Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 113-121).

Thesis (Ph.D. in Immunology) -- University of Colorado at Denver and Health Sciences Center, 2006. / Typescript. Includes bibliographical references (leaves 151-168). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

Une petite population de lymphocytes T exprimant les deux corécepteurs CD4 et CD8 et appelée double positive (DP), a été détectée dans le sang périphérique de donneurs sains et de patients atteints de diverses pathologies dont la sclérose en plaques (SEP). Nous avons émis l’hypothèse qu’il s’agissait de lymphocytes T hautement activés pouvant contribuer à l’inflammation chronique présente dans la SEP. Nous avons comparé les cellules T DP obtenues du sang de donneurs sains et de patients atteints de la SEP et non traités. La fréquence des cellules DP était similaire chez les patients et les donneurs sains. La proportion de lymphocytes T DP qui exprimaient les chaines du récepteur de l’interleukine-15 (IL-15) était plus élevée que pour les autres populations lymphocytaires. Des mesures d’induction de la phosphorylation du STAT5 (signal transducer and activator of transcription) ont démontré que les cellules DP ont répondu à des doses plus faibles et pour de plus longues périodes à l’IL-15 comparativement aux autres lymphocytes T. Le pourcentage de lymphocytes T DP ayant la capacité de produire l’interféron-gamma et des enzymes lytiques était élevé chez les témoins sains mais ces niveaux étaient significativement réduits chez les patients atteints de la SEP. La caractérisation phénotypique de cellules DP a suggéré que ces cellules ont des propriétés similaires aux lymphocytes T activés. Bien qu’il ne s’agisse que d’une caractérisation partielle, il semble que les lymphocytes T DP perdent une partie de leurs propriétés chez les patients atteints de la SEP. / A small population of T lymphocytes expressing both CD4 and CD8 called double positive (DP) T lymphocytes has been detected in the peripheral blood of healthy donors and patients affected by different pathologies such as multiple sclerosis (MS). We hypothesize that these cells represent a highly activated T lymphocyte subset that could contribute to the characteristic inflammation found in MS. Thus, we compared DP T cells from healthy donors to those from untreated MS patients. We found similar frequencies of DP T lymphocytes between both groups. A higher percentage of DP T lymphocytes expressed the IL-15R (interleukin 15 receptor) than other T cell populations. Moreover, IL-15 triggered the phosphorylation of STAT5 in a greater proportion of CD4+CD8+ T lymphocytes compared to other T cells. A greater percentage of CD4+CD8+ T lymphocytes can produce interferon gamma and lytic enzymes compared with other T cell subsets. However, those levels were drastically lower in MS patients. The phenotypic characterization of the DP cells suggests they have similar properties as activated T cells. Even though the characterization process is still in its infancy, it appears that the DP T cells may lose some of their properties in MS patients.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 131-153).

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 89-102).

Made available in DSpace on 2015-07-22T20:50:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-04-29. Added 1 bitstream(s) on 2015-08-11T03:25:40Z : No. of bitstreams: 1 Publico-062a.pdf: 992519 bytes, checksum: 41750ff4e6e38ad6517d6c7541049844 (MD5). Added 1 bitstream(s) on 2015-08-11T03:25:40Z : No. of bitstreams: 2 Publico-062a.pdf: 992519 bytes, checksum: 41750ff4e6e38ad6517d6c7541049844 (MD5) Publico-062b.pdf: 1669897 bytes, checksum: 5ca81b8b1f9a75f45902de9ce4bc36f7 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O GB vírus C (GBV-C) está constituído por uma fita única de RNA de polaridade positiva e pertence à família Flaviviridae. Possui uma seqüência e organização genómica parecida ao vírus da hepatite C, (HCV). A infecção pelo GBV-C não foi associada a nenhuma patologia, embora, na co infecção com o HIV, tenha sido associada a uma sobrevida maior e retardo no desenvolvimento da imunodeficiência. O efeito benéfico do GBV-C parece ser mediado por alterações na resposta imune celular; contudo, os possíveis mecanismos para explicar esse efeito ainda não foram esclarecidos. Neste trabalho investigamos a freqüência e características genotípicas assim como o impacto da infecção pelo GBV-C nos indivíduos infectados pelo HIV-1. No primeiro manuscrito examinamos os conhecimentos descritos na literatura referentes à coinfecção e propusemos algumas hipóteses para explicar esses efeitos. Posteriormente, descrevemos a taxa de infecção, a prevalência, incidência e características genotípicas do GBV-C nesta população. Assim, uma considerável freqüência de infecção pelo GBV-C foi observada e a análise filogenética dos isolados de GBV-C mostraram ser do genótipo 1 e 2. Foi observada também uma correlação inversa entre a carga viral do GBV-C e a carga viral do HIV na inclusão e um ano depois, assim como uma correlação positiva, mas não significativa, entre a carga viral do GBV-C e a contagem de linfócitos T CD4+. Finalmente, avaliamos o efeito da viremia pelo GBV-C na ativação celular em recém infectados pelo HIV-1. Os pacientes foram agrupados em GBV-C viremicos e não virémicos e foram avaliados para a contagem de linfócitos T, marcadores de ativação celular e carga viral do GBV-C e HIV-1. Foram realizadas análises de univariada e multivariada para identificar variáveis associadas com ativação celular. Demonstramos que a viremia pelo GBV-C foi correlacionada com uma diminuição da ativação celular nos indivíduos HIV positivos e este efeito mostrou se independente da carga viral do HIV. Assim, esta associação entre a replicação do GBV-C e menor ativação celular pode explicar, pelo menos em parte, a proteção conferida pelo GBV-C na progressão da doença nos indivíduos infectados pelo HIV-1. / GB virus C (GBV-C) is a single stranded positive sense RNA virus, which is a member of the Flaviviridae. It has a close sequence homology and genomic organization to hepatitis C virus (HCV). No disease has been associated with GBV-C infection but coinfection with human immunodeficiency virus (HIV) leads to improved morbidity and mortality for the HIV infected subjects. The mechanism of the beneficial effect of GBV-C appears to be mediated by alterations in the cellular immune response. In this study we investigated the frequency and genotyping characteristics as well as the impact of the GBV-C infection among recently HIV-1 infected individuals. In the first manuscript we examined the current knowledge concerning this co-infection and developed hypotheses to explain its effects. Subsequently, we described the rate of infection, the prevalence, incidence and genotypic GBV-C characteristics in this population. In that regard, a considerable frequency of GBV-C infection was observed and the phylogenetic analysis of the GBVC isolates revealed the predominance of genotypes 1 and 2. Also, it was observed an inverse correlation between GBV-C load and HIV-1 load at the enrollment and after one year of follow-up, and a positive, but not statistically significant, correlation between GBV-C load and CD4+ T lymphocyte counts. Finally, we have investigated the effect of GBV-C viremia on T cell activation in early HIV-1-infection. The volunteers were enrolled into two groups: GBV-C viremic and non viremic, all co-infected with HIV-1. They were evaluated for T cell counts, cellular activation markers, GBV-C RNA detection, and HIV-1 viral load. Non-parametric univariate and multivariate analyses were carried out to identify the variables associated with cellular activation. We demonstrated that the GBV-C viremia is correlated with a lower T cell activation in HIV-1-infected individuals and this effect was independent of HIV-1 viral load. The association between GBV-C replication and lower T-cell activation may explain, at least in part, the protection conferred by this virus against disease progression to immunodeficiency in HIV-1-infected patients. / TEDE / BV UNIFESP: Teses e dissertações