Since its first isolation 15 years ago, Helicobacter pylori has been recognized as an underlying agent in the genesis of peptic ulcers and as a significant risk factor for gastric cancer. Our laboratory was the first to propose and demonstrate the feasibility of a vaccine versus H. pylori. During the initial funding period of this proposal we demonstrated that antibodies were not required for protection versus Helicobacter infections and we made significant progress in defining a role for cell-mediated immunity in protection. We also showed that not only mucosal vaccination, but also systemic immunization with either Th1 or Th2 biasing adjuvants could be protective. A major problem was that all immunization protocols resulted in a least short term enhanced gastric inflammation upon challenge with liver bacteria, however. There is an urgent need to discern whether experimental infection results in a Th1 type of immune response accompanied by chronic inflammation, we believe that induction of Th2 responses offers the best hope for safe Helicobacter vaccination. Therefore, we propose the study the inflammatory response and Th phenotype of H. pylori challenged mice immunized by both mucosal and systemic Th1 and Th2 inducing protocols. We will also use this information to help define the mechanisms by which cell-mediated immune responses participate in protective immunity. In addition, we will extend this research into non- human primates and humans by phenotyping the immune responses of both infected and immunized individuals. Finally, we will continue to evaluate a noel Helicobacter vaccine candidate. We have also shown that 80% of the human subjects from Project 1 are infected with H. pylori. It is very possible that interactions between H. pylori and Entamoeba histolytica affect the disease outcomes associated with these two pathogens. Sharing data and resources among these projects may offer us the opportunity to study such interactions in the future. This project also shares goals and resources with project 4, which also seeks to understand the role T cell cytokines play in mucosal diseases. This project will use Core B to produce monoclonal antibodies for ELISPOT analysis.
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