Blunting Colitis by Targeting Gut Microbial Antigen-Loaded Antigen-Presenting Cells
Date
2019-04-30
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Abstract
The non-obese diabetic (NOD) mouse is commonly used for studying type-1 diabetes (T1D). Among many β-cell auto-antigens (Ags), the Santamaria lab has focused on understanding the role of the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) in T1D pathogenesis. In NOD mice, a highly-diabetogenic CD8+ T-cell population recognizing a H-2K-restricted IGRP206-214 epitope is found in the islets of pancreas. The deletional tolerance of these cells occurs independently of IGRP206-214/Kd recognition, particularly in the post-neonatal period when commensals actively colonize the gut. Hence, the first part of this thesis focused on identifying microbial epitope(s) similar to IGRP206-214 and determining the biological importance of such recognition in NOD mice and humans. Our findings suggested that an integrase protein expressed by several species of the genus Bacteroides contains a mimic for auto-Ag pancreatic -cell IGRP (residues 206-214; IGRP206-214). Bacteroides integrase promoted the recruitment of diabetogenic high-avidity IGRP206-214-specific 17.4-CD8+ T-cells into the gut and suppressed experimental colitis by targeting BacIYL36-44-presenting gut microbial Ag-loaded Ag-presenting cells (APCs). This suggests that Bacteroides integrase is a beneficial Ag for the host in suppressing colitis and that the suppression of pro-inflammatory APCs is beneficial in controlling inflammation in the gut. The Santamaria lab has shown that administration of disease-relevant peptide/major histocompatibility complex (pMHC II)-coated NPs in mice suppressed three different autoimmune diseases—T1D, experimental autoimmune encephalomyelitis (EAE: a model of MS) and experimental arthritis—without affecting systemic immunity, which resulted from the induction/expansion of disease-relevant Tr1-like CD4+ T-cells. The suppression of autoimmunity was mainly mediated by IL-10 and TGF- secretion by Tr1-like cells. By considering the importance of Tregs in the suppression of inflammatory bowel disease (IBD), In the second part of my thesis work, we developed pMHC II nanomedicines displaying peptides from prevalent gut microbial Ags (Bacteroides integrase, flagellin, Yidx and Fla-2) and tested their efficacy in murine models of colitis. We found that gut microbial Ag-relevant pMHC II-NPs induced/expanded cognate Tr1-like CD4+T-cells, resulting in the suppression of DSS-induced and T-cell transfer models of colitis without compromising mucosal immune response. The suppressive capacity of Tr1-like cells was mainly mediated by the secretion of IL-10 and TGF1 in the susceptible hosts.
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Keywords
IBD, pMHC nanotherapy, T-cells, Dendritic cells
Citation
Hebbandi Nanjundappa, R. (2019). Blunting Colitis by Targeting Gut Microbial Antigen-Loaded Antigen-Presenting Cells (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.