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Title: Extracellular vesicle signalling in liver disease and transplantation
Author: Mastoridis, Sotiris
ISNI:       0000 0004 8500 1159
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Extracellular vesicles (EVs) are released by all studied cells, including those of the liver, and are responsible for a multitude of physiological functions including immunomodulation. We focus on two distinct clinical settings, namely native liver dysfunction and liver transplantation, and argue that the repertoire, content, and functional properties of circulating EVs undergo significant changes in these contexts with important consequences on immune responses. To this end, we set out a novel approach to the multiparametric characterisation of exosomes and other small EV subsets by advanced imaging flow cytometry. We apply this technique to a cohort of liver transplant recipients and suggest that allograft-derived EVs present in the circulation following transplantation contribute to the transfer of donor-Human Leukocyte Antigen (HLA) and other immunomodulatory molecules to recipient antigen presenting cells (APC). We describe why this process, not seen in a cohort of kidney transplant recipients, is important in the context of semidirect alloimmune response generation, and how it may relate to the known propensity towards tolerance - which characterises liver transplantation specifically. Next, we perform exosomal miRNA profiling across a spectrum of liver failure syndromes: stable cirrhosis, decompensated cirrhosis, acute on chronic liver failure (ACLF), and acute liver failure. We establish that the main driver of perturbations in exosomal miRNA is the degree of liver failure, and we outline the prognostic capacity of particular exosomal miRNAs. We focus particularly on ACLF, a recently described clinical entity associated with systemic inflammation. We suggest that ACLF is associated with a distinct profile of EV-miRNA, we discover functional targets of identified miRNA using novel in vitro assays, and we show EVs in ACLF to have an impaired capacity to regulate monocyte activation. In summary, the data presented herein show that the circulating EV profile is influenced by liver pathophysiology (whether native or transplanted), and the repertoire of cargo carried by EVs in these contexts to have important consequences on immune responses and disease processes. In light of these findings, we make suggestions as to the diagnostic and therapeutic potential of EVs in the clinical settings of liver failure and transplant rejection.
Supervisor: Martinez-Llordella, Marc ; Sanchez Fueyo, Alberto Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available