Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Magdalena Filipowicz Sinnreich, University of Basel,
- Second opponent: Professor Reidar Fossmark, NTNU - Norwegian University of Science and Technology,
- Third member and chair of the evaluation committee: Associate professor Asbjørn Christophersen, University of Oslo
Chair of the Defence
Professor II Runar Almaas, University of Oslo
Principal Supervisor
Professor Espen Melum, University of Oslo
Summary
This thesis explores how bile and immune cells contribute to the development of cholestatic liver diseases such as primary sclerosing cholangitis (PSC). Primary sclerosing cholangitis is a chronic fibroinflammatory bile duct disease leading to severe liver damage where current treatment options are limited and liver transplantation the only curative option. The cause of PSC remains unknown, but genetic studies suggest that the immune system plays a central role in the disease development. A better understanding of how the immune system influences the inflammatory process in the bile ducts may therefore open new therapeutic strategies for PSC.
Valestrand and colleagues demonstrate in this thesis that bile from patients with chronic liver diseases contains substances that activate the immune cells natural killer T (NKT) cells and mucosa-associated invariant T (MAIT) cells. These immune cells are abundant in the liver and have properties that can regulate immune processes in both protective and harmful directions. In a mouse model where the common bile duct was ligated, leading to accumulation of bile (cholestasis), the NKT cells were found to be specifically activated. When the common bile duct of mice lacking NKT cells was ligated, these mice developed less liver injury compared to bile duct ligated wild type mice. This indicates that NKT cells contribute to liver damage during cholestasis. To investigate the role of bile duct cells in NKT cell related disease progression in cholestasis, a new mouse model was generated with specific loss of CD1d on bile duct cells, a molecule mediating NKT cell activation. By ligating the common bile duct of the novel model with specific loss of CD1d, bile duct cells were not found to be the main contributors to NKT cell related liver injury in acute cholestasis.
These results provide new insight into how the immune system and bile interact in cholestatic liver diseases such as PSC. MAIT and NKT cells represent potential targets for future treatment aimed at protecting the liver and thereby improve quality of life and survival for patients with these serious liver diseases.
Additional information
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