Helicobacter pylori (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 an 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. Additionally, challenge of immunized mice induces a significant rise in CD4+ TH1 cell-dependent gastric inflammation that resolves following eradication of the bacteria. Based on studies performed in the previous funding period we have demonstrated that IFN? is the dominant cytokine associated with protective immunity but that IFN?-knockout mice can still be protectively immunized. Significant protection can also be achieved in p35-/- mice (IL-12 knockout mice) although not to the degree of wild type mice. Depletion of p40 however (IL-12/IL-23 double knockout mice) destroys the efficacy of vaccination. Since IL-23-dependent, proinflammatory, IL-17-producing cells (TH-17 cells) have been shown to develop in the absence of IFN? in other models, we hypothesize that immunization primarily results in the development of IL-12-dependent IFN?- producing TH1 cells that promote protective inflammation when recruited to the gastric mucosa in response to H. pylori challenge. In the absence of IFN?, IL-23-dependent TH-17 cells develop with the same potential to promote protective inflammation when recruited to the gastric mucosa following H. pylori challenge. We will explore H. pylori-associated immunity and pathogenesis in two specific aims designed to 1) determine the roles of IL-12 and IL-23-mediated T cell inflammatory pathways in promoting protective immunity against H. pylori via TH1 and TH-17 mediated pathways, and 2) investigate factors in the gastric mucosa that prevent the activation of these pathways during chronic infection with H. pylori by characterizing the recruitment and retention of regulatory T cells. By studying the inflammation associated with protective immunity against H. pylori we hope to elucidate complimentary or compensatory mechanisms that might be confounding the characterization of the protective immune response.

Public Health Relevance

A thorough investigation of the immune response to H. pylori will enhance our knowledge of the role that T cells play in promoting beneficial inflammatory pathways, increase our understanding of immunoregulation in the gastrointestinal mucosa, and suggest potential avenues for immunotherapy (including enhanced vaccines) for the treatment H. pylori infection, inflammatory bowel diseases, and other pathologies associated with the gut.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046461-17
Application #
7822951
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
1993-12-15
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
17
Fiscal Year
2010
Total Cost
$308,705
Indirect Cost
Name
University of Maryland Baltimore
Department
Pediatrics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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