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Theses Canada
Item – Theses Canada
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Item – Theses Canada
OCLC number
1019466157
Link(s) to full text
LAC copy
Author
Dissanayake, Dilan Thushara.
Title
Investigating the factors that govern the induction of an in vivo cytotoxic T-lymphocyte response against a tissue-borne antigen.
Degree
Ph. D. -- University of Toronto, 2012
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, 2013.
Description
1 online resource
Notes
Includes bibliographical references.
Abstract
<?Pub Inc> In addition to their activity against intracellular pathogens, it is now clear that CD8+ T-lymphocytes also mediate anti-tissue responses. In order to manipulate these responses in the setting of tumor immunity or autoimmunity, it is necessary that we understand the parameters that promote CD8+ activation. In the first section of this thesis, a transgenic mouse model was used to explore the effectiveness of peptide/adjuvant-based and dendritic cell (DC)-based vaccination techniques at eliciting CD8-mediated anti-pancreatic responses. It was found that, while peptide vaccines were unable to stimulate autoimmunity, the transfer of DCs promoted autoimmune diabetes in a manner that was dependent upon the toll-like receptor (TLR)-based maturation of the DCs. Furthermore, the diabetes induction was dependent upon the engagement of the immunodominant CD8+ population and a second T-cell specificity, indicating that polyclonal responses may be required for effective tissue destruction. In the second section of this thesis, I explored the requirements for CD28-signaling during the activation of naïve self-reactive CD8+ T-cells. The transfer of mature DCs was insufficient to promote diabetes in CD28-deficient animals, whereas infection with lymphocytic choriomeningitis virus could induce diabetes in the same animals. Anti-tissue responses were further explored in tumor-bearing mice following DC transfer and demonstrated that a critical determinant of the induction of anti-tissue immunity in the absence of CD28-derived costimulatory signals, was the persistence of antigen presentation. In the final section of this thesis, I explored the role of nuclear factor kappa B 1 (NF-[kappa]B1) in DC maturation using the DC transfer model described above. Surprisingly, NF-[kappa]B1-deficient DCs were capable of inducing diabetes without the need for external stimulation. Furthermore, the absence of NF-[kappa]B1 in unstimulated DCs was associated with dysregulated production of tumor necrosis factor alpha (TNF-[alpha]), and this cytokine was required for the proper upregulation of the cytotoxic effector molecule granzyme B in CD8+ T-cells that infiltrated the pancreatic islets. This work therefore presents a novel model of autoimmune tissue destruction, in which defined genes and pathways that contribute to DC-T-cell interactions can be explored in an 'in vivo' non-TCR transgenic setting.
ISBN
9780494930823
0494930829
9780494930823
Date modified:
2022-09-01