Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via Toll-like receptor 7
| Autor: | Andre Boonstra, Zwier M. A. Groothuismink, Andre van Vliet, Joep de Bruijne, James Appleman, Harry L.A. Janssen, Bettina E. Hansen, Bi-Sheng Liu, Lisa A Bauman, Hendrik W. Reesink, James L. Freddo, M. Rahimy, Robert J. de Knegt, Jeroen van de Wetering de Rooij, Simon P. Fletcher, J.F. Bergmann, Daphne M. Hotho |
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| Přispěvatelé: | Gastroenterology & Hepatology, Hematology, Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Agonist
Adult Male Interferon Inducers Adolescent medicine.drug_class Peripheral blood mononuclear cell Antiviral Agents Drug Administration Schedule Young Adult Immune system SDG 3 - Good Health and Well-being Interferon medicine Humans Pharmacology (medical) Prodrugs Lymphocytes Aged Pharmacology Toll-like receptor Interferon inducer business.industry Hepatitis C Hepatitis C Chronic Middle Aged medicine.disease Infectious Diseases Toll-Like Receptor 7 Immunology RNA Viral Female business Viral load medicine.drug |
| Zdroj: | Antiviral Therapy, 17(4), 657-667. International Medical Press Ltd Antiviral therapy, 17(4), 657-667. International Medical Press Ltd |
| ISSN: | 1359-6535 |
| Popis: | Background ANA773, an oral prodrug of a small-molecule Toll-like receptor (TLR)7 agonist, induces a dose-related decrease in serum HCV RNA levels in chronic hepatitis C patients. Methods The prodrug ANA773 was administered to healthy individuals and chronic hepatitis C patients. At different time points during the course of treatment, modulation of the phenotype and function of peripheral leukocytes were evaluated to determine the role of distinct immune cells on the clinical outcome of therapy. Results Early after administration of the TLR7 agonist, a mild transient reduction of the number of lymphocytes was observed in both healthy individuals and chronic hepatitis C patients. Moreover, repeated administration of ANA773 resulted in transiently reduced numbers of myeloid and plasmacytoid dendritic cells (DC) in blood. Interestingly, reduced plasmacytoid DC numbers as well as increased serum interferon (IFN)-α and IFN-γ inducible protein (IP)-10 levels were observed only in virological responders (≥1 log10 IU/ml reduction of HCV RNA levels upon ANA773 treatment), but were absent in virological non-responders. In vitro stimulation of peripheral blood mononuclear cells from virological responders showed a high frequency of IFN-α-producing plasmacytoid DC upon stimulation in vitro with ANA773, whereas no IFN-α was induced in non-responders. Conclusions These findings indicate that the viral load decline in chronic hepatitis C patients treated with the TLR7 agonist ANA773 is likely due to intrinsic differences in the induction of endogenous IFNs and IFN-stimulated gene products (IFN-α and IP-10) upon TLR7 ligation. |
| Databáze: | OpenAIRE |
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