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Anchoring interferon alpha to apolipoprotein A‐I reduces hematological toxicity while enhancing immunostimulatory properties
Author(s) -
Fioravanti Jessica,
González Iranzu,
MedinaEcheverz José,
Larrea Esther,
Ardaiz Nuria,
GonzálezAseguinolaza Gloria,
Prieto Jesús,
Berraondo Pedro
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24306
Subject(s) - scavenger receptor , interferon , in vivo , biology , immune system , cytotoxic t cell , cytokine , alpha interferon , immunology , in vitro , lipoprotein , cholesterol , biochemistry , microbiology and biotechnology
Abstract 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. 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. (H EPATOLOGY 2011;)