Harford, Laura Elizabeth (2023). Understanding immune deficit in alcohol related liver disease with the development of a human 3D organoid model. University of Birmingham. Ph.D.
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Harford2023PhD.pdf
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Abstract
The UK is in the midst of a liver disease epidemic. Deaths are rising, and yet awareness and treatment options remain limited. In patients with alcohol related liver disease (ARLD), outcomes are particularly poor, and patients are highly susceptible to infection. In this project we aimed to understand how the peripheral immune phenotype changes in patients with both chronic and acute ARLD, and how this is influenced by crosstalk with a damaged liver. We were able to analyse blood samples from patients with different stages of ARLD, and investigate changes in peripheral blood cell composition. We saw striking differences in neutrophil number and phenotype, which also translated to reduced phagocytic ability – particularly in patients with acute alcoholic hepatitis. Utilising progenitor cells from both cirrhotic and healthy primary liver tissue, we developed a human 3D organoid model to generate cells which we were able to expand and differentiate to both a ductal-like and hepatocyte-like state. Differentiated organoids showed expression of key detoxification enzymes and liver markers, as well as ability to form lipid droplets. We saw some differences between ARLD and donor derived organoids, including altered expression of albumin and complement genes. The model showed limited responses to alcohol exposure, however ductal organoids induced an increase in NETosis in healthy neutrophils and both ductal and hepatocyte-like organoids exhibited strong neutrophil chemotactic properties. We have therefore generated a human tissue derived model which can support the study of liver-neutrophil crosstalk in ARLD, and have evidence which may contribute to explanations of reduced neutrophil functionality and increased sepsis risk in these patients.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | |||||||||
| School or Department: | Institute of Immunology and Immunotherapy | |||||||||
| Funders: | Wellcome Trust | |||||||||
| Subjects: | Q Science > Q Science (General) Q Science > QM Human anatomy |
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| URI: | http://etheses.bham.ac.uk/id/eprint/13850 |
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