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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats
Karen Louise Thomsen, Holger Jon Møller, Jonas Heilskov Graversen, Nils E Magnusson, Søren K Moestrup, Hendrik Vilstrup, Henning Grønbæk
Karen Louise Thomsen, Hendrik Vilstrup, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
Holger Jon Møller, Department of Clinical Biochemistry, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
Jonas Heilskov Graversen, Affinicon Aps, Incuba Science Park, DK 8200 Aarhus N, Denmark
Jonas Heilskov Graversen, Søren K Moestrup, Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark
Nils E Magnusson, Department of Clinical Medicine, Faculty of Health, Medical Research Laboratory, Aarhus University, DK-8000 Aarhus C, Denmark
Søren K Moestrup, Department of Biomedicine, University of Aarhus, DK-8000 Aarhus C, Denmark
Author contributions: Thomsen KL, Møller HJ and Grønbæk H conceived and designed the study; Thomsen KL and Magnusson NE acquired the data and analysed the samples; Thomsen KL, Vilstrup H and Grønbæk H analysed and interpreted the data; Thomsen KL drafted the manuscript; Møller HJ, Graversen JH, Moestrup SK, Vilstrup H and Grønbæk H critically revised the manuscript for important intellectual content; all authors saw and approved the final manuscript.
Supported by The NOVO Nordisk foundation; the Aarhus University Research Foundation; and Clinical Institute, Aarhus University, Denmark.
Institutional animal care and use committee statement: The study was performed in accordance with local and national guidelines for animal welfare and reviewed and approved by the national Animal Ethics Committee, protocol No. 2010/561-1918.
Conflict-of-interest statement: Møller HJ, Graversen JH and Moestrup SK are inventors for the CD163-dexamethasone conjugate and minority shareholders in Affinicon Aps. All other authors have nothing to disclose.
Data sharing statement: Dataset is available from the corresponding author at karethom@rm.dk.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Karen Louise Thomsen, MD, PhD, Department of Hepatology and Gastroenterology, Aarhus University Hospital, 44 Nørrebrogade, DK-8000 Aarhus C, Denmark.
karethom@rm.dk
Telephone: +45-78-463897 Fax: +45-78-462740
Received: February 22, 2016
Peer-review started: February 22, 2016
First decision: March 24, 2016
Revised: May 4, 2016
Accepted: May 31, 2016
Article in press: June 2, 2016
Published online: June 18, 2016
Processing time: 113 Days and 9.6 Hours
AIM: To study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats.
METHODS: Wistar rats were injected intravenous with either the CD163 targeted dexamethasone-conjugate (0.02 mg/kg) or free dexamethasone (0.02 or 1 mg/kg) 24 h prior to lipopolysaccharide (LPS) (2.5 mg/kg intraperitoneal). We measured plasma concentrations of tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6) 2 h post-LPS and liver mRNAs and serum concentrations of the rat acute phase protein α-2-macroglobulin (α-2-M) 24 h after LPS. Also, plasma concentrations of alanine aminotransferase and bilirubin were measured at termination of the study. Spleen weight served as an indicator of systemic steroid effects.
RESULTS: The conjugate halved the α-2-M liver mRNA (3.3 ± 0.6 vs 6.8 ± 1.1, P < 0.01) and serum protein (201 ± 48 μg/mL vs 389 ± 67 μg/mL, P = 0.04) after LPS compared to low dose dexamethasone treated animals, while none of the free dexamethasone doses had an effect on liver mRNA or serum levels of α-2-M. Also, the conjugate reduced TNF-α (7208 ± 1977 pg/mL vs 21583 ± 7117 pg/mL, P = 0.03) and IL-6 (15685 ± 3779 pg/mL vs 25715 ± 4036 pg/mL, P = 0.03) compared to the low dose dexamethasone. The high dose dexamethasone dose decreased the spleen weight (421 ± 11 mg vs 465 ± 12 mg, P < 0.05) compared to controls, an effect not seen in any other group.
CONCLUSION: Low-dose anti-CD163-dexamethasone conjugate effectively decreased the hepatic acute phase response to LPS. This indicates an anti-inflammatory potential of the conjugate in vivo.
Core tip: We aimed to study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats. The central finding of the study was a reduction in liver mRNA and plasma levels of the acute phase protein α-2-macroglobulin, and plasma tumour necrosis factor-α and interleukin 6 by administration of the conjugate prior to a lipopolysaccharide-induced inflammatory response. This anti-acute phase effect exceeded that of the therapeutic dexamethasone dose and did not cause systemic adverse effects. Thus, the antibody conjugate may be a potential candidate in future anti-inflammatory macrophage-directed therapy, e.g., in liver diseases with Kupffer cells activation.
