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Permanent link (DOI): https://doi.org/10.7939/R3C411

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FUNCTION OF MYELOID DENDRITIC CELLS Open Access

Descriptions

Other title
Subject/Keyword
immune evasion
nuclear factor-kappa B
myeloid dendritic cells
apoptosis
hepatitis C virus
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Zhao,Li
Supervisor and department
D. Lorne Tyrrell
Examining committee member and department
Evans, David (Medical Microbiology and Immunology)
Kane, Kevin (Medical Microbiology and Immunology)
Schang, Luis (Biochemistry)
Michalak, Thomas (Memorial university)
Adamko, Darryl (Pediatrics)
Department
Department of Medical Microbiology and Immunology
Specialization
Immunology
Date accepted
2012-04-30T09:45:45Z
Graduation date
2012-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Approximately 70% of patients infected with hepatitis C virus (HCV) develop chronic infection, which has been reported to be due to impaired specific T cell responses. Myeloid dendritic cells (mDCs) are potent antigen-presenting cells that regulate T cell responses, however their role during chronic hepatitis C (CHC) is not fully understood. My hypothesis was that the activity of mDCs to regulate T-cell response against HCV might be changed during CHC infection, and this change might contribute to the impaired T-cell responses that lead to the persistence of HCV infection. The objectives of my thesis were to compare the immunogenic activity (which stimulates T-cell proliferation), tolerogenic activity (which kills T cells), and apoptosis of mDCs from CHC patients and healthy donors. In this thesis, I found that mDCs from CHC patients expressed lower level of activating molecules, HLA-DR and CD86, compared to mDCs from healthy volunteers. When mDCs were cocultured with T cells, there were fewer T cells proliferating in the patient group than in the healthy group. This result indicated that the ability of mDCs to stimulate T cell proliferation was impaired in CHC patients. Moreover, mDCs from CHC patients underwent spontaneous apoptosis at a higher rate than mDCs from healthy donors. Nuclear factor-kappa B (NF-κB) activity, which is critical for mDC function and prevention of apoptosis, was diminished in mDCs from CHC patients. I further studied the tolerogenic activity of mDCs during CHC infection. mDCs from CHC patients expressed up-regulated levels of Fas ligand and the ligand 2 of PD-1 compared to mDCs from healthy volunteers. mDCs from CHC patients can kill T cells, while mDCs from healthy volunteers could not. This result indicated that the tolerogenic activity of mDCs was up-regulated in CHC patients. In conclusion, mDCs from CHC patients demonstrated functional changes with increased apoptosis, and diminished NF-κB activity. mDCs from CHC patients have impaired immunogenic activity to stimulate T-cell proliferation, and have up-regulated tolerogenic activity to kill T cells. These changes might be additional novel mechanisms of immune evasion by HCV, and contribute to the impaired specific T-cell responses observed in CHC patients.
Language
English
DOI
doi:10.7939/R3C411
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Li Zhao, Justin Shields, and D. Lorne Tyrrell, Functional changes, increased apoptosis, and diminished nuclear factor-kappaB activity of myeloid dendritic cells during chronic hepatitis C infection. Human Immunolology, 2010. 71(8): 751-62.

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