RESUMO
Interferon-alpha (IFN-alpha) is widely used for the treatment of malignant and viral diseases. Conflicting results of IFN-alpha-mediated effects on dendritic cell (DC) homeostasis have been reported and its impact on human blood DC is largely unknown. We investigated the phenotypic, migratory, and allostimulatory activities of plasmacytoid DCs (PDCs) and myeloid DCs (MDCs) upon in vitro exposure to IFN-alpha without the addition of exogenous DC growth factors. IFN-alpha-exposed PDCs exhibited an increase in viability but showed an immature phenotype and a diminished allostimulatory potential. Furthermore, IFN-alpha-treated PDCs displayed a dramatically augmented expression of CD54 and CD62L as well as an increased migratory response to CC chemokine ligand (CCL)19, CXC chemokine ligand (CXCL)11, and CXCL12, suggesting an enhanced ability to migrate into peripheral lymph nodes through high endothelial venules. Myeloid DCs exposed to IFN-alpha exhibited a matured phenotype with an increased propensity to migrate toward lymph node chemokines, yet without gaining an enhanced allostimulatory capacity. Our results provide new insights into the differential immunomodulatory action of IFN-alpha on distinct human blood DC subsets and thus, may present translational significance.
Assuntos
Células Dendríticas/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Interferon-alfa/farmacologia , Análise de Variância , Contagem de Células , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Endocitose/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Fatores Imunológicos/farmacologia , Imunofenotipagem , Teste de Cultura Mista de Linfócitos , Masculino , Pessoa de Meia-Idade , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Receptores de Quimiocinas/metabolismo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
OBJECTIVES: Combination therapy with interferon and ribavirin is the most effective treatment for chronic hepatitis C today. Before pegylated interferons became available, higher and more frequent doses of interferon were expected to be more effective than the standard regimen of three million units thrice weekly. In fact, daily dosing is still proposed for non-pegylated interferon. The aim of this study was to compare the efficacy and safety of daily versus thrice-weekly interferon alfa-2b in combination with ribavirin as first-line treatment of chronic hepatitis C. METHODS: A total of 116 treatment-naive patients were randomised to receive either interferon alfa-2b three million units daily or thrice-weekly in combination with ribavirin for 24 weeks. Patients with hepatitis C virus (HCV) genotype 1 who were HCV-RNA negative at 24 weeks continued treatment with thrice-weekly interferon plus ribavirin for another 24 weeks. Sustained virological response was defined as an undetectable HCV-RNA level 24 weeks after treatment was completed (end of follow-up). RESULTS: In an intention-to-treat analysis, HCV-RNA was undetectable at the end of treatment in 71% and 74% of patients treated with daily and thrice-weekly interferon, respectively. At the end of follow-up, HCV-RNA was undetectable in 47% and 57% of patients treated with daily and thrice-weekly interferon, respectively. Sustained virological response rates were almost twice as high in patients with genotypes 2 and 3 as in patients with genotype 1 but were not different between treatment groups. CONCLUSIONS: This study could not show any difference between daily and thrice-weekly standard interferon plus ribavirin in achieving end-of-treatment and sustained virological responses in chronic hepatitis C.