Worldwide, H. pylori is the leading cause of gastritis, peptic ulceration and gastric malignancy. In developing countries, such as Chile, 60-80% of children are infected with H. pylori, but they rarely develop ulceration. In adults, chronic H. pylori infection, which is T helper 1 (Thl)-mediated, predisposes to peptic ulceration and gastric adenocarcinoma. Since large-scale medical eradication is impractical, an effective vaccine is highly desirable. Development of such a vaccine requires elucidation of the mechanism(s) by which H. pylori induces inflammation, particularly in children, the principal target population for vaccination. Accordingly, we hypothesize that: (1) H. pylori infection in children (<18 yrs) induces a local T regulatory (Tr) response (IL-10 and TGF-( production) that down-regulates an underlying Thl response and reduces the frequency of peptic ulceration. (2) In a mouse model that recapitulates human H. pylori infection, H. pylori urease (or other antigens) drives an IL-10/TGF-( dominated Tr response in young animals but a predominant Thl response in adult animals. (3) Delivery of H. pylori urease and either IL-10 or FoxP3 in a novel poliovirus vaccine vector to young mice protects the animals against H. pylori. These hypotheses will be tested with three specific aims: 1) Determine whether H. pylori infection in children and adolescents induces gastric T cell-derived IL-10 and TGF-( (a Tr response), in contrast to IFN-y and IL-2 (a Thl response) characteristic of H. pylori-infected adults. 2) Determine whether the Tr vs Thl dichotomy in H. pylori-infected children vs adults occurs in H. pylori-infected mice in order to define the molecular mechanisms of protection. 3) Determine whether vaccination of young mice with a novel poliovirus vector (replicons) incorporating the gene for the B subunit of H. pylori urease plus IL-10 or FoxP3 (the Tr cell transcription factor) protects mice against H. pylori infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054495-10
Application #
7624725
Study Section
Special Emphasis Panel (ZRG1-GMPB (01))
Program Officer
Hamilton, Frank A
Project Start
1998-09-30
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
10
Fiscal Year
2009
Total Cost
$297,443
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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