Authors: Metzler, Sarah
Title: The role of innate lymphoid cells 1 and natural killer cells during drug induced liver damage
Language (ISO): en
Abstract: Worldwide, approximately two million deaths per year are caused by different liver diseases. The understanding of the underlying mechanisms causing liver diseases remain incomplete. In the last two decades, the involvement of different immune cells during liver disease progression, regeneration and homeostasis have been closely investigated and offered new therapeutic strategies and targets. Recently, natural killer (NK) cells have been observed to contribute to the progression of drug induced liver injury (DILI). In vitro results of primary human hepatocytes (PHH) and human hepatocyte cell lines pretreated with valproic acid, ketoconazole, promethazine and isoniazid showed enhanced expression of activating NK cell ligands. Moreover, enhanced NK cell activity was observed which was characterized by the higher interferon gamma (IFN) production and increased cytotoxicity against the pretreated hepatocytes. In order to validate the in vivo relevance of these findings and investigate the DILI mechanism, the first aim was to reproduce the enhanced NK cell activity ligand expression in drug pretreated primary mouse hepatocytes (PMH). The data of drug pretreated PMH revealed higher expression levels of activating NK cell ligands which were more pronounced in combination with tumor necrosis factor alpha (TNF). In the next step, the aim was to establish a drug induced liver injury mouse model with the most promising drug valproic acid. The attempts to establish a valproic acid induced liver injury mouse model were not successful, since the treatments did not cause increased NK cell numbers in the liver, higher expression of activating NK cell ligands on hepatocytes nor liver damage. During the last decade, another immune cell type was identified which seem to be involved in liver damage, regenaration and homeostasis: innate lymphoid cell 1 (ILC1). Until today, there is not much known about ILC1s, however they have been described to possess a memory potential. Therefore, another aim of this thesis was to identify and characterize the memory potential of ILC1s after multiple applications of the hepatotoxic compound carbon tetrachloride (CCl4). After multiple doses of CCl4 injected in a 30 days interval, memory like ILC1s were discovered which were able to produce more interferon gamma (IFN). Further experiments revealed a transient effect of ILC1s in the liver, since higher cell numbers were observed on day one but until day three, the ILC1 cell numbers were again comparable to control cell numbers. Additionally, the memory effect of ILC1s is long-lasting. Nevertheless, the localization and function of memory like ILC1s in the liver need to be further investigated to evaluate the possible contribution to liver disease progression, regeneration and homeostasis.
Subject Headings: NK cells
ILC1s
Liver
DILI
Memory like cells
CCI4
VPA
Subject Headings (RSWK): Leber
URI: http://hdl.handle.net/2003/40955
http://dx.doi.org/10.17877/DE290R-22805
Issue Date: 2022
Appears in Collections:Chemische Biologie

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