Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes

Molecular Therapy: Methods & Clinical Development

Erik I. Christensen¹  Anders Etzerodt¹  Holger J. Møller²  Hendrik Vilstrup³  Henning Grønbæk³  Pia Svendsen⁴  Søren K. Moestrup⁴  Jonas H. Graversen⁴  Rasmus Røge⁵  Henrik Hager⁶ 

[1] Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark;Department of Clinical Biochemistry, Aarhus University Hospital, 8000 Aarhus, Denmark;Department of Hepatology, Aarhus University Hospital, 8000 Aarhus, Denmark;Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark;Department of Pathology, Aalborg University Hospital, 9100 Aalborg, Denmark;Department of Pathology, Vejle Hospital, University of Southern Denmark, 5000 Odense, Denmark;

关键词: macrophages;    glucocorticoid;    inflammation;    dexamethasone;    antibody-drug conjugates;    CD163;    fructose;    steatohepatitis;   

DOI  :  10.1016/j.omtm.2016.11.004

来源: DOAJ

【 摘 要 】

Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation of liver macrophages are suggested to be essential to disease progression. In the present study, we show that a low dose of an anti-CD163-IgG-dexamethasone conjugate targeting the hemoglobin scavenger receptor CD163 in Kupffer cells and other M2-type macrophages has a profound effect on liver inflammatory changes in rats on a high-fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non-conjugated dexamethasone or dexamethasone conjugated to a control IgG did not have this effect but instead exacerbated liver lipid accumulation. The low-dose anti-CD163-IgG-dexamethasone conjugate displayed no apparent systemic side effects. In conclusion, macrophage targeting by antibody-directed anti-inflammatory low-dose glucocorticoid therapy seems to be a promising approach for safe treatment of fructose-induced liver inflammation.

【 授权许可】

Unknown