Paediatrics (RCH) - Theses
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ItemVaccinating against Helicobacter pylori-induced gastritis( 2019)Infections caused by stomach dwelling bacteria Helicobacter pylori which infect half of the World's population are the main cause of gastric pathologies including peptic ulcers and gastric adenocarcinoma, the latter being the 5th most prevalent cancer-related ailment and the 3rd leading cause of cancer-related deaths. It is known that the chronic inflammation caused by H. pylori rather than the infection itself drives gastric pathologies. An essential feature of this gastritis is a disruption in the cell-cell junctions between gastric epithelial cells which maintain an impermeable barrier between the stomach lumen and sub-epithelial regions of the stomach tissue. The opening of these cell junctions is believed a critical step in the initial development and progression of gastritis. Despite a very high global prevalence of H. pylori infection and its direct association with stomach cancer, there is no vaccine available against H. pylori infection or the associated gastritis. In fact, conventional vaccine approaches targeting bacterial infection have not been able to provide optimum protection against new infection or eradicate pre-existing H. pylori infection even after decades of vaccine research, suggesting a limitation of conventional vaccine approaches against H. pylori infection. While antibiotics are available to treat H. pylori infection, rapidly increasing antibiotic resistance indicates that the therapeutic use of antibiotics is likely to be ineffective in the future. Therefore, further research is required to develop novel vaccine strategies, specifically for individuals already infected with H. pylori in order to prevent H. pylori-associated malignancies. A newly discovered H. pylori virulence factor known as HtrA is reported to disrupt the integrity of gastric epithelial barrier by cleaving epithelial tight and adherens junction proteins occludin, claudin-8 and E-cadherin. The studies presented in this thesis intended to target H. pylori HtrA in a therapeutic vaccine approach with a hypothesis that a vaccine that can block H. pylori HtrA activity may prevent the development of gastritis. Vaccination of mice with recombinant HtrA protein, adjuvanted with alum (named as HtrA vaccine in this thesis) was able to completely prevent the development of gastritis in 70% of the mice infected with H. pylori before vaccination. Exceptional to any previously published H. pylori vaccine study, the HtrA vaccine did not affect H. pylori colonisation but only reduced gastritis, which is a unique phenomenon associated with the HtrA vaccine. The effectiveness of the HtrA vaccine was found to be associated with the interval between vaccine dosages, and protection against gastritis was observed by increasing the interval between consecutive vaccinations from 2 to 4 weeks and reducing the number of vaccine doses from 4 to 3 doses per mouse. The adaptive immune responses generated by the HtrA vaccine include Th1, Th2 and Th17 memory immune responses as well as systemic and mucosal anti-HtrA IgG and IgA antibodies. In the stomach, however, the HtrA vaccine differentially produced IgG antibodies and a Th2 immune response. Examination of the mechanism by which vaccine can prevent gastritis was shown, by using antibody-deficient mice (μMT) and their sibling littermate controls, that antibodies were potential effector molecules in preventing gastritis by neutralising enzymatic activity of HtrA and an absolute requirement for the vaccine to work. However, this protective effect of antibodies also requires an elevated gastric IL-13 response. The immunological model by which the HtrA vaccine prevented gastritis was proposed to be a combined effect of gastric IgG1 and IL-13 response. In conclusion, the studies in this thesis not only demonstrated a novel therapeutic potential of the HtrA vaccine to prevent gastritis but also identified elements of the immune system participating in protection. The HtrA vaccine provides a unique and alternative approach to overcome the limitations of conventional vaccine studies by preventing the pathological effects of H. pylori. Moreover, the therapeutic potential of the HtrA vaccine makes it suitable for the large fraction of individuals already infected with H. pylori.