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Permanent link (DOI): https://doi.org/10.7939/R3NM2Q

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Activation of Natural Killer T cells and Dendritic cells with Caulobacter crescentus: Implications for developing tumour immunity Open Access

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Other title
Subject/Keyword
tumour immunity
Caulobacter crescentus
Dendritic cells
non-pathogenic bacteria
Natural killer T cells
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Loo, Eric Wah-Leck
Supervisor and department
Agrawal, Babita (Surgery)
Examining committee member and department
Agrawal, Babita (Surgery)
Singh, Bhagirath (University of Western Ontario, Microbiology and Immunology)
Anderson, Colin (Surgery)
Rayat, Gina (Surgery)
Kane, Kevin (Medical Microbiology and Immunology)
Department
Department of Surgery
Specialization
Experimental Surgery
Date accepted
2013-01-08T11:46:40Z
Graduation date
2013-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Cancer remains a leading cause of mortality worldwide. Efforts to develop immuno-therapies to control the growth of cancer, while limiting host cell damage, have focused on targeting specific tumour associated antigens. These treatments have yielded some clinical success however; the limited targeting of tumour antigens potentially allows the tumour to escape the treatment through antigen mutation or down-regulation of expression. In this thesis, we focused on the ability of non-pathogenic, Gram negative bacteria, Caulobacter crescentus to stimulate innate immunity to generate a response capable of controlling the growth of syngeneic tumours. We evaluated the ability of C.crescentus to activate natural killer T cells (NKT) and dendritic cells (DCs) as both cell populations affect the continued development of the inflammatory process. The activation of NKT cells was determined using Ja18-/- or CD1d-/- mice which lacked either a subset or all CD1d-dependent NKT cells respectively. NKT cell activation was determined through measurements of the early activation marker CD69 and various cytokines such as IFN-gamma. DC activation by C.crescentus was characterized through observations made with bone marrow derived DCs and their ability to express co-stimulatory markers such as CD40, CD54, CD80, and CD86. The interaction of C.crescentus stimulated NKT cells and DCs revealed that C. crescentus stimulated NKT cells through a contact dependent pathway which may not require the recognition of the CD1d-lipid complex. Additionally, the interaction of C.crescentus activated NKT cells and DCs resulted in an enhanced expression of factors that are known promoters of Th1 cellular immunity such as IL-12p70 and CD40. The immunity stimulated by C.crescentus was shown to slow the growth of EL4 subcutaneous tumours. Interestingly, through the course of our studies we revealed a role for a subset of NKT cells, type 1 NKT cells, absent in Ja18-/- mice to support the growth of syngeneic tumours. We found that Ja18-/- mice bone marrow derived DCs expressed increased Th1 promoting factors. This novel observation indicates a role for NKT cells in the development and maintenance of DC homeostasis in the wild-type animal.
Language
English
DOI
doi:10.7939/R3NM2Q
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
Loo, E. W., M. J. Krantz, and B. Agrawal. 2012. High dose antigen treatment with a peptide epitope of myelin basic protein modulates T cells in multiple sclerosis patients. Cell. Immunol. 280: 10-15.

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