ κύτταρα, έπειτα από διέγερση με Gram θετικά και Gram αρνητικά βακτήρια (αναλογία ΝΚ κύτταρα προς βακτήρια 10:1), παρουσία ή απουσία εξωγενούς IL-2. Μικρή παραγωγή IFN-γ παρατηρήθηκε μόνο στα PBMCs, με μεγαλύτερη συγκέντρωση στις 20 ώρες έπειτα από διέγερση με L.monocytogenes, ενώ δεν παρατηρήθηκε παραγωγή TNF-α. Ο λόγος ΝΚ κύτταρα: βακτήρια (10:1) που χρησιμοποιήθηκε, η έλλειψη βοηθητικών κυττάρων και ο μικρός χρόνος διέγερσης, πιθανώς να ήταν και οι αιτίες που δεν παρήχθησαν καθόλου κυτταροκίνες από τα ΝΚ κύτταρα, ενώ η χαμηλή παραγωγή IFN-γ από τα PBMCs, πιθανώς να οφείλεται, είτε στην παραγωγή IL-10 από τα μακροφάγα είτε στο ότι το ερέθισμα διέγερσης δεν ήταν αρκετό, ώστε να ενεργοποιηθούν πλήρως. Περαιτέρω μελέτες χρειάζονται για την πλήρη κατανόηση της έκκρισης των κυτταροκινών από τα ΝΚ κύτταρα, παρουσία παθογόνων και δυνητικά παθογόνων μικροοργανισμών. / Natural killer (NK) cells comprise about 10% of all circulating lymphocytes and play crucial role to innate immune responses. NK cells can recognize tumor or infected cells and kill them by the release of cytotoxic molecules and cytokines. The aim of the study was to identify IFN-γ and TNF-α production from peripheral blood mononuclear cells (PBMCs) and purified ΝΚ cells, after stimulation with Gram positive and Gram negative bacteria (in ratio 10 NK:1 bacteria), in the presence or the absence of exogenous IL-2. Only PBMCs produced IFN-γ, with greater amounts after 20 hours stimulation with L.monocytogenes, while no production of TNF-α was observed. The low ratio, the absence of accessory cells and the short time of stimulation, probably, were responsible for the fact that no cytokine were produced from NK cells, whereas the low production of IFN-γ from PBMCs was, probably, due to the production of IL-10 from macrophages Alternatively, it is possible that the ratio and the time points were not enough for the full stimulation of PBMCs. Additional studies are needed to demonstrate the NK cytokine profile pattern, in the presence of pathogens and potential pathogen microorganisms.

The core themes in Thai art have traditionally been didactic Buddhist ethical works and popular folkloric beliefs. Both are permeated with a cosmology and worldview that is supernatural but which is pervaded with ethical implications for people’s daily lives. Buddhist art aims to encourage selfless acts for the good of others, including other individuals, society, the country and the natural world. Such abstract themes have been rendered accessible to ordinary people by means of fantastical creatures and supernatural myths that insinuate moral values and demonstrate a coherent Theravada worldview that is uniquely Thai. This thesis explores the popular manifestations of such phenomena at the intersection of traditional folk beliefs and practices, popular entertainment, Thai official/ royal high culture and confessional Buddhist ethical instruction by analysing the art forms associated with temple fairgrounds at major festivals. Based on a review of related literature and analysis of Thai artists, it concludes that the renaissance of traditional Thai culture is reciprocal with authentic grassroots activities such as temple fairs fostered and supported by traditional patronage and cultural resources from the royal court culture and Buddhist ethics. Based on this analysis, my own work offers a modern rendering in the spirit of traditional forms utilising modern multimedia methods to create an immersive and interactive artistic experience.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2015-05-15T15:30:01Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese VALE RIA versão digital - 13-04-2015.pdf: 1990902 bytes, checksum: 9eeb1d5ff93da209400b4799b7ddd5f0 (MD5) / Made available in DSpace on 2015-05-15T15:30:01Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese VALE RIA versão digital - 13-04-2015.pdf: 1990902 bytes, checksum: 9eeb1d5ff93da209400b4799b7ddd5f0 (MD5) Previous issue date: 2014-08-28 / A infecção pelo vírus da imunodeficiência humana (HIV) compromete progressivamente o sistema imunológico, levando a depleção das células T CD4+ e suas funções, caracterizando a síndrome da imunodeficiência adquirida (AIDS). A resposta inata é determinante para estabelecer um estado antiviral, que mantém o equilíbrio entre o vírus e o hospedeiro. Os interferons tipo III também chamados de interferons lambda (IFN-λ1 ou IL-29; IFN-λ2 ou IL-28a; IFN-λ3 ou IL-28b), assim como, as Células Natural Killer (NK), são componentes da imunidade inata que desenvolvem papéis importantes no controle da replicação viral. O polimorfismo de único nucleotídeo (SNP) no gene IFNL3 que codifica o IFN-λ3 mostrou uma forte associação com cura espontânea e sucesso na resposta ao tratamento na infecção pelo HCV. Entretanto, a influência do polimorfismo no IFNL3 na resposta ao tratamento para HIV é controversa. Visando investigar associação entre SNP no IFNL3 com a resposta ao tratamento para HIV, assim como seu efeito nos marcadores de superfície de células NK foram realizados respectivamente dois estudos resultando em dois artigos intitulados: ―Genótipos CC/CT do IFNL3 rs12979860 como marcadores genéticos na resposta imunológica e virológica à TARV em pacientes brasileiros infectados com HIV”, realizado em uma amostra constituída por 266 pessoas vivendo com HIV/AIDS, submetidas à TARV por 12 meses e atendidas no Hospital Correia Picanço (HCP), sendo 30 não respondedores a TARV, e 236 respondedores imunológico e/ou virológico apresentando aumento de T CD4+ e carga viral indetectável. Em um modelo de regressão logística multivariada os genótipos CC/CT rs12979860 do IFNL3 (p= 0,027 OR 2,52 IC 1,02-6,21) e níveis baixos de T CD4+ (p= 0,002 OR 0,997 IC 0,995-0,999, respectivamente) antes da terapia foram independentemente associados à resposta virológica e imunológica a TARV. Dessa maneira, a presença dos genótipos CC/CT rs12979860 no IFNL3 foram associados a um efeito positivo para a resposta imunológica e virológica a TARV, o que pode ser explorado como um possível marcador genético de resposta considerando o período de 12 meses. No segundo artigo, Associação do polimorfismo do gene do IFNL3 e aumento da expressão de CD69 em células NK de pessoas vivendo com HIV sem TARV, foi explorada a hipótese de que os genótipos CC/CT estariam relacionados com uma maior ativação das células NK. Desta forma, o estudo foi constituído por 25 pessoas vivendo com HIV (PVHA) sem TARV, atendidas no HCP, e por 25 indivíduos sem HIV (controle), atendidas no Centro de Testagem e Aconselhamento (CTA), localizado na cidade do Cabo, PE, onde foi comparada a diferença do número da população de células NK e marcadores de ativação entre esses grupos. Os resultados mostraram um aumento da subpopulação NK CD56+CD16- e diminuição de NK CD56+CD16+ (p < 0.001), assim como aumento dos marcadores HLA-DR e CD38 em ambas subpopulações em PVHA quando comparados com o controle. Quanto ao polimorfismo do IFNL3 e a ativação de NK, foi observada uma relação entre a expressão de CD69 e os genótipos CC/CT, porém os marcadores HLA-DR e CD38 não mostraram diferenças de expressão em relação a essa SNP. Em conclusão, o presente estudo mostra evidências que apoiam a influência do polimorfismo do IFNL3 na resposta ao tratamento do HIV e na ativação de células NK em PVHA.

Made available in DSpace on 2018-08-01T21:35:47Z (GMT). No. of bitstreams: 1 tese_12379_Tese - COVRE L.P. 2018.pdf: 30345373 bytes, checksum: ec3dc8e879b3ba71ae62497eaf04c63e (MD5) Previous issue date: 2018-05-28 / As células natural killer (NK) são fundamentais na resposta imune inata. As funções dessas células são reguladas pela sinalização de receptores de ativação ou inibição. Durante seu desenvolvimento, as células NK podem sofrer uma diferenciação terminal progressiva, que está associada a modificações fenotípicas e deficiências funcionais. Neste trabalho, descrevemos aspectos relacionados a estas características decorrentes do envelhecimento ou induzidas durante a leishmaniose cutânea localizada causada por Leishmania braziliensis. Demonstramos que indivíduos idosos apresentaram um aumento na população de células NK expressando alta frequência do receptor inibitório KLRG1. Essas células possuem perfil de diferenciação terminal e ativam espontaneamente o sensor metabólico denominado proteína quinase ativada por AMP (AMPK). O estímulo através do receptor KLRG1 foi capaz de aumentar a fosforilação de AMPK, impedindo a desfosforilação dessa quinase mediada por PP2C. Além disso, a ativação de AMPK suprimiu a citotoxicidade, a produção de granzima B e de IFN-&#947; nas células NK. Células com a via KLRG1-AMPK ativa apresentaram reduções da capacidade proliferativa, da expressão da subunidade catalítica da telomerase (TERT) e no comprimento dos telômeros, bem como aumento do dano ao DNA. Todos esses fatores são associados a redução no crescimento celular e ao fenótipo de imunosenescência adquirido durante o envelhecimento. Da mesma forma, pacientes com leishmaniose cutânea localizada demonstraram um aumento do fenótipo maduro de células NK, com expansão da subpopulação CD56dim. Além disso, foram observados a diminuição dos marcadores imaturos NKG2A, CD161 e CD27, seguidos pelo aumento na expressão dos receptores NKG2C, KIR (CD158a) e acúmulo de células terminalmente diferenciadas caracterizadas como KLRG1bright e CD57bright. Células NK de pacientes com LCL apresentaram aumento da citotoxicidade, produção de granzima B e de citocinas inflamatórias quando comparadas com controles saudáveis. No entanto, também apresentaram uma baixa capacidade proliferativa, associada à presença de células KLRG1bright e CD57bright e encurtamento significativo dos telômeros quando comparado aos controles saudáveis. Juntos, nossos dados demonstram que o envelhecimento e a infecção causada por Leishmania podem afetar o fenótipo e a função de células NK, levando ao acúmulo de células terminalmente diferenciadas. Assim, a elucidação dos mecanismos que levam a esse comprometimento, como a via KLRG1 / AMPK, podem ser futuramente explorados como forma de retardar ou mesmo reverter as deficiências observadas nestas populações. Além disso, a identificação desses fatores pode ter implicações importantes para o desenvolvimento de estratégias terapêuticas, que irão auxiliar no processo de maturação funcional de células NK e aprimorar a resposta imunológica durante infecções e câncer.