Host and Bacterial Factors in Disease due to H. Pylori

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Helicobacter pylori remains the most prevalent infectious disease in the world, with up to100% of people colonized in some populations. Disease due to H. pylori is variable, however: only a minority of infected individuals develops clinical disease. It has become increasingly clear that this variability is attributable to differences in host immune response, and that understanding the immune mechanisms that contribute to disease will be essential for controlling gastritis and the subsequent sequelae such as peptic ulcer disease and cancer. Our laboratory uses an established adoptive transfer model to study the adaptive immune response to H. pylori. CD4 (helper) T cells are necessary and sufficient to induce disease in H. pylori infected mice, and regulatory T cells suppress gastritis. Infection is associated with IFN_ but recent data indicate that, contrary to previous assumptions, several immune pathways including Th1, Th17, and possibly others contribute to gastritis due to H. pylori. Our central hypothesis is that the balance between Th-1, Th-17, and T regulatory cells determines the outcome of gastritis due to H. pylori. Our overall goals are to determine the role of cross-regulation between Th-1 and Th-17 in regulation of gastritis and to determine the mechanism of Treg cells in suppression of Th-1 independent and Th-17 independent gastritis. The two specific aims are: Aim 1: To determine the interactions between IFN_ and IL-17 in H. pylori gastritis. Aim 2: To determine the mechanism by which CD4CD25Foxp3+ regulatory T cells regulate Th1- or Th17- independent inflammation due to H. pylori. In this revision we have eliminated long-term experiments and thereby decreased the number of mice to be used. This will allow us to hire additional staff to ensure rapid completion of the remaining experiments. With these changes we fully expect to complete these experiments in 2 years.