B1 - Regulation of immune-mediated liver injury


Principal Investigator:

Prof. Dr. rer. nat. Gisa Tiegs
Department of Experimental Immunology and Hepatology
University Medical Center Hamburg-Eppendorf
Martinistr. 52
20246 Hamburg
Phone: +49-40-7410-58731
Fax: +49-40-7410-57150
E-Mail: g.tiegs@uke.de

PD Dr. rer. nat. Andrea Kristina Horst
Institut für Experimentelle Immunologie und Hepatologie
Universitätsklinikum Hamburg-Eppendorf
Martinistr. 52
20246 Hamburg
Tel.: +49-40-7410-56374
Fax: +49-40-7410-57150
E-Mail: ahorst@uke.de

Participating staff:

Elena Tasika – MTA
Dr. Birgit Schiller – PostDoc
Mareike Kellerer – PhD student

Project description

The liver as a tolerogenic organ is constantly challenged by microbial and food antigens. Hence, liver tolerance is modulated by the gut microbiota and their metabolites which lead induce immune regulatory T cells (Tregs), depending on their composition. Treg induction and homeostasis is controlled by IL-2-signaling. Immune-checkpoint regulators, such as CEACAM1, affect IL-2-mediated signaling pathways; the anti-inflammatory properties of Tregs are mediated in part by IL-10 secretion.

Inflammatory and autoimmune liver disease emerge by inappropriate immune regulation and loss of tolerance. Loss of tolerance is propagated by a progressive dysbalance in pro-inflammatory and regulatory T cells. Hence, identification of novel mechanisms in immune regulation or immune-checkpoint inhibitors in cell-bound or soluble and/ or by particular components of the microbiome offers novel routes to therapy development.

Figure 1: Tolerance induction in response to liver inflammation: Influence of the gut and immune-regulatory molecules, such as CEACAM1 and IL-10.

The aim of this project is to decipher novel mechanisms of immune regulation and tolerance induction in response to liver injury. During the first funding period, we demonstrated in a mouse model for CD4+ T cell-dependent liver injury provoked by Concanavalin A (ConA) injection that tolerance induction after repeated ConA exposure depends on IL-10-producing, CXCR3+Tbet+ Tregs. Furthermore, we showed that hepatocytes and liver-resident endothelial cells (LSECs) as non-professional antigen-presenting cells in the liver, participate in the generation of IL-10-producing Tregs and that they interfere with pathways of T cell activation. In the current funding period, we will determine the role of the gut microbiota for the induction of IL-10-producing Tregs in the liver.

We will identify soluble factors produced by commensal microbes which are implicated in liver inflammation and tolerance induction. Bacterial metabolites, such as short-chain fatty acids are candidate substances involved in the regulation of liver tolerance. Additionally, we will address the role of the membrane-bound and soluble form of the microbial receptor and immune-checkpoint regulator CEACAM1 in T cell activation and antigen-presentation by intrahepatic, non-professional antigen-presenting cells. Our current publications show that CEACAM1 stimulates signaling via the IL-2 receptor and thus controls Treg induction in the liver (Hepatology, 2018).

Related news:

Horst AK, Wegscheid C, Schaefers C, Schiller B, Neumann K, Lunemann S, Langeneckert AE, Oldhafer KJ, Weiler-Normann C, Lang KS, Singer BB, Altfeld M, Diehl L, Tiegs G.

Carcinoembryonic antigen-related cell adhesion molecule 1controls IL-2-dependent regulatory T-cell induction in immune-mediated hepatitis in mice.
Hepatology. 2018 Jan 29. doi: 10.1002/hep.29812. [Epub ahead of print]

Neumann K, Karimi K, Meiners J, Voetlause R, Steinmann S, Dammermann W, Lüth S, Asghari F, Wegscheid C, Horst AK, Tiegs G

A Proinflammatory Role of Type 2 Innate Lymphoid Cells in Murine Immune-Mediated Hepatitis
J Immunol. 2017 Jan 1;198(1):128-137.

Horst AK, Neumann K, Diehl L, Tiegs G

Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells
Cell Mol Immunol. 2016 May;13(3):277-92. doi: 10.1038/cmi.2015.112. Epub 2016 Apr 4. Review

B01 in 60 SekundenVideoarchiv

B01 in 60 Sekunden online seit 30.09.2018