5 resultados para CD4 T lymphocyte count

em AMS Tesi di Dottorato - Alm@DL - Università di Bologna


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Background and rationale for the study. This study investigated whether human immunodeficiency virus (HIV) infection adversely affects the prognosis of patients diagnosed with hepatocellular carcinoma (HCC).Thirty-four HIV-positive patients with chronic liver disease, consecutively diagnosed with HCC from 1998 to 2007 were one-to-one matched with 34 HIV negative controls for: sex, liver function (Child-Turcotte-Pugh class [CTP]), cancer stage (BCLC model) and, whenever possible, age, etiology of liver disease and modality of cancer diagnosis. Survival in the two groups and independent prognostic predictors were assessed. Results. Among HIV patients 88% were receiving HAART. HIV-RNA was undetectable in 65% of cases; median lymphocyte CD4+ count was 368.5/mmc. Etiology of liver disease was mostly related to HCV infection. CTP class was: A in 38%, B in 41%, C in 21% of cases. BCLC cancer stage was: early in 50%, intermediate in 23.5%, advanced in 5.9%, end-stage in 20.6% of cases. HCC treatments and death causes did not differ between the two groups. Median survival did not differ, being 16 months (95% CI: 6-26) in HIV positive and 23 months (95% CI: 5-41) in HIV negative patients (P=0.391). BCLC cancer stage and HCC treatment proved to be independent predictors of survival both in the whole population and in HIV patients. Conclusions. Survival of HIV infected patients receiving antiretroviral therapy and diagnosed with HCC is similar to that of HIV negative patients bearing this tumor. Prognosis is determined by the cancer bulk and its treatment.

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As proviral human immunodeficiency virus type 1 (HIV-1) DNA can replenish and revive viral infection upon attivation, its analysis, in addition to RNA viral load, could be considered a useful marker during the follow-up of infected individuals, to evaluate reservoir status, especially in HAART-treated patients when RNA viral load is undetectable by current techniques and the antiretroviral efficacy of new, more potent therapeutic regimens. Standardized methods for the measurement of the two most significant forms of proviral DNA, total and non-integrated, are currently lacking, despite the widespread of molecular biology techniques. In this study, total and 2-LTR HIV-1 DNA proviral load, in addition to RNA viral load, CD4 cell count and serological parameters, were determined by quantitative analysis in peripheral blood mononuclear cells (PBMC) in naïve or subsequently HAART-treated patients with acute HIV-1 infection in order to establish the role of these two DNA proviral forms in the course of HIV infection. The study demonstrated that HAART-treated individuals show a significant decrease in both total and 2-LTR circular HIV-1 DNA proviral load compared with naïve patients: these findings confirm that HIV-1 reservoir decay correlates with therapeutic effectiveness. The persistence of small amounts of 2-LTR HIV-1 DNA form, which is considered to be a molecular determinant of infectivity, in PBMC from some patients demonstrates that a small rate of replication is retained even when HAART is substantially effective: HAART could not eradicate completely the infection because HIV is able to replicate at low levels. Plasma-based viral RNA assays may fail to demonstrate the full extent of viral activity. In conclusion, the availability of a new standardized assay to determine DNA proviral load will be important in assessing the true extent of virological suppression suggesting that its quantification may be an important parameter in monitoring HIV infection.

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Il trapianto delle cellule staminali emopoietiche umane CD34+ in combinazione con le cellule T regolatorie CD4+/CD25+ FoxP3+ (Tregs) potrebbe prevenire l'alloreattività verso le cellule staminali emopoietiche e ridurre il rischio di rigetto in trapianti allogenici HLA non correlati. Per dimostrare questa ipotesi abbiamo messo in coltura le cellule CD34+ e le cellule CD4+/CD25+ isolate con metodica immunomagnetica (Miltnyi Biotec)da sangue periferico non manipolato,sangue periferico mobilizzato con G-CSF o da Cordone ombelicale. Gli esperimenti svolti in vitro, hanno evidenziato che le cellule Tregs arricchite, ottenute dalla stessa fonte delle cellule CD34+( autologhe), mostravano un effetto inibitorio maggiore sulle celulle T alloreattive, rispetto alle cellule Tregs ottenute da un donatore terzo(allogenico).Inoltre l'attività immunosoppressoria delle Tregs era mantenuta dopo stimolazione con cellule CD34+ allogeniche e i Tregs non modificavano l'attività clonogenica delle cellule staminali CD34+. Avendo ottenuto questi dati in vitro abbiamo trapiantato in topi NOD/SCID le cellule Tregs e le cellule CD34+ in rapporto 1:1 o 1:2 ed è stato osservato un normale attecchimento delle cellule staminali. Incubando queste cellule con dosi fisiologiche di timoglobulina derivata da coniglio (nota molecola immunosopressoria) non veniva modificato il numero dei Tregs dopo 6 giorni di coltura. Dopo l'esposizione alla Timoglobulina, inoltre, i Tregs mantenevano la loro attività soppressoria, aumentava l'espressione del recettore chemochinico CCR7, e venivano rilasciate diverse citochine principalmente l'interleuchina 10(IL-10). Tali dati dimostrano come sia le cellule tregs autologhe che quelle allogeniche potrebbero essere trapiantate insieme alle cellule staminali CD34+ dopo un regime preparatorio di terapia che include la timoglobulina. A tale scopo sono state eseguite selezioni di Tregs da aferesi di donatori sani mobilizzati con G-CSF su scala clinica utilizzando biglie immunomagnetiche Clinical grade (Miltenyi Biotec) e sono state confrontate 2 modalità di selezione con due o tre passaggi con o senza la deplezione dei monociti CD14+.Si è dimostrato così che è possibile selezionare un numero uguale di CD34+ e Tregs ,che con la metodica che prevede la deplezione dei monociti si ottiene una popolazione di cellule Tregs più pura ( > 80%) e infine le applicazioni possibili di questi risultati includo: trapianto di cellule CD34+ del donatore insieme a cellule Tregs in trapianti aploidentici ; infusione of cellule tregs isolate da PBSC mobilizzati con G-nei casi di pazienti con GVHD steroide-resistente; infusione di G-Tregs del donatore nei casi di rigetto di organo trapiantato da of donatore ancora vivente.

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Previous studies in the group led to the identification of CD4+FOXP3- cells with regulatory functions in human blood that coproduce IL-10 and IFN-gamma. These cells do not belong to the Treg cell lineage since they are Foxp3- but they show some similarities with Th1 cells since they express CCR5, T-bet and produce high levels of IFN-gamma. Thus, they share relevant characteristics with both T regulatory type I cells (Tr1) and Th1 cells and we called them Th1-10 cells. In this study we presented a molecular characterization of Th1-10 cells that includes a gene expression and a microRNA profiling and performed functional studies to assess Th1-10 cells regulatory properties. We demonstrated that Th1-10 cells have a high regulatory potential being able to block the proliferation of activated CD4 naïve T cells to a similar extent as conventional Treg cells, and that this suppression capacity is at least partially mediated by secreted IL10. We showed also that Th1-10 cells are closely related to Th1 effector memory cells and express genes involved in cytotoxicity. In particular, they express the transcription factor EOMES and the cytotoxic effector molecules GZMA and GZMK, and they release cytotoxic granules upon stimulation. Moreover, we found that Eomes regulates cytotoxic functions in CD4+ T cells. We demonstrated that miR-92a, selectively downregulated in Th1-10 cells, directly targets the 3âUTR of EOMES.and this finding identifies miR-92a as a possible mediator of Th1-10 cytotoxicity. Th1-10 cells retain some proliferative capacity when sorted ex vivo and activated in vitro via their TCR, and this effect is markedly enhanced by IL-15, which also had a pro-survival effect on Th-10 cells. Thus, in contrast to conventional cytotoxic T cells, Th1-10 cells have cytotoxic and regulatory functions and are not terminally differentiated, since they retain proliferative capacity.

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The recent advent of Next-generation sequencing technologies has revolutionized the way of analyzing the genome. This innovation allows to get deeper information at a lower cost and in less time, and provides data that are discrete measurements. One of the most important applications with these data is the differential analysis, that is investigating if one gene exhibit a different expression level in correspondence of two (or more) biological conditions (such as disease states, treatments received and so on). As for the statistical analysis, the final aim will be statistical testing and for modeling these data the Negative Binomial distribution is considered the most adequate one especially because it allows for "over dispersion". However, the estimation of the dispersion parameter is a very delicate issue because few information are usually available for estimating it. Many strategies have been proposed, but they often result in procedures based on plug-in estimates, and in this thesis we show that this discrepancy between the estimation and the testing framework can lead to uncontrolled first-type errors. We propose a mixture model that allows each gene to share information with other genes that exhibit similar variability. Afterwards, three consistent statistical tests are developed for differential expression analysis. We show that the proposed method improves the sensitivity of detecting differentially expressed genes with respect to the common procedures, since it is the best one in reaching the nominal value for the first-type error, while keeping elevate power. The method is finally illustrated on prostate cancer RNA-seq data.