Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and plays an etiologic role in the development of gastritis, peptic ulcers, and gastric cancer. Infection persists for life despite the induction of histologic gastritis and specific immune responses yet the mechanisms that prevent the host from eradicating H. pylori remain ill-defined. Paradoxically, studies in mice have shown that anti- H. pylori immunity can be induced by vaccination, indicating that activation of the immune response differs in significant ways between vaccination and infection. Depletion studies in mice have shown that lack of IL-10, or CD25+ Treg cells confers the ability to develop more severe inflammation and protective immunity against H. pylori. Therefore, regulatory T cells might play an important role in limiting the natural host response to infection. These Treg cells have been identified in the gastric mucosa of patient gastric biopsies and in vitro analysis of patient lymphocytes reveals increased lymphocyte activity when these cells are depleted. The source of these regulatory T cells remains obscure however, and the limits of their regulatory activity have not been established. This proposal will test the hypothesis that Helicobacter infection activates Treg cells in mucosa of the small intestines which then disseminate to the gastric mucosa where they limit the host inflammatory response. Additionally, that these Treg cells have significant regulatory activity over effector T cells activated in concert with the Treg cells similar to the host response to commensal flora, but not effector T cells activated in organized lymphoid structures under conditions that approximate acute pathogenic bacterial infection. We will address this hypothesis by: 1) Establishing the tissue origin of H. pylori-specific Treg cells through adoptive transfer of isolated cell populations and the use of organ- specific deletion models in mice, 2) Defining the elements of the microenvironment that contribute to the activation of H. pylori-specific Treg cells by evaluating the contribution of specific antigen presentation cells and antigen presentation co-receptors in a murine model of H. pylori pathogenesis, and 3) Determining the extent of H. pylori-specific Treg cell activity with regard to their ability to regulate H. pylori-specific effector cells activated in various tissues under differing conditions in mice. These studies will increase our understanding of gastrointestinal immunoregulation and the design of better immunologic or pharmacologic therapies for inflammation-based disorders.
The bacterium Helicobacter pylori infects the human stomach and is an etiologic agent for gastritis, ulcers, gastric lymphoma, and gastric cancer. The host develops an inflammatory response but is not able to eradicate the bacteria because the host also down-regulates important aspects of the protective immune response. The identification of the source of these regulatory cells and understanding the limits of their activity will aid in the development of immunologic and pharmacologic treatments for patients at risk or afflicted with inflammation based disorders.
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