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Anchoring interferon alpha to apolipoprotein A-I reduces hematological toxicity while enhancing immunostimulatory properties.
- Source :
-
Hepatology (Baltimore, Md.) [Hepatology] 2011 Jun; Vol. 53 (6), pp. 1864-73. Date of Electronic Publication: 2011 May 02. - Publication Year :
- 2011
-
Abstract
- Unlabelled: Interferon alpha (IFNα) is widely used for the treatment of viral hepatitis but substantial toxicity hampers its clinical use. In this work, we aimed at improving the efficacy of IFNα therapy by increasing the IFNα half-life and providing liver tropism. We selected apolipoprotein A-I (ApoA-I) as the stabilizing and targeting moiety. We generated plasmids encoding IFNα, albumin bound to IFNα (ALF), or IFNα linked to ApoA-I (IA) and mice were treated either by hydrodynamic administration of the plasmids or by injection of the corresponding recombinant proteins or high-density lipoproteins containing IA. The plasma half-life of IA was intermediate between IFNα and ALF. IA was targeted to the liver and induced higher hepatic expression of interferon-stimulated genes than IFNα or even ALF. IA exhibits stronger in vivo antiviral activity than IFNα and the hematologic cytopenic effects of IA are milder than those observed when using IFNα or ALF. In contrast to IFNα, IA does not cause activation-dependent cell death of lymphocytes in vitro. Accordingly, in vivo studies showed that IA boosts T-cell immune responses more efficiently than IFNα or ALF. The difference in immunostimulatory activity between IFNα and IA disappears in scavenger receptor class B type I (SR-BI) knockout mice, suggesting that crosstalk between SR-BI and IFNα receptor is essential for enhanced induction of cytotoxic T cells by IA.<br />Conclusion: Anchoring IFNα to ApoA-I prolongs the half-life of IFNα and promotes targeting to the liver. Importantly, the fusion protein shows increased immunostimulatory properties and lower hematological toxicity.<br /> (Copyright © 2011 American Association for the Study of Liver Diseases.)
- Subjects :
- Animals
Antiviral Agents pharmacokinetics
Antiviral Agents pharmacology
Antiviral Agents therapeutic use
Apolipoprotein A-I pharmacology
Apolipoprotein A-I therapeutic use
Apoptosis drug effects
CD36 Antigens genetics
CD36 Antigens physiology
Cell Line
Cell Line, Tumor
Disease Models, Animal
Female
Half-Life
Hepacivirus drug effects
Hepacivirus isolation & purification
Hepatitis C drug therapy
Hepatitis C physiopathology
Interferon-alpha pharmacology
Interferon-alpha therapeutic use
Lymphocytes drug effects
Lymphocytes pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Receptor Cross-Talk physiology
Receptor, Interferon alpha-beta physiology
Recombinant Fusion Proteins pharmacology
Recombinant Fusion Proteins therapeutic use
Apolipoprotein A-I pharmacokinetics
Hepatitis C immunology
Immunization
Interferon-alpha pharmacokinetics
Liver metabolism
Liver virology
Recombinant Fusion Proteins pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1527-3350
- Volume :
- 53
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Hepatology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 21425312
- Full Text :
- https://doi.org/10.1002/hep.24306