Helicobacterpylori (H. pylori) is a major cause of chronic active gastritis, primary peptic ulcer disease and is strongly linked to gastric cancer. Individuals infected with H. pylori mount immune and inflammatory response which fail to clear the infection and may contribute to disease. Despite the inability of the host to clear this infection, we have shown that mice can be protected from H. pylori infection by vaccination. Based on studies performed in the previous funding period, we have demonstrated that CD4 positive T cells, but not antibodies or CD8 positive T cells, are required for protection from H. pylori. Using semi-quantitative RT-PCR, we measuredgastric cytokine expression in protected and unprotected mice to determine which cytokines were associated with protection. Based on these studies, the elimination ofH. pylori in an immunized host does not seem to follow any of the existing paradigms for clearance of or protection from a mucosal pathogen. Interestingly, IL-12 was required for protection but many of the typical effector molecules of IL-12 were not required (iNOS, IFN-g and TNF alpha.). Presently, the best correlate with protective immunity seems to be gastric inflammation. We alsoobserved that inflammation associated with protective immunity was transient and declined to background levels when the infection was eliminated. Therefore, we hypothesize that gastric inflammation not only can lead to serious clinical consequences such as the development of gastric cancer and peptic ulcer disease (if it is chronic), but a transient inflammation may also be required for protection following immunization. In an extension of our previous work, we will focus on identifying the elements of the transient host inflammatory response that mediateprotection fromH, pylori infection. In a second related aim, we will focus on identifying the genes that regulates the severe chronic gastric inflammation associated with persistent Helicobacter infection that ultimately results in a subset of infected individuals developing gastric cancer and peptic ulcer disease. Thus, studying the inflammation associated with H. pylori infection--both the beneficial aspects which may be associated with vaccination and the bad aspects which are associated with disease--is the common theme of this application.
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