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Title: The T-lymphocyte/hepatic stellate cell axis in liver fibrosis
Author: Maltby, Julia
ISNI:       0000 0001 3617 7367
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2004
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Although most human liver diseases are characterised by T-lymphocyte infiltration, many previous studies have focussed on Kupffer cells as intermediaries in HSC activation. This thesis examines how T-lymphocytes may directly influence HSC activation via cytokines (IL-10, IL-4, IL-13) and the balance of Th1/Th2 responses or via cell-cell interactions and analyses a T-lymphocyte mediated animal model of liver fibrosis. Previous studies have suggested that IL-10 exerts an anti-fibrotic effect on CC1₄ induced liver fibrosis independent of its anti-inflammatory activity. this thesis demonstrates that IL-10 deleted HSC demonstrate increased procollagen-1 and α-SMA mRNA in vitro compared to wild type controls but treatment with recombinant IL-10 did not inhibit HSC activation in vitro or reduce CC1₄ induced liver fibrosis in vivo. IL-13 was found to increase HSC activation, stimulating both proliferation and collagen synthesis in vitro. This provides a potential mechanism for the documented effect of IL-13 in promoting liver fibrosis due to murine schistosomiasis. IL-4 was found to increase HSC proliferation, in addition to its previously demonstrated effect of increasing collagen synthesis. Administration of concanavalin-A (Con-A) to mice causes an acute hepatitis mediated by CD4+ T-lymphocyte activation. Repeated Con-A injections have previously been shown to result in liver fibrosis which has been assumed to be CD4+ mediated. In this thesis, CD4 deleted mice were found to develop as much fibrosis as wild types after repeated Con-A injection implying that this is not a pure CD4 mediated model. Data suggested that T-cells bearing neither a CD4+ nor CD8+ phenotype might be implicated. Studies of T-cell/HSC interactions in vitro showed that both co-culture with Th1 and Th2 cells and treatment with conditioned media had a marked anti-proliferative effect on HSC. The effect of co-culture was shown to be dependent on direct cell-cell contact.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available