Worldwide, the most common bacterial pathogen of the gastrointestinal tract among humans is Helicobacter pylori. Chronic infection with this noninvasive organism is the leading cause of gastritis, gastroduodenal ulcer and gastric carcinoma. In the U.S., the cohort prevalence of H. pylori increases approximately 10 percent per decade, whereas in developing countries, such as Chile, up to 80 percent of school-age children are already infected. Prolonged infection and its attendent inflammation predispose the gastric mucosa to malignant transformation, causing gastric cancer to be the leading cause of death in many developing countries. Since therapeutic eradication of H. pylori is expensive and unlikely in many countries, an effective vaccine is highly desirable, but its development will require elucidation of the mechanism(s) by which H. pylori causes mucosal inflammation. Accordingly, we hypothesize that: 1) After colonization of gastric mucosa, H. pylori releases antigens that are absorbed Into the lamina propria where they stimulate T helper type 1 (Th1) mucosal lymphocytes to produce cytokines that promote a cellular inflammatory response. 2) H. pylori antigens, such as urease, can be delivered in novel vaccines to induce protection against infection. 3) Along with the antigen, regulatory cytokines can be delivered in the vaccine to direct the local response from a Th1 inflammatory response to a Th2 humoral response. These hypotheses will be tested with the following four specific aims: 1) Determine whether human H. pylori gastritis in geographically diverse populations is associated predominantly with Th1 CD4+ lymphocytes, which promote a delayed hypersensitivity response, or with Th2 CD4+ lymphocytes, which promote a humoral B cell response. 2) Determine which H. pylori products stimulate purified primary mucosal cells to produce the cytokines associated with H. pylori gastritis (Specific Aim 1). 3) Characterize the cytokine response in mice infected with H. pylori in order to identify the dominant antigens that induce gastric inflammation and the Th cytokines (Specific Aim 2). 4) Using two new vaccine strategies readily adaptable to the human, determine whether oral vaccination with the dominant H. Pylori antigen(s) (Specific Aim 3) and immunoregulatory cytokines (Specific Aims 1 and 2) protect mice against challenge infection.
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