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Hepatology. 2015 Jul;62(1):279-91. doi: 10.1002/hep.27793. Epub 2015 Apr 22.

Liver inflammation abrogates immunological tolerance induced by Kupffer cells.

Author information

1
Department of Medicine III, RWTH University-Hospital Aachen, Aachen, Germany.
2
Institute for Molecular Medicine and Experimental Immunology, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
3
Department of Pharmacology, RWTH University-Hospital Aachen, Aachen, Germany.
4
Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands.
5
Department of Nephrology, Mount Sinai School of Medicine, New York, NY.
6
Washington University, Division of Immunobiology, St. Louis, MO.
7
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.

Abstract

The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against particle-bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune-mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low-dose peptide antigens coupled to inert particles, immunological readouts, and sophisticated intravital multiphoton microscopy-based imaging of liver in mice. We show that liver resident macrophages, Kupffer cells (KCs), but not hepatic monocyte-derived macrophages or dendritic cells (DCs), are the central cellular scavenger for circulating particle-associated antigens in homeostasis. KC-associated antigen presentation induces CD4 T-cell arrest, expansion of naturally occurring Foxp3(+) CD25(+) interleukin-10-producing antigen-specific regulatory T cells (Tregs) and tolerogenic immunity. Particle-associated tolerance induction in the liver protected mice from kidney inflammation in T-cell-mediated glomerulonephritis, indicating therapeutic potential of targeting KC for immune-mediated extrahepatic disorders. Liver inflammation in two independent experimental models of chronic liver injury and fibrosis abrogated tolerance induction and led to an immunogenic reprogramming of antigen-specific CD4 T cells. In injured liver, infiltrating monocyte-derived macrophages largely augment the hepatic phagocyte compartment, resulting in antigen redistribution between myeloid cell populations and, simultaneously, KCs lose signature markers of their tolerogenic phenotype.

CONCLUSIONS:

Hepatic induction of tissue-protective immunological tolerance against particulate antigens is dependent on KCs as well as on a noninflamed liver microenvironment, thereby providing mechanistic explanations for the clinical observation of immune dysfunction and tolerance break in patients with advanced liver diseases.

PMID:
25810240
DOI:
10.1002/hep.27793
[Indexed for MEDLINE]

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