Since the rediscovery of Helicobacter pylori (H. pylori) in the early 1980's, studies have now demonstrated that H. pylori plays an etiologic role in the development of gastritis, peptic ulcer disease, and gastric cancer. The investigators have previously demonstrated the importance of the host as a factor in disease outcome following gastric Helicobacter infection. A related issue, is whether the host immune response contributes to the pathogenesis or acts to protect the host from infection. Using the H.felis/mouse model, the investigators have demonstrated that the T-cell mediated immune response to Helicobacter infection can contribute either to the pathogenesis or act in concert with the humoral immune response to clear this infection. Specifically, the results of studies funded during the previous granting period indicate the Helicobacter infection activates antigen specific cell-mediated immune responses in immunized or infected hosts. These responses have a phenotype which is either pro-inflammatory in nature (TH1) or protective in nature (TH2). Adoptive transfer of Helicobacter-specific TH1 lymphocytes exacerbates gastric inflammation in recipients. However, transfer of a TH2 cell line from immunized/protected mice decreases the magnitude of infection in the recipients. There continues to be a number of unanswered questions, however, which are the focus of this proposal. Using the recently developed H. pylori/mouse model, a number of contemporary techniques, such as the use of knock-out or transgenic mice, recombinant cytokine therapy, and adoptive transfer studies, will be used to further investigate the role of the host immune response in preventing or promoting chronic H. pylori gastroduodenal disease. the investigators will specifically assess the contribution of the humoral immune system in preventing H. pylori gastroduodenal disease following immunization as well as assess the contribution of the host cellular immune response in preventing or promoting H. pylori gastroduodenal disease. An in-depth understanding of the pro-inflammatory mechanisms employed by the host in this model will contribute to our general understanding of immune regulation and the pathogenesis of infectious disease. Finally, these aims are a logical extension of the work previously performed in their laboratory and may ultimately allow them to develop a safe and efficacious sub-unit vaccine to prevent morbidity and potential long-term consequences of Helicobacter infection.
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