Abstract

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. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054495-08
Application #
7261408
Study Section
Special Emphasis Panel (ZRG1-GMPB (01))
Program Officer
Hamilton, Frank A
Project Start
1998-09-30
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
8
Fiscal Year
2007
Total Cost
$303,513
Indirect Cost

  Institution

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

  Publications

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