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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Regulation of intestinal regulatory T cells by prostaglandin E₂

Crittenden, Siobhan January 2018 (has links)
Pathogenesis of autoimmune and auto-inflammatory diseases is induced by auto-aggressive helper T (Th) cells (i.e. Th1 and Th17 cells), and can be controlled by regulatory T cells (Tregs) characterized by expression of the transcription factor Foxp3. Thus, development of autoimmunity is regulated by the balance of Tregs and Th1/Th17 cells. Prostaglandin E₂ (PGE₂) is a bioactive lipid mediator with immune-modulatory potential that acts through 4 receptors (EP1-4). It has been shown that PGE₂ facilitates Th1 and Th17 cell development and expansion, therefore promoting autoimmune inflammation. However, the role of PGE₂ in Treg development and function is largely unclear. The aim of this PhD was to test the hypothesis that PGE₂ regulates Treg development, function and subsequent immune response. I observed that in vivo inhibition of endogenous PGE₂ biosynthesis using a COX inhibitor resulted in increased Foxp3+ Tregs in various lymphoid organs. This response was prevented by addition of an EP4 agonist. PGE₂-EP4 signalling particularly inhibits RORγt+ Tregs in the intestine. This was not observed in either antibiotic-treated mice or MyD88/TRIF double-knockout mice, suggesting gut commensal microbiota involvement. In addition, PGE₂ has a role in microbiota-dependent regulation of intestinal CD11c+MHCII+CD11b+CD103- mononuclear phagocytes (MNPs) which drive intestinal Treg expansion through production of type 1 interferons. Consistent with these in vivo observations, gut microbial metabolites from indomethacin treated mice enhanced in vitro RORγt+ Treg differentiation in the dendritic cell- T cell co-culture system. Adoptive transfer of caecal microbiota from COX inhibitor- treated mice into naïve mice also provided protective benefits in a chemical (DSS)-induced colitis disease model. In summary, this work has demonstrated that PGE₂ affects intestinal Tregs, indicating a novel mechanism for interaction of PGE₂, the adaptive immune system and the gut microbiota in homeostasis within this environment. These findings increase our understanding of the role of PGE₂ in development of inflammatory bowel disease and offer potential therapeutic strategies for treating this disease.
2

The Roles of Selectin Ligands and Innate Immune Responses in Modulating Resistance to Intracellular Bacterial Infections in Murine Hosts with Altered Immunity

Agbayani, Gerard Patrick 29 August 2018 (has links)
Listeria monocytogenes (LM) and Salmonella enterica serovar Typhimurium (ST) are intracellular bacterial pathogens that cause invasive disease in immune-altered individuals, including the immunocompromised and pregnant women. The mechanisms that modulate innate immunity to intracellular infection, particularly during pregnancy, are not well-understood. Functional selectin ligands play critical roles in leukocyte recruitment during inflammation. Increased control of LM infection in functional selectin ligand-deficient (FtDKO) mice is associated with increased levels of circulating innate immune cells, despite defective leukocyte migration compared to WT mice. Adoptive transfer of WT and FtDKO bone marrow (BM) cells to irradiated WT and FtDKO recipients demonstrates that BM reconstitution and the increased neutrophil phenotype of FtDKO mice is independent of functional selectin ligand expression within the host environment. Thus, functional selectin ligand deficiency enhances inherent innate immune resistance to intracellular infection. We then examined the impact of pregnancy-associated immunological changes on maternal susceptibility to intracellular infections. ST infection in pregnant mice results in profound systemic infection, increased fetal loss and enhanced serum and placental expression of pro-inflammatory cytokines. Pregnant mice showed decreased ratios of pro-inflammatory Th17 cells relative to anti-inflammatory regulatory T cells (Tregs) when compared to non-pregnant mice during infection. Functional inactivation of Tregs in vivo restored control of infection and normal Th17-to-Treg ratios, and reduced fetal loss. These indicate that modulation of Th17 and Treg responses impacts maternal and fetal protection from ST infection. Lastly, we examined the roles of type I interferons (IFNs) in modulating innate immunity to intracellular infections during pregnancy. Type I IFN receptor deficiency (IFNAR-/-) enhances immunity to LM and ST in the non-pregnant state by limiting pathogen-induced leukocyte death. We show that pregnant IFNAR-/- mice infected with LM retain increased protection from infection relative to WT controls. In contrast, protection conferred by IFNAR deficiency against ST infection in the non-pregnant state is abrogated during pregnancy. Distinctive maternal responses to LM and ST are associated with differential regulation of leukocyte distribution and cytokine expression in maternal systemic and/or placental compartments. Taken together, modulation of key mechanisms involved in leukocyte recruitment, immune-regulation and cytokine signaling impact host susceptibility to intracellular infections.

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