Mucosal immune tolerance to luminal microbes is a highly regulated process a lack of which leads to chronic inflammation of the GI tract. H. pylori is a gastric pathogen able to cause severe chronic gastritis and ulcers in <15% of infected individuals, but the majority developed a mild gastritis without symptoms. The long-term objective of this proposal is to understand the mechanisms of mucosal tolerance in the stomach. We will build on our observations made during the K08 funding period studying the dendritic cells (DCs)-mediated mechanism of H. pylori immune escape and use the H. pylori colonization model to study gastric mucosal tolerance. Our preliminary results support the notion that Hp induction of regulatory T cells (Tregs) is mediated by DCs. Therefore, we hypothesize that H. pylori triggers a host tolerogenic response by interacting with DCs via a IRAK-M-mediated, TGF-2-dependent mechanism which alters the H. pylori Teffector/Treg balance leading to the development of host tolerance to H. pylori and chronic colonization.
The specific aims are:
Aim 1) To Determine the role of tissue DCs in H. pylori tolerance. DC subset in the stomach will be characterized during acute H. pylori infection and mechanism of H. pylori uptake and lymph node migration by DC will be elucidated. The requirement of DCs in H. pylori uptake and tolerance induction will be studied using DC ablation.
Aim 2) Investigate the role of DC TLR and intracellular modulators of tolerogenic DC programming. First we will determine whether H. pylori stimulated DCs induce Tregs requires immunogenic H. pylori. Next, the role of IRAK-M in Treg induction will be explored. The role of TLR9 will also be explored using H. pylori DNA stimulation and TLR9 null mice.
Aim 3) To analyze the role of DC-Treg induction in modulating H. pylori tolerance. We will use in vivo adoptive transfer of H. pylori-stimulated BMDCs into mice to induce H. pylori- specific Tregs and then use CD25 neutralizing antibodies to study the effect of Treg depletion on H. pylori tolerance. The role of Th1 and Th17 cells in H. pylori tolerance will be studied using IFN-3 and Th17A null mice. The effect of modulation TGF-2 on Treg induction by H. pylori stimulated DCs will be studies using cell lines over-expressing TGF-2 or produces a TGF-2 receptor that neutralizes DCs in the microenvironment. The health relatedness of this proposal is to understand the mechanism of mucosal tolerance to H. pylori to begin to address the factors that lead to reduced tolerance. The finding of this project will provide not only provide novel insight into the mechanism of mucosal tolerance to luminal bacteria, but also enhance our understanding of the development of tolerance in the gastric immune compartment. New targets may be discovered useful for designing therapies to restored immune homeostasis in patients with chronic inflammatory conditions by targeting DCs regulatory mechanisms or by using bacterial products (e.g., prebiotics, probiotics).

Public Health Relevance

The health relatedness of this proposal is to understand the mechanism of mucosal tolerance in order to begin to address the factors that lead to a break in tolerance. The finding of this project will provide not only provide novel insight into the mechanism of mucosal tolerance to luminal bacteria, but also enhance our understanding of the development of tolerance in the gastric immune compartment. New targets may be discovered useful for designing therapies to restored immune homeostasis in patients with chronic inflammatory conditions by targeting DCs regulatory mechanisms or by using bacterial products (e.g., prebiotics, probiotics).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087708-03
Application #
8423787
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
2011-02-04
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$370,634
Indirect Cost
$132,284
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Sun, Xia; Zhang, Min; El-Zaatari, Mohamad et al. (2016) CCR2 mediates Helicobacter pylori-induced immune tolerance and contributes to mucosal homeostasis. Helicobacter :
Nagao-Kitamoto, Hiroko; Shreiner, Andrew B; Gillilland 3rd, Merritt G et al. (2016) Functional Characterization of Inflammatory Bowel Disease-Associated Gut Dysbiosis in Gnotobiotic Mice. Cell Mol Gastroenterol Hepatol 2:468-481
Yang, Jyh-Chin; Lin, Chun-Jung; Wang, Hong-Long et al. (2015) High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori infection. Clin Gastroenterol Hepatol 13:895-905.e5
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
Shreiner, Andrew B; Kao, John Y; Young, Vincent B (2015) The gut microbiome in health and in disease. Curr Opin Gastroenterol 31:69-75
Grasberger, Helmut; Gao, Jun; Nagao-Kitamoto, Hiroko et al. (2015) Increased Expression of DUOX2 Is an Epithelial Response to Mucosal Dysbiosis Required for Immune Homeostasis in Mouse Intestine. Gastroenterology 149:1849-59
Takabayashi, Hidehiko; Shinohara, Masahiko; Mao, Maria et al. (2014) Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice. Gastroenterology 147:396-406.e7
Xu, Dabo; Gao, Jun; Gillilland 3rd, Merritt et al. (2014) Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Gastroenterology 146:484-96.e4
El-Zaatari, Mohamad; Chang, Yu-Ming; Zhang, Min et al. (2014) Tryptophan catabolism restricts IFN-γ-expressing neutrophils and Clostridium difficile immunopathology. J Immunol 193:807-16
Chang, Yu-Ming; El-Zaatari, Mohamad; Kao, John Y (2014) Does stress induce bowel dysfunction? Expert Rev Gastroenterol Hepatol 8:583-5

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