McKay, DerekSharkey, KeithMatisz, Chelsea2016-12-162016-12-1620162016Matisz, C. (2016). The Adoptive Transfer of Helminth Antigen-Pulsed Dendritic Cells as a Novel Therapy for Colitis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28006http://hdl.handle.net/11023/3492The incidence of autoimmune, inflammatory, and allergic diseases—such as inflammatory bowel disease (IBD)—is increasing in westernized societies at alarming rates. Similarly, dramatically reduced exposure to infectious organisms, including helminth parasites, has been observed. The important role that pathogens play in the shaping and functioning of our immune systems, both evolutionarily and developmentally speaking, has led to the hygiene hypothesis: that reduced exposure to organisms can predispose to immune dysregulation under certain contexts. Infection with helminth parasites has therefore been explored as a potential treatment for certain autoimmune diseases, with mixed success. This work extends upon the traditional paradigm of helminth therapy, and explores the potential of using helminth antigens to develop a cellular therapy as a novel treatment for colitis. The adoptive transfer of bone marrow-derived dendritic cells (DC) treated with an antigen extract from the rat tapeworm Hymenolepis diminuta (HD) significantly attenuated the severity of the dinitrobenzene sulfonic acid (DNBS) model of colitis in mice: these HD-DC cells localized in the spleen, mesenteric lymph nodes (MLN), and colons of recipient mice. HD-DCs evoked significant increases in IL-4 and IL-10 in secondary lymphoid organs. Mechanistically, HD-DCs suppressed colitis through mobilization of recipient IL-10, and IL-4Ra signaling; further, HD-DCs drove the proliferation of CD4+ splenocytes, which also suppressed colitis in recipients via IL-10. HD-DCs that lacked IL-10 or IL-4Ra were unable to suppress colitis, suggesting these cells are a source of IL-10, and must respond to IL-4. In the absence of MHC II signaling HD-DCs were unable to drive splenic IL-4 or IL-10, but were still able to suppress disease, suggesting an alternative mechanism of DNBS suppression in the absence of TCR engagement: increased TGF-B produced by splenocytes of MHC II knock out (KO) HD-DC recipients, relative to WT HD-DC recipients, points to this anti-inflammatory cytokine as a potential mechanism. Further, MHC II KO HD-DCs were still capable of inducing an anti-colitic CD4+ splenocyte, suggesting a non-canonical means of T cell activation at play. Combined, these proof-of-principle studies highlight the potential for helminth antigen-based cellular therapy as a novel treatment strategy for IBD.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.Biology--CellParasitologyImmunologyPathologyHelminthHelminth antigensHelminth therapyDENDRITIC CELLSCell TherapyColitisDNBSdoctoral thesis10.11575/PRISM/28006