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Lat est clé dans le développement des cellules T. En l'absence de Lat, le développement des cellules T au niveau du thymus est complètement bloqué au stade DN3. Le développement des lymphocytes T est très diminué dans des souris knockin LatY136F dans lesquelles la tyrosine présente en position 136 de la protéine Lat est remplacée par une phénylalanine. De manière paradoxale, le petit nombre de cellules T qui émergent dans la périphérie des souris LatY136F donnent naissance à un syndrome lymphoprolifératif Th2 sévère. Ce projet vise à identifier les facteurs génétiques qui contribuent au développement d'un tel syndrome lymphoprolifératif. A la suite d'un crible génétique basée sur une mutagenèse à l'ENU (N-éthyl-N-nitrosurea), des lignées de souris mutantes LatY136F présentant une pathologie atténuée ou exacerbée ont été fixées et les mutations induites chimiquement ont été cartographiées et identifiées. En particulier, nous avons obtenu une lignée mutante appelée Basilic dépourvue du syndrome lymphoprolifératif. Le clonage positionnel assisté par les techniques de séquençage à haut-débit de l'ADN ont permis l'identification d'un gène appelé, Rltpr ou Lrrc16c, et ne possédant aucune fonction immunologique connue. Nous avons montré que Rltpr constitue un élément clé de la voie de signalisation opérée par la molécule de costimulation CD28. Les résultats principaux obtenus au cours de la thèse sont présentés sous forme d'un article publié. Un chapitre de perspective est consacré ensuite aux améliorations que nous pourrions apporter au type d'approche que nous avons réalisé. Enfin une dernière rubrique traite des outils permettant la manipulation du génome de la souris. / Lat is essential for proper T cell development. In the absence of Lat, intra thymic T cell development is completely blocked at an early stage known as the DN3 stage. LatY136F mice in which the tyrosine found at position 136 of Lat was replaced by a phenylalanine, also showed an impaired sequence of intrathymic T cell development. Paradoxically, the small number of improperly selected T cells that reach the periphery of LatY136F mice expand in an uncontrolled manner and trigger a severe Th2 lymphoproliferative disorder. The present thesis project aimed at identifying genetic factors contributing to the development of such a lymphoproliferative disorder. Using a sensitized ENU mutagenesis screen, we identified and characterized mutations that dampened or exacerbated the LatY136F pathology. A mutation that is called Basilic and that acts in a T cell intrinsic manner and completely prevented the LatY136F lymphoproliferative disorder was characterized in a comprehensive manner. Positional cloning assisted by next generation DNA sequencing demonstrated that Basilic corresponds to a mutation in a gene called Rltpr or Lrrc16c, the function of which was previously completely unknown in the frame of the immune system. Further functional studies performed during this project showed that Rltpr corresponded to a “missing link” involved in the signaling cascade that mediates the function of the co-stimulatory molecule CD28. Consistent with that view, nullozygous Cd28 mutant mice were found to be a phenocopy of the Basilic mice and as such prevented lymphoproliferative disorder in LatY136F mice. The Basilic mutation also resulted in a defect in regulatory T cell development.

Significant benzene exposure has historically been associated with the development of a host of hematological disorders in humans and animals. In particular, benzene is known to cause disturbances of the peripheral blood, aplastic anemia and cancer of the lymphohematopoietic system. In 1928, the first modern report of an association between cancer and benzene exposure was published. This case report was followed by additional reports from around the world. In most instances, ailments resulted from long term, high level exposure to benzene found in glues, and through accidental industrial spills. Throughout the 1960's and 1970's, case reports accumulated linking benzene exposure to hematological cancers, particularly among leather workers in Turkey and Italy. At the time, only qualitative measures of benzene exposure were often available and most exposure information was based upon short term grab samples and subjective symptoms. However, this situation changed drastically in the mid-1970s, when the first report was published on a little known industry that manufactured rubber hydrochloride, also known as Pliofilm. This clear film product was made from natural rubber latex and processing utilized benzene in multiple stages. It appeared from the outset that there were an unusually large number of acute leukemia cases in this cohort of workers. Since that time, multiple follow-up evaluations of the same cohort have attempted to refine the benzene exposure of these workers. Benzene has subsequently been classified as a human carcinogen by several regulatory bodies and the allowable 8 hour time-weighted average has been lowered to 1 ppm. In pursuing the goal of protecting workers, regulatory bodies utilize a linear extrapolation, or no threshold dose, approach to cancer causation. This methodology assumes that every exposure brings an incremental rise in risk. In this work, the linear extrapolation methodology is tested utilizing the criteria proposed by Sir Bradford Hill. The Hill Criteria are used to critically evaluate the weight of evidence for a threshold dose that can cause hematological cancer in humans following benzene exposure. This evaluation revealed that there is sufficient evidence for a threshold dose and that linear extrapolation is designed to protect, not predict disease.

Aims: To explore the clinical significance of EBV infection in adult renal transplant recipients when detected in the late post-transplant period. Methods: (1) A prospective observational study recruiting 499 stable adult kidney transplant recipients with serial blood sampling for EBV DNAemia and assessment of clinical outcomes and associated factors. (2) A retrospective analysis of PTLD incidence, timing and outcomes in relation to EBV infection. Results: EBV DNAemia in stable kidney transplant recipients is common, found in 46% of recruited individuals screened over 1 year, with persistent DNAemia seen in 10%. DNAemia prevalence increased significantly with time from transplant (p<0.0001) from 16% within 1 year of transplant to 66% in those transplanted for 20-24 years. High baseline DNA levels predicted persistence of DNAemia. Time adjusted analyses showed significant association of DNAemia with EBV seronegative status and previous PTLD and low DNAemia rates with Mycophenolate Mofetil (MMF) use and lymphopenia. The mechanism did not appear to be directly linked to MMF induced B cell depletion. Chronic high viral load detection was significantly associated with time from transplant, EBV seronegative status at transplant, ciclosporin use and plasma detection of DNA. No significant differences in overall patient survival at 3 years, clinical symptoms or clinical findings such as anaemia, thrombocytopenia or rate of decline in renal function were seen between stable transplant recipients with and without EBV DNAemia. PTLD incidence also increases with time from transplant and was greatest during the 10th-14th post-transplant years. Disease was EBV positive in 68% cases. No statistically significant differences in overall patient survival, or overall disease complete response rates were seen in relation to recipient EBV serostatus or EBV status of PTLD histology. Conclusions: EBV DNAemia prevalence increases with time from transplant but was not associated with worse patient or graft survival or specific symptoms. PTLD incidence including EBV negative disease also increases with time from transplant but response rates and survival were not influenced by EBV serostatus or histological status.

Le développement de bactéries sous la forme de communautés multicellulaires, appelées biofilms, engendre la formation d’un environnement très hétérogène dans lequel les bactéries sont confrontées à différents stress nécessitant un rapide réajustement de leur métabolisme et de leur physiologie. Cette capacité d’adaptation ainsi que des études transcriptomiques, suggèrent fortement que les bactéries vivant sous forme de biofilm puissent présenter des propriétés nouvelles en comparaison à des bactéries planctoniques. Cela nous a conduit à examiner si la formation de biofilm chez Escherichia coli pouvait engendrer des modifications originales de l’enveloppe bactérienne. Nous avons tout d’abord comparé la structure du lipopolysaccharide de bactéries issues de cultures planctoniques et biofilms et mis en évidence que la formation de biofilm chez les bactéries à Gram négatif entraine une augmentation du niveau de palmitoylation du lipide A dépendante de l’enzyme PagP et contribuant à la tolérance des bactéries aux agents antimicrobiens. L’étude des mécanismes sous-jacents a permis de déterminer que cette augmentation du niveau de palmitoylation est, en partie, causée par une induction de l’expression de pagP qui est spécifique au biofilm et regulée par RcsB en réponse à l’osmolarité du biofilm. Nous avons également étudié l’impact de l’adaptation des bactéries au mode de vie biofilm sur la structure de la paroi bactérienne et mis en évidence des différences dans les ponts inter peptidiques présents au sein du peptidoglycane qui pourraient conduire à une augmentation de la rigidité de l’enveloppe bactérienne ainsi qu’à la résistance au stress chez les bactéries. Pour finir, nous avons examiné si les protéines SPFH (QmcA HflK HflC YqiK) associées à des microrégions spécialisées de la membrane -ou radeaux lipidiques- pouvaient jouer un rôle dans la formation de biofilm chez E. coli. Alors que les gènes codant pour ces protéines ne semblent pas être induits en biofilm ni être essentiels à son développement, nous avons identifié plusieurs régulateurs influençant leur expression ainsi que plusieurs fonctions associées aux protéines SPFH que nous sommes en train d’étudier. / The development of bacterial multicellular communities, called biofilms, creates a highly heterogeneous environment, in which bacteria subjected to various stresses need to quickly readjust their metabolism and physiology. This capacity of adaptation, confirmed by many transcriptome analyses, strongly suggest that biofilm bacteria could display novel properties compared to individualized cells. This prompted us to investigate whether biofilm formation could trigger original membrane modifications in Escherichia coli. We first compared the lipopolysaccharide structure of planktonic and biofilm bacteria and demonstrated that biofilms formed by Gram-negative bacteria undergo an increase in lipid A palmitoylation mediated by the PagP enzyme and contributing to bacterial resistance to antimicrobial peptides and host immune defenses. Investigation of the underlying mechanisms of this phenomenon allowed determining that increased lipid A palmitoylation is, at least partially, due to a biofilm-specific and RcsB-dependent induction of pagP expression in response to biofilm osmolarity. We also investigated how bacterial adaptation to the biofilm environment could impact the cell wall structure and identified differences in peptidoglycan linkages that could increase cell rigidity and bacterial resistance to stress. Finally, we investigated the potential role in biofilm formation of E. coli SPFH proteins (QmcA HflK HflC YqiK) associated with dynamic membrane microdomains - or lipid rafts-. Whereas SPFH encoding genes are not differentially expressed in biofilm and are not essential for biofilm formation, we identified several regulators impacting their expression and several functions associated to SPFH proteins that we identified is currently under investigation.

Risk of skin cancer and lymphoproliferative diseases in patients after kidney transplantation Author: Kristína Sidorová Tutor: doc. PharmDr. Josef Malý, Ph.D. Consultant: Mgr. Barbora Vaňková Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Introduction and aims: Organ transplantations (Tx) are associated with the lifelong use of immunosuppressive therapy (IS), which carries with it, among other risks, an increased incidence of malignancies. The most common malignancies after Tx are skin tumors, post-transplant lymphoproliferative diseases (PTLD) are also more common in transplant patients. The aim of the study was to determine the incidence of skin tumors and PTLD in patients with kidney Tx within one transplant center and to analyze the risk factors associated with these diseases. Methods: Retrospective longitudinal study was conduted in the Teaching Hospital Hradec Králové. The study included patients from the age of 18 who had overcome kidney Tx until 24 April 2019, were registered in a transplant clinic in Hradec Králové and had a medical record in the hospital information system. Data collection from medical records took place from 15 April 2019 to 31 December 2019. Collected data included demographic characteristics, family history,...

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 5 uppsatser.

Made available in DSpace on 2014-12-17T14:14:03Z (GMT). No. of bitstreams: 1 AldairSP_DISSERT.pdf: 3401140 bytes, checksum: 29fad07626595e61c30bdf3a90539133 (MD5) Previous issue date: 2014-02-26 / Chronic lymphoproliferative disorders (DLPC) are lymphoid system diseases characterized by the abnormal proliferation of mature lymphocytes that affect B cells, T lymphocytes and NK cells. The aim of the study was to demonstrate the relevance of immunophenotyping by flow cytometry in patients with prolonged lymphocytosis and / or cytomorphological changes compatible with lymphoproliferative diseases. In this study 460 patients (244 men and 216 women) with DLPC were evaluated. Were analyzed by flow cytometry with a panel of monoclonal antibodies consisting of CD3, CD4, CD5, CD8, CD10, CD19, CD22, CD23, CD25, CD38, CD45, CD16/CD56, and HLADR heavy and light chains of immunoglobulins. It also examines information regarding age, gender of patients and laboratory data as leucocytes, cytomorphological analysis, platelet count and hemoglobin determination. The results showed 398 cases of chronic lymphoproliferative disorders and 62 of DLPC B cell lymphoproliferative diseases T. B showed the following distribution : 253 cases of chronic lymphocytic leukemia (CLL), 42 cases of multiple myeloma ( MM ), 37 cases of lymphoma non - Hodgkin lymphoma in leukemic phase (NHL) , 17 cases of pro- B lymphocytic leukemia ( B -PLL), 15 cases of mantle cell lymphoma (MCL ), 12 cases of plasma cell leukemia ( PCL), 9 cases of lymphoma Burkitt (Linf B), 8 cases of leukemia villous cells ( LCV), 3 cases of splenic lymphoma with villous cells (LECV), a case of follicular lymphoma (LF) and a Waldenstr?n macroglobulinemia ( MW). The diseases source NK / T were 23 cases of peripheral T cell lymphoma (LCTP), 14 cases of T prolymphocytic leukemia (T -PLL), 10 cases of leukemia T of large granular lymphocytes (LGL -T) 9 cases of leukemia cells of adult T (LCTA), 5 cases of Sezary syndrome (SS) and a case of large granular NK leukemia (LGL -NK) lymphocytes. In conclusion, the combined use of the monoclonal antibody panel careful cytomorphological analysis was shown to be essential in immune diagnosis and classification of chronic lymphoproliferative disorders. This study was approved by the IRB - HUOL under number 356 / 09 / Os transtornos linfoproliferativos cr?nicos (DLPC) s?o doen?as do sistema linfoide caracterizadas pela prolifera??o anormal de linf?citos maduros que acometem c?lulas B, linf?citos T e c?lulas NK. O objetivo do estudo foi demonstrar a relev?ncia da imunofenotipagem por citometria de fluxo em pacientes portadores de linfocitose prolongada e/ou altera??es citomorfol?gicas compat?veis com doen?as linfoproliferativas. Neste estudo foram avaliados 460 pacientes (244 homens e 216 mulheres) com DLPC. Foram analisados por citometria de fluxo com um painel de anticorpos monoclonais constitu?do por CD3, CD4, CD5, CD8, CD10, CD19, CD22, CD23, CD25, CD38, CD45, CD16/CD56, HLADR e cadeias leves e pesadas de imunoglobulinas. Foram tamb?m investigadas informa??es referentes ? idade, ao g?nero dos pacientes e aos dados laboratoriais como: leucometria, an?lise citomorfol?gica, contagem de plaquetas e determina??o da hemoglobina. Os resultados demonstraram 398 casos de doen?as linfoproliferativas cr?nicas B e 62 de DLPC de c?lula T. As doen?as linfoproliferativas B apresentaram a seguinte distribui??o: 253 casos de leucemia linfoc?tica cr?nica (LLC), 42 casos de mieloma m?ltiplo (MM), 37 casos de linfoma n?o Hodgkin em fase leuc?mica (LNH), 17 casos de leucemia pr?-linfoc?tica B (LPL-B), 15 casos de linfoma de c?lulas do manto (LCM), 12 casos de leucemia de c?lulas plasm?ticas (LCP), 9 casos de linfoma de Burkitt (Linf B), 8 casos de leucemia de c?lulas vilosas (LCV), 3 casos de linfoma espl?nico de c?lulas vilosas (LECV), um caso de linfoma folicular (LF) e um de macroglobulinemia de Waldenstr?n (MW). As doen?as de origem T/NK foram: 23 casos de linfoma de c?lulas T perif?ricas (LCTP), 14 casos de leucemia pr?linfoc?tica T (LPL-T), 10 casos de leucemia de grandes linf?citos T granulares (LGLT), 9 casos de leucemia de c?lulas T do adulto (LCTA), 5 casos de S?ndrome de Sezary (SS) e um caso de leucemia de grandes linf?citos NK granulares (LGL-NK). Em conclus?o, o uso do painel de anticorpos monoclonais combinado ? an?lise citomorfol?gica cuidadosa mostrou-se essencial no diagn?stico e classifica??o imune das doen?as linfoproliferativas cr?nicas. O presente estudo foi aprovado pelo CEP HUOL sob n?mero 356/09

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23421号 / 医博第4766号 / 新制||医||1053(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小濱 和貴, 教授 妹尾 浩, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Nas últimas décadas, verificou-se diferenças nas classificações da World Health Organization (WHO) de 2001 e da European Organization for Research and Treatment of Cancer (EORTC) de 1997 para os linfomas cutâneos primários. Em 2005, representantes dessas classificações se reuniram e em consenso estabeleceram a classificação WHO-EORTC que foi adotada pela última classificação da WHO de 2008. O presente estudo visa a avaliar a aplicabilidade dessa nova classificação em casuística retrospectiva de um único centro de referência no diagnóstico e tratamento de linfomas cutâneos. Assim, todos os casos de linfoma cutâneo de células T, excluindo-se micose fungóide (MF) e síndrome de Sézary (SS), no período de 1986 a 2009, foram analisados em relação aos aspectos clínicos, histopatológicos e imunofenotípicos, incluindo-se a realização de novas reações imunoistoquímicas. Os casos foram, então, classificados de acordo com critérios estabelecidos na classificação WHO de 2008. Houve, assim, 33 casos de linfomas cutâneos de células T não-MF e não-SS, sendo 08 (24,2%) de linfoma cutâneo de grandes células anaplásicas, 05 (15,2%) de papulose linfomatóide, 06 (18,1%) de linfoma extranodal de células NK/T tipo nasal, 05 (15,2%) de neoplasia de células dendríticas plasmocitóides blásticas, 05 (15,2%) de linfoma/leucemia de células T do adulto e 04 (12,1%) de linfoma de células T periféricas, sem outra especificação. Portanto, a classificação WHO de 2008 é aplicável à maioria dos casos de linfoma cutâneo de células T não-MF e não-SS. Entretanto, permanecem casos não classificáveis, alguns dos quais com curso clínico agressivo / Recent years have witnessed differences between the World Health Organization (WHO) 2001 and the European Organization for Research and Treatment of Cancer (EORTC) 1997 classification systems of primary cutaneous lymphomas (PCLs). In 2005, a joint WHO-EORTC classification system for PCLs has been reached and was adopted by last WHO 2008 classification. This study was performed to assess the applicability of this new classification to a single referral center. All cutaneous T-cell lymphoma (CTCL) cases, excluding mycosis fungoides (MF) and Sezary syndrome (SS), who were referred from 1986 to 2009 were included. The clinical features, histological and immunohistochemical stainings were reviewed, and additional stains were performed as needed. The cases were then reclassified according to the WHO 2008 classification. There were 33 cases of non-MF and non-SS CTCL, included 08 (24.2%) CD30+ anaplastic large-cell lymphomas, 05 (15.2%) cases of lymphomatoid papulosis, 06 (18.1%) extranodal NK/T-cell lymphoma nasal type, 05 (15.2%) blastic plasmacytoid dendritic cell neoplasm, 05 (15.2%) adult T-cell lymphoma/leukemia and 04 (12.1%) peripheral T-cell lymphomas, unspecified. The new WHO 2008 classification is applicable to most nonMF and non-SS CTCL cases. However, there is still a substantial subset of T-cell PCLs which cannot be classified beyond the unspecified peripheral T-cell category, some of which may have an aggressive course