Matrix degrading enzymes in IBD : dependence on TNFa and identification of IgG plasma cells as a novel source of MMP-3
Matrix degrading enzymes in IBD : dependence on TNFa and identification of IgG plasma cells as a novel source of MMP-3
In this thesis I have undertaken two separate but related studies looking at the control and the source of MMP-3 in IBD tissues.
Thalidomide is an immunomodulatory drug that inhibits TNFα production by peripheral blood mononuclear cells (PBMC) and has been used in the treatment of resistant CD. However its mode of action is unknown and its clinical effectiveness remains unclear. Recently, experimental thalidomide derivatives have been developed that are reportedly more potent inhibitors of TNFα, though they have not been tested in IBD. In this study I investigated the effect of thalidomide and derivatives on lamina propria mononuclear cell (LPMC) TNFα and MMP-3 production. Though thalidomide inhibits PBMC TNFα production, it does not inhibit LPMC TNFα and MMP-3 production. In contrast, the thalidomide derivative CC-10004 inhibits production of both PBMC and LPMC TNFα, and downregulates LPMC MMP-3 production form subjects with IBD. Accordingly, CC-10004 may be a new and effective therapy for the treatment of IBD.
One of the most striking features in IBD is the vast influx of IgG plasma cells into the diseased mucosa. However these cells are difficult to isolate, and consequently little is known about the immune mediators they produce. In this study I have developed a novel method of isolating a pure population of functionally active plasma cell form the gut. I then showed that IgG plasma cells from patients with IBD are long-lived in-vitro and produce MMP-3. Depleting plasma cells may therefore represent a novel strategy to help treat IBD.
University of Southampton
Gordon, John N
3f07dd32-289a-46a8-9ad3-d2ad2b1592d3
2006
Gordon, John N
3f07dd32-289a-46a8-9ad3-d2ad2b1592d3
Gordon, John N
(2006)
Matrix degrading enzymes in IBD : dependence on TNFa and identification of IgG plasma cells as a novel source of MMP-3.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
In this thesis I have undertaken two separate but related studies looking at the control and the source of MMP-3 in IBD tissues.
Thalidomide is an immunomodulatory drug that inhibits TNFα production by peripheral blood mononuclear cells (PBMC) and has been used in the treatment of resistant CD. However its mode of action is unknown and its clinical effectiveness remains unclear. Recently, experimental thalidomide derivatives have been developed that are reportedly more potent inhibitors of TNFα, though they have not been tested in IBD. In this study I investigated the effect of thalidomide and derivatives on lamina propria mononuclear cell (LPMC) TNFα and MMP-3 production. Though thalidomide inhibits PBMC TNFα production, it does not inhibit LPMC TNFα and MMP-3 production. In contrast, the thalidomide derivative CC-10004 inhibits production of both PBMC and LPMC TNFα, and downregulates LPMC MMP-3 production form subjects with IBD. Accordingly, CC-10004 may be a new and effective therapy for the treatment of IBD.
One of the most striking features in IBD is the vast influx of IgG plasma cells into the diseased mucosa. However these cells are difficult to isolate, and consequently little is known about the immune mediators they produce. In this study I have developed a novel method of isolating a pure population of functionally active plasma cell form the gut. I then showed that IgG plasma cells from patients with IBD are long-lived in-vitro and produce MMP-3. Depleting plasma cells may therefore represent a novel strategy to help treat IBD.
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Published date: 2006
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Local EPrints ID: 466266
URI: http://eprints.soton.ac.uk/id/eprint/466266
PURE UUID: 81b58ce3-7bf5-4957-a538-3c24a5bfa290
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Date deposited: 05 Jul 2022 04:59
Last modified: 16 Mar 2024 20:36
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Author:
John N Gordon
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