Universität zu Köln

Schwinge, Dorothee, von Haxthausen, Franziska, Quaas, Alexander, Carambia, Antonella, Otto, Benjamin, Glaser, Fabian, Hoeh, Benedikt, Thiele, Nina, Schoknecht, Tanja, Huber, Samuel ORCID: 0000-0001-9325-8227, Steffens, Niklas, Lohse, Ansgar W., Herkel, Johannes ORCID: 0000-0001-9055-9999 and Schramm, Christoph (2017). Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related to IL-12 signaling. J. Hepatol., 66 (4). S. 798 - 806. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1600-0641

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Abstract

Background & Aims: Reduced numbers of regulatory T cells (Treg) have been reported in patients with primary sclerosing cholangitis (PSC); therefore, Treg expansion might serve as a therapeutic approach. Here, we explored whether treatment with IL-2/IL-2 monoclonal antibody complex (IL-2/IL-2Ab complex) could provide in vivo Treg expansion and treatment of experimental sclerosing cholangitis. Methods: Treg were expanded by repeated injection of IL-2/IL2Ab complex in mouse models of cholangitis (Mdr2(-/-), DDC) or colitis (dextran sulfate sodium [DSS]) as control. In vitro suppressive capacity and gene expression were analyzed in isolated hepatic and splenic Treg. Results: In vivo expansion resulted in a 5-fold increase in hepatic Treg, which localized within the inflamed portal tracts. However, although Treg expansion was associated with reduced proinflammatory IL-17 and increased anti-inflammatory IL-10 production by hepatic lymphocytes, the severity of cholangitis was not reduced. In contrast, DSS-induced colitis could be improved by Treg expansion, suggesting a selectively reduced functionality of intrahepatic Treg. Indeed, hepatic Treg manifested reduced Foxp3 expression and reduced suppressive capacity compared to splenic Treg. Hepatic Treg dysfunction could be linked to increased IL-12 signaling due to an upregulation of the IL-12 receptor. Accordingly, IL-12 receptor beta 2 knockout mice (IL12rb2(-/-)) were able to maintain hepatic Treg functionality. Conclusions: Hepatic Treg expanded in vivo failed to improve the course of cholangitis, which was related to the effects of hepatic IL-12 on Treg. Therefore, neutralization of IL-12 should be considered as part of treatment strategies targeting Treg in sclerosing cholangitis. Lay summary: Primary sclerosing cholangitis (PSC) is associated with a paucity of regulatory T cells (Treg) that have a particular ability to control immune responses; therefore, in vivo expansion of Treg might serve as a treatment of cholangitis. However, in a mouse model of PSC, we show that Treg enrichment in the liver was not sufficient to provide effective control of cholangitis, as the suppressive functionality of hepatic Treg was significantly limited by IL-12 signals. Thus, neutralization of IL-12 should be considered as part of treatment strategies to improve the efficacy of Treg-based treatments for liver diseases.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schwinge, Dorothee UNSPECIFIED UNSPECIFIED UNSPECIFIED von Haxthausen, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Quaas, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Carambia, Antonella UNSPECIFIED UNSPECIFIED UNSPECIFIED Otto, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Glaser, Fabian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeh, Benedikt UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoknecht, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Huber, Samuel UNSPECIFIED orcid.org/0000-0001-9325-8227 UNSPECIFIED Steffens, Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Lohse, Ansgar W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herkel, Johannes UNSPECIFIED orcid.org/0000-0001-9055-9999 UNSPECIFIED Schramm, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-236004
DOI:	10.1016/j.jhep.2016.12.001
Journal or Publication Title:	J. Hepatol.
Volume:	66
Number:	4
Page Range:	S. 798 - 806
Date:	2017
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1600-0641
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LOW-DOSE INTERLEUKIN-2; IN-VIVO EXPANSION; AUTOIMMUNE HEPATITIS; SUSCEPTIBILITY LOCI; CUTTING EDGE; MOUSE MODEL; LIVER; INFLAMMATION; TOLERANCE; EXPRESSION Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23600