Schoelzel, K;
(2017)
Investigating immunological and metabolic pathways involved in the pathogenesis of chronic liver disease.
Doctoral thesis , UCL (University College London).
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Abstract
Chronic liver disease affects a large number of people with a rising incidence, and is characterized by the development of liver fibrosis, eventually resulting in cirrhosis, Treatment options for end-stage liver disease are limited and liver cirrhosis represents the main risk factor for hepatocellular carcinoma (HCC), highlighting the need for novel therapeutic approaches. In this thesis, metabolic as well as immunological pathways contributing to the development of liver fibrosis and subsequent HCC have been investigated. Hepatic stellate cells (HSCs) are considered as the key players in fibrosis development, as their activation results in excessive extracellular matrix deposition, leading to the establishment of liver fibrosis. In addition, tumour-stromal interactions between HSCs and HCC play a role in HCC pathogenesis, and are therefore considered as a potential target for novel HCC therapy. In this thesis, the role of the AMPK pathway in tumour-stromal interactions between HSCs and HCC has been investigated, with a special focus on pharmacologically targeting AMPK in both HSCs and HCC. Moreover, the development of liver fibrosis and cirrhosis is accompanied by a chronic inflammatory immune response, fostering a pro-fibrogenic environment, especially in the context of autoimmune liver disease (AILD). Mucosal-associated invariant T cells (MAIT cells) are a recently discovered subset of innate like T cells that represent up to 40% of all liver lymphocytes. Besides being crucial for anti-microbial defence, MAIT cells contribute to autoimmune diseases and are thought to play an important role in tissue inflammation in the liver, as they secrete pro-inflammatory cytokines upon activation. Therefore, the role of MAIT cells for the development of liver fibrosis in AILD was explored. More specifically, the MAIT cell subset was characterized in human patients with AILD, and mechanisms of MAIT cell activation, as well as MAIT cell – HSC interactions were investigated.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Investigating immunological and metabolic pathways involved in the pathogenesis of chronic liver disease |
| Event: | University College London |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Keywords: | HCC, AMPK, cancer, cirrhosis, chronic liver disease, MAIT cells, mucosal-associated invariant T cells, autoimmune liver disease, hepatic stellate cells, liver immunology |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1553193 |
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