Immunobiology and Prevention of H. pylori Disease

University Of Alabama At Birmingham, Birmingham AL

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] pylori infection in children (<18 yrs) induces a local T regulatory (Tr) response (IL-10 and TGF-( [unreadable] production) that down-regulates an underlying Thl response and reduces the frequency of peptic [unreadable] ulceration. (2) In a mouse model that recapitulates human H. pylori infection, H. pylori urease (or [unreadable] other antigens) drives an IL-10/TGF-( dominated Tr response in young animals but a predominant [unreadable] Thl response in adult animals. (3) Delivery of H. pylori urease and either IL-10 or FoxP3 in a novel [unreadable] poliovirus vaccine vector to young mice protects the animals against H. pylori. These hypotheses [unreadable] will be tested with three specific aims: [unreadable] [unreadable] 1) Determine whether H. pylori infection in children and adolescents induces gastric T cell-derived [unreadable] IL-10 and TGF-( (a Tr response), in contrast to IFN-y and IL-2 (a Thl response) characteristic of [unreadable] H. pylori-infected adults. [unreadable] [unreadable] 2) Determine whether the Tr vs Thl dichotomy in H. pylori-infected children vs adults occurs in H. [unreadable] pylori-infected mice in order to define the molecular mechanisms of protection. [unreadable] [unreadable] 3) Determine whether vaccination of young mice with a novel poliovirus vector (replicons) [unreadable] incorporating the gene for the B subunit of H. pylori urease plus IL-10 or FoxP3 (the Tr cell [unreadable] transcription factor) protects mice against H. pylori infection. [unreadable] [unreadable]