Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Lund, 1994. / Published dissertation. Includes bibliographical references.

Thesis (Ph. D.)--University of Lund, 1994. / Published dissertation. Includes bibliographical references.

La prédiction du devenir du greffon et de sa survie permettrait d’optimiser la prise en charge des patients transplantés. Le suivi des patients transplantés rénaux inclue des mesures répétées de marqueurs longitudinaux tels que la créatinine sérique et l’exposition aux médicaments immunosuppresseurs. L’approche statistique récemment proposée des modèles conjoints permet d’analyser la relation entre un processus longitudinal et la survenue d’un événement clinique. Dans la première partie de ce travail de thèse, nous avons utilisé les modèles conjoints à classes latentes pour étudier l’impact du profil de créatinine sérique au cours des 18 premiers mois post-greffe sur la survie du greffon à long terme. Dans la cohorte étudiée, trois groupes homogènes caractérisés par une trajectoire spécifique de l’évolution de la créatinine sérique en fonction du temps et un risque d’échec de greffe spécifique ont été identifiés. Les probabilités individuelles de l’échec de greffe pendant les 10 premières années post-transplantation ont été calculées sur la base du modèle conjoint développé. Chez les patients qui n’avaient pas développé d’anticorps anti-HLA spécifiques du donneur, le risque d’échec de greffe en fonction du temps était prédit avec un niveau de performance satisfaisant en termes de spécificité, sensibilité et précision.L’utilité clinique de cet outil devra être évaluée avec une approche dynamique. Dans une seconde partie, les modèles non linéaires à effets mixtes combinés avec l’approche des modèles de mélange a été utilisée pour analyser (i) l’association entre la variabilité de l’exposition au tacrolimus au cours du temps et l’adhésion au traitement rapportée par le patient et (ii) l’impact de cette variabilité d’exposition sur le risque de rejet aigu. Ce modèle a montré un effet significatif de la variabilité de l’exposition au cours du temps du tacrolimus sur la survenu de rejet aigu au-delà de 3 mois post-transplantation. Au contraire, aucune association entre l’adhésion et la variabilité de l’exposition au tacrolimus d’une part, et le risque de rejet aigu d’autre part n’a été observée dans cette étude qui n’incluait que des patients modérément non-adhérents. Ce résultat pose la question de l’impact d’une non adhésion modérée sur le devenir du greffon. / Prediction of graft outcome would be useful to optimize patient care. Follow-up of kidneytransplant patients include repeated measurements of longitudinal markers, such as serum creatinine and immunosuppressive drug exposure. Recently proposed joint models areappropriate to analyze relationship between longitudinal processes and time-to-event data. In the first part of present work, we used the approach of joint latent class mixed models tostudy the impact of time-profiles of serum creatinine collected within the first 18 months after kidney transplantation on long-term graft survival. The studied cohort was parted into three homogenous classes with a specific time-evolution of serum creatinine and a specific risk of graft failure. The individual predicted probabilities of graft failure up to 10 years posttransplantation, calculated from this joint model were satisfying in terms of sensitivity, specificity and overall accuracy, for patients who had not developed de novo donor specificanti-HLA antibodies. The clinical usefulness of developed predictive tooI needs to beevaluated with a dynamic approach. In the second part, non-linear mixed effects models witha mixture of distribution for random effects were used to investigate (i) the associationbetween variability over time of tacrolimus exposure and self-reported drug adherence and(ii) the impact of this variability on the acute rejection risk. This model found a significantimpact of tacrolimus time-exposure variability on acute rejection onset beyond 3 months posttransplantation. On the contrary, no association between adherence and (i) variability oftacrolimus time-exposure and (ii) acute rejection was observed in our study which included moderate non-adherent patients only. This result questions the impact of moderate nonadherence on graft outcome.

NOD mice model human type 1 diabetes and have been used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. Costimulation blockade-based tolerance protocols that induce prolonged skin and permanent islet allograft survival in non-autoimmune mice have failed in NOD mice. To investigate the underlying mechanisms, we generated NOD hematopoietic chimeras. We were able to show that dendritic cell maturation defects seen in NOD mice are partially corrected in mixed hematopoietic chimeras. Furthermore, skin allograft survival was dependent upon the phenotype of the bone marrow donor, demonstrating that in the NOD the resistance to tolerance induction resides in the hematopoietic compartment. In addition, we studied congenic NOD mice bearing insulin dependent diabetes (Idd) loci that reduce diabetes incidence. The incidence of diabetes is reduced in NOD.B6 Idd3 mice, and virtually absent in NOD.B6 Idd3Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice is prolonged as compared to NOD mice, and in NOD.B6 Idd3Idd5 mice islet allograft survival is similar to that achieved in C57BL/6 mice. Alloreactive CD8 T cell depletion in NOD mice treated with costimulation blockade is impaired, but is partially restored in NOD.B6 Idd3 mice, and completely restored in NOD.B6 Idd3Idd5 mice. Idd3 results from variations in Il2 gene transcription. We hypothesized insufficient levels of IL-2 in NOD mice contributes to impaired deletion of alloreactive CD8 T cells and shortened islet allograft survival. We observed using synchimeric mice that co-administration of exogenous IL-2 to NOD mice treated with costimulation blockade led to deletion of alloreactive CD8 T cells comparable to that in C57BL/6 mice and prolonged islet allograft survival. However, some Idd loci impaired the induction of transplantation tolerance. These data suggest that Idd loci can facilitate or impair induction of transplantation tolerance by costimulation blockade, and that Idd3 (IL-2) is critical component in this process.

Contexte : Le virus Torque Teno (TTV) est un petit virus à ADN fortement prévalent dont la réplication est étroitement liée à l'état immunitaire. Un nombre croissant de publications soulignent le potentiel de la charge virale du TTV en tant qu'indicateur d'immunosuppression chez les patients transplantés. Des tests cliniques sont nécessaires pour caractériser davantage son potentiel en tant que marqueur d'immunosuppression.Objectifs : Présentation de la faisabilité/optimisation et démonstration des performances analytiques et cliniques du premier test standardisé utilisé pour détecter et quantifier l'ADN du TTV humain dans le sang total et le plasma de diverses populations. La charge virale du TTV a été analysée sur des échantillons de sang total prélevés chez 31 volontaires sains, chez 53 donneurs de reins décédés et cours du suivi de 42 receveurs d’une greffe de rein.Résultats : La limite de détection de la trousse développée était de 2,2 log10 copies/ml dans le sang total et le plasma, la linéarité et la précision ont été démontrées entre 1,61 et 10,61 log10 copies/ml dans le sang total. La prévalence de l'ADN du TTV dans le sang variait significativement entre les groupes : 45% chez les volontaires sains, 74% chez les donneurs et 83% chez les receveurs de rein. Chez les receveurs de rein, les cinétiques TTV précoces étaient comparables à celles précédemment présentées dans la littérature (dans d'autres contextes de transplantation) : la charge virale est passée d'une moyenne de 4,3 log10 à 7,9 log10 copies/mL dans les 75 premiers jours post transplantation. L’analyse des séquences de TTV par séquençage haut débit nous a permis de décrire la prévalence des génotypes de TTV chez 20 donneur et receveurs appariés.Conclusion : Ce test TTV a montré une sensibilité analytique, une spécificité, une linéarité et une précision élevée. Avec ce test, la cinétique précoce chez les receveurs de rein est proche de celle précédemment décrite chez les receveurs de greffe de poumon. C'est un outil standardisé utile pour évaluer davantage la charge de TTV en tant que biomarqueur de l'état immunitaire qui pourrait améliorer la stratégie de traitement individuel. / Background: Torque teno viruses (TTV) are small DNA viruses with high prevalence whose replication is closely linked to immune status. A growing number of publications underlined the potential of TTV viral load as an indicator of immunosuppression. Clinical assays are necessary to further characterize their potential as immunosuppression markers.Objectives: To demonstrate the performance of the first standardized Research Use Only assay to detect and quantify human TTV DNA in whole blood and plasma.Study design: We established analytical and clinical performances for TTV load measurement in various populations. The TTV kinetics were followed in kidney recipients. TTV viral load was analyzed on whole blood samples from 31 healthy volunteers, 53 kidney deceased donors and 42 kidney recipients follow-up.Results: Limit of detection was 2.2 log copies/mL in whole blood and plasma, linearity and precision were demonstrated over the range 1.61 to 10.61 log10 copies/mL in whole blood. Prevalence of TTV DNA in blood differed significantly among groups: 45% in healthy volunteers, 74% in donors and 86% in kidney recipients. In kidney recipients, early TTV kinetics were comparable to those previously observed with in-house assays in other transplant settings: viral load increased from an average of 4.3 log10 to 7.9 log10 copies/mL within the first 75 days post transplantation. Sequence analysis of TTV by high throughput sequencing allowed us to describe the prevalence of TTV genotypes in 20 matched donors and recipients.Conclusion: This TTV assay showed high analytical sensitivity, specificity, linearity and precision. With this assay, early kinetics in kidney recipients are close to that previously described in lung transplant recipients. It is a useful standardized tool to further evaluate TTV load as a biomarker of immune status that could improve individual treatment strategy.

Le virus de l’hépatite C (VHC) est l’une des causes majeures de cirrhose du foie et de carcinome hépatocellulaire. Au courant de la première partie de ma thèse, nous nous sommes intéressés à caractériser plus en détail le rôle de SR-BI dans l’infection par le VHC. Bien que les mécanismes impliquant SR-BI dans la liaison du virus à l’hépatocyte aient été partiellement caractérisés, le rôle de SR-BI dans les étapes suivant la liaison du VHC reste encore largement méconnu. Afin de mieux caractériser le rôle de l’interaction VHC/SR-BI dans l’infection par le VHC, notre laboratoire à généré une nouvelle classe d’anticorps monoclonaux anti-SR-BI inhibant l’infection virale. Nous avons pu démontrer que SR-BI humain jouait un rôle dans le processus d’entrée du virus à la fois lorsde l’étape de liaison du virus à la cellule hôte mais aussi au cours d’étapes suivant cette liaison. Ainsi il serait intéressant de cibler cette fonction de SR-BI dans le cadre d’une stratégie antivirale pour lutter contre l’infection parle VHC. Dans la seconde partie de ma thèse, nous avions pour but de caractériser les mécanismes moléculaires intervenant dans la réinfection du greffon lors de la transplantation hépatique (TH). Nous avons ainsi identifiés 3 mutations adaptatives dans la glycoprotéine d’enveloppe E2 responsables de l’entrée virale augmentée du variant hautement infectieux. Ces mutations influent sur la dépendance au récepteur CD81 du VHC résultant en une entrée virale accrue. L’identification de ces mécanismes va nous permettre une meilleure compréhension de la pathogénèse de l’infection par le VHC, et est un premier pas pour le développement d’une stratégie préventive antivirale ou vaccinale. / Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. In the first part of my PhD, we aimed to further characterize the role of scavenger receptor class B type I (SR-BI) in HCV infection. While the SR-BI determinants involved in HCV binding have been partially characterized, the post-binding function of SR-BI remains remained largely unknown. To further explore the role of HCV-SR-BI interaction during HCV infection, we generated a novel class of anti-SR-BI monoclonal antibodies inhibiting HCV infection. We demonstrated that human SR-BI plays a dual role in the HCV entry process during both binding and post-binding steps. Targeting the post-binding function of SR-BI thus represents an interesting antiviral strategy against HCV infection. In the second part of my PhD, we aimed to characterize the molecular mechanisms underlying HCV re-infection of the graft after liver transplantation (LT). We identified threeadaptive mutations in envelope glycoprotein E2 mediating enhanced entry and evasion of a highly infectious escape variant. These mutations markedly modulated CD81 receptor dependency resulting in enhanced viral entry. The identification of these mechanisms advances our understanding of the pathogenesis of HCV infection and paves the way for the development of novel antiviral strategies and vaccines.

A tese trata de questões referentes à economia dos transplantes renais, enfocando os mecanismos institucionais e de incentivos relacionados à captação de órgãos no Brasil, bem como a eficiência dos estados brasileiros que captam e realizam tais transplantes. A questão investigada na tese por meio dos ensaios foi analisar os efeitos e as implicações da estrutura de incentivos sobre o número de órgãos (inclusive rim) captados, ou seja, sobre o comportamento do sistema público de transplantes. Buscou-se também avaliar a eficiência desse sistema e sua tendência de comportamento ao longo do período 2006-2011. Foi conduzida inicialmente uma apresentação de alguns fatos estilizados para a possível elaboração de estratégias referente ao problema de pesquisa, entre os quais se destacaram: i) o tamanho e o tempo de espera nas filas por transplante de órgãos, no período recente, vêm apresentando uma tendência crescente; ii) o Brasil ocupa o segundo lugar no número absoluto de transplantes renais, atrás apenas dos Estados Unidos; iii) o país apresenta o maior programa público de transplantes de órgãos sólidos; iv) o processo de captação de órgãos tem-se apresentado uma atividade com elevada variabilidade entre os estados brasileiros, gerando um desequilíbrio entre a oferta e a demanda por órgãos e v) o sistema de transplante renal é classificado como uma modalidade terapêutica eficiente. No segundo ensaio da tese, analisaram-se os mecanismos de incentivos oferecidos aos hospitais que realizam a captação de rim para transplantes no Brasil. A abordagem teórica usada foi o modelo Principal-Agente, num contexto de informação assimétrica. No modelo, o SUS foi classificado como o Principal (receptor de órgãos captados) e os hospitais captadores, como Agentes. O SUS, por meio de um contrato, busca maximizar o seu objetivo de obter o maior número de órgãos para transplante e, para atingi-lo, delega ações aos hospitais. Os Agentes decidem se lhes interessam criar uma estrutura e condições para a captação de tal órgão. De acordo com os resultados do modelo Agente-Principal, verificou-se que o SUS (Principal) tem adotado diversas medidas de incentivos aos hospitais que realizam a captação de órgãos, tais como: criação de um fundo específico para financiamento dos transplantes (FAEC - Fundo de Ações Estratégicas e Compensação); pagamento uniforme para hospitais universitários e não universitários; expansão dos tipos de procedimentos hospitalares a serem pagos pelo SUS; reajuste frequente das remunerações pagas por procedimento da Tabela de Procedimentos do Sistema de Informações Hospitalares do Sistema Único de Saúde; cursos e/ou encontros com os profissionais da saúde que atuam no processo de doação-transplante e criação de novos incentivos financeiros para hospitais que realizam transplantes na rede pública. Portanto, se os profissionais recebem maiores incentivos, esses podem agir com eficiência no processo de captação do órgão e, consequentemente, contribuem para que ocorra uma redução no tempo e nas filas de espera por transplantes. Objetivando avaliar a eficiência dos estados brasileiros no sistema de transplante renal e a produtividade deles ao longo do tempo, fez-se uso do ferramental da Análise Envoltória de Dados-DEA e do Índice de Malmquist e suas decomposições (efeito Emparelhamento e Deslocamento de Fronteira). Utilizou-se uma amostra de 22 estados no período 2006-2011. O método DEA com Retornos Variáveis de Escala (BCC) orientado no sentido do produto foi aplicado nesse estudo. Cada estado foi considerado como Unidade de Tomada de Decisão (DMU). Os dados classificados como inputs (recursos) foram os seguintes: gastos (nominal) totais com transplantes renais, gastos (nominais) com serviços hospitalares e gastos (nominais) com serviços dos profissionais relacionados ao setor. Como output (produto) foi usado o número de rins transplantados. Os resultados indicaram que existe entre os estados brasileiros uma discrepância significativa em relação à captação e o número de transplantes de rins. Isso gerou uma ineficiência no sistema de transplante renal no país e pode estar ocorrendo em virtude do funcionamento não adequado da gestão; do não seguimento das regras nacionais (como por exemplo, vinculação das equipes a centros transplantadores; distribuição adequada de imunossupressores; encaminhamento de órgãos não aproveitados para estados próximos; execução da tipagem HLA de toda a lista de espera de rim) que causam prejuízos aos pacientes; das comissões intra-hospitalares não ativas e das equipes hospitalares sobrecarregadas. Portanto, alguns estados que participam do processo de captação e doação de rins para transplante estão apresentando ineficiência em termos de ordem administrativa e operacional. / The thesis is about the economy of kidney transplants, focusing on the institutional mechanisms and incentives related to organ harvesting in Brazil, as well as the efficiency of the Brazilian states that perform such transplants. The essays investigated the effects and implications of the incentives structure on the number of organs (including kidney) harvested by the transplants public system. The efficiency of this system and its performance over the 2006-2011 period was also evaluated. Firstly some stylized facts related to the subject were presented, among which stand out: i) the size of queues and waiting times for organ transplantation in recent years have grown; ii) Brazil ranks second in the absolute number of kidney transplants, behind only the United States, iii) the country has the largest public program for solid organs transplantation, iv) the process of organ harvesting has high variability among Brazilian states, creating an imbalance between supply and demand for organs and v) the kidney transplantation system is as an effective therapeutic modality. In the second essay the mechanisms of incentives offered to hospitals that perform kidney harvesting in Brazil were analyzed. The theoretical model used was the Principal-Agent in a context of asymmetric information. In the model, SUS was rated as the Principal (receptor of harvested organs) and the harvesting hospitals, as agents. SUS seeks to maximize the number of organs for transplantation in a contract through which it delegates the harvesting to hospitals. Agents decide whether they are interested in creating a framework and conditions for harvesting organs. The results of the Principal-Agent model indicate that SUS (the Principal) has adopted various incentives to hospitals that perform organ harvesting, such as creating a specific fund to finance transplants (FCSA - Fund for Compensation and Strategic Actions); same payment for university and non-university hospitals, expanding the types of hospital procedures to be paid by SUS; frequent remuneration raises of the amount paid by the procedures in Table of Procedures of the Hospital Information System of the Unified Health System; courses and / or meetings with health professionals working in the donation-transplantation process and creation of new financial incentives to hospitals that perform transplants for the public system. So, if the professional receives stronger incentives, he will act more effectively in the organ harvesting and will thereby contribute to a reduction in waiting lines for transplantation. In order to evaluate the efficiency of the Brazilian states in kidney transplant and their productivity over time, the Data Envelopment Analysis-DEA was used and the Malmquist index and its decomposition (Pairing effect and Boundary Displacement) to a sample of 22 states over five years (2006-2011). The DEA model with variable returns to scale (BCC) directed towards the product was applied in this study. Each state was considered a Decision Making Unit (DMU). Data classified as inputs (resources) were the following: total amount spent (nominal) with kidney transplants, amount spent (nominal) with hospital services and amount spent (nominal) with the professional services related to that sector. As output (product) was used the number of transplanted kidneys. The results indicated that there is a significant discrepancy among the Brazilian states in harvesting and transplanting kidneys. This fact has led to inefficiency in the country’s kidney transplant system and it may be so due to inadequate management, to ignoring natiimmunosuppressants; forwarding not used organs to nearby states, implementation of HLA exam to the entire waiting list for kidney transplant) causing harm to patients; to inactive in-hospital committees and to overloaded hospital staff. Therefore, some states in the process of kidney harvesting and transplantation are showing operational and managerial inefficiencies.onal directives (eg, vinculating teams to transplant centers; proper distribution of immunosuppressants; forwarding not used organs to nearby states, implementation of HLA exam to the entire waiting list for kidney transplant) causing harm to patients; to inactive in-hospital committees and to overloaded hospital staff. Therefore, some states in the process of kidney harvesting and transplantation are showing operational and managerial inefficiencies.

No description available.

Made available in DSpace on 2015-12-06T23:47:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2008 / Objetivos: 0 estudo procurou determinar os fatores de risco associados a infeccao de sitio cirurgico e do trato urinario pos-transplante simultaneo de rim-pancreas. Foi tambem estudada a incidencia de infeccao de sitio cirurgico e infeccao do trato urinario nesta coorte de pacientes e os principais patogenos causadores destas infeccoes. Metodo: 0 estudo foi realizado no Hospital São Paulo, hospital terciario de ensino da Universidade Federal de São Paulo. 0 estudo utilizou uma coorte de pacientes que incluiu todos os pacientes que realizaram transplante simultaneo de rim-pancreas no periodo de 01 de dezembro de 2000 a 31 de dezembro de 2006 (119 receptores). Estes pacientes foram acompanhados atraves do prontuario, por um periodo de um mes pos-transplante, para desenvolvimento de infeccao de sitio cirurgico, e durante todo 0 periodo de internacao apos 0 transplante para 0 desenvolvimento de infeccao do trato urinario hospitalar. Os criterios usados para 0 diagnostico de infeccao hospitalar foram definidos pelo Centers for Disease Control and Prevention (CDC). E foram realizados dois estudos tipo caso-controle aninhado (do ingles Nested Case Control), onde foram avaliados os fatores de risco para infeccao de sitio cirurgico e infeccao do trato urinario nesta coorte de pacientes. A analise multivariada foi realizada pela tecnica de regressao logistica multipla, utilizando as variaveis com p≤ 0,05 na analise univariada. 0 metodo utilizado foi 0 Stepwise forward. Resultados: A mortalidade nos primeiros 30 dias apos 0 transplante foi 11,8%. A infeccao de sitio cirurgico ocorreu em 55 (46,2%) pacientes submetidos ao transplante. Os principais microrganismos foram: Klebsiella pneumoniae, 10 (28%); Staphylococcus aureus, 8 (22%); Pseudomonas aeruginosa, 8 (22%); Acinetobacter baumannii, 4 (11 %). Ap6s a regressao logistica multivariada, as variaveis independentemente associadas a ISC foram: necrose tubular aguda (OR=4,4; IC95%= 1,77 - 10,99; p=0,001); fistula renal ou pancreatica pos-­transplante (OR=7,25; IC95%= 1,35 - 38,99; p=0,02) e rejeicao do enxerto (OR=4,28; IC95%= 1,59 - 11,48; p=0,004). A infeccao do trato urinario ocorreu em 29 (24,4%) pacientes submetidos ao transplante. Os principais microrganismos foram: Klebsiella pneumoniae 13 (43,5%), Acinetobacter baumannii 7 (23,5%), Enterobacter spp 2(7%), Pseudomonas aeruginosa 2 (7%).Apos a regressao logistica multivariada, as variaveis independentemente associadas a ITU foram: tempo de hipertensao arterial (OR=1, 1; IC95%= 1,00 - 1,02; p=0,01); uso de alcool pelo doador (OR=7,49; IC95%= 1,01 - 55,66; p=0,04) e uso de drogas vasoativas no doador (OR=0,08; IC95%= 0,01 - 0,84; p=0,03) e, como fator protetor: diurese residual pre-transplante (OR=0,16; IC95%= 0,04 - 0,59; p=0,006). Conclusao: Nosso estudo demonstrou que variaveis relacionadas ao procedimento cirurgico estao mais relacionadas ao desenvolvimento de infeccao de sitio cirurgico e que variaveis relacionadas ao receptor e doador estao mais relacionadas ao surgimento de infeccao do trato urinario em pacientes submetidos a transplante simultaneo rim­-pancreas. Nosso estudo e um dos primeiros a avaliar fatores de risco para essas duas importantes infeccoes nosocomiais nessa coorte de pacientes. / BV UNIFESP: Teses e dissertações