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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GMPB (01))
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Bimczok, D; Kao, J Y; Zhang, M et al. (2015) Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells. Mucosal Immunol 8:533-44
Brawner, Kyle M; Morrow, Casey D; Smith, Phillip D (2014) Gastric microbiome and gastric cancer. Cancer J 20:211-6
Das, Soumita; Sarkar, Arup; Ryan, Kieran A et al. (2014) Brain angiogenesis inhibitor 1 is expressed by gastric phagocytes during infection with Helicobacter pylori and mediates the recognition and engulfment of human apoptotic gastric epithelial cells. FASEB J 28:2214-24
Serrano, Carolina; Wright, Shelton W; Bimczok, Diane et al. (2013) Downregulated Th17 responses are associated with reduced gastritis in Helicobacter pylori-infected children. Mucosal Immunol 6:950-959
Bimczok, Diane; Smythies, Lesley E; Waites, Ken B et al. (2013) Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells. J Immunol 190:6626-34
Smith, P D; Smythies, L E; Shen, R et al. (2011) Intestinal macrophages and response to microbial encroachment. Mucosal Immunol 4:31-42
Bimczok, Diane; Grams, Jayleen M; Stahl, Richard D et al. (2011) Stromal regulation of human gastric dendritic cells restricts the Th1 response to Helicobacter pylori. Gastroenterology 141:929-38
Shen, Ruizhong; Meng, Gang; Ochsenbauer, Christina et al. (2011) Stromal down-regulation of macrophage CD4/CCR5 expression and NF-?B activation mediates HIV-1 non-permissiveness in intestinal macrophages. PLoS Pathog 7:e1002060
Huff, K R; Akhtar, L N; Fox, A L et al. (2011) Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa. Mucosal Immunol 4:420-7
Shen, Ruizhong; Richter, Holly E; Smith, Phillip D (2011) Early HIV-1 target cells in human vaginal and ectocervical mucosa. Am J Reprod Immunol 65:261-7

Showing the most recent 10 out of 40 publications