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).
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).
|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|
|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|
|Chang, Yu-Ming; El-Zaatari, Mohamad; Kao, John Y (2014) Does stress induce bowel dysfunction? Expert Rev Gastroenterol Hepatol 8:583-5|
|Rubenstein, Joel H; Inadomi, John M; Scheiman, James et al. (2014) Association between Helicobacter pylori and Barrett's esophagus, erosive esophagitis, and gastroesophageal reflux symptoms. Clin Gastroenterol Hepatol 12:239-45|
|El-Zaatari, Mohamad; Chang, Yu-Ming; Zhang, Min et al. (2014) Tryptophan catabolism restricts IFN-?-expressing neutrophils and Clostridium difficile immunopathology. J Immunol 193:807-16|
|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; Kao, John Y; Tessier, Art et al. (2013) Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets. PLoS One 8:e58935|
|Sun, Yundong; Zhang, Min; Chen, Chun-Chia et al. (2013) Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology 144:1478-87, 1487.e1-8|
|Rubenstein, Joel H; Morgenstern, Hal; McConell, Daniel et al. (2013) Associations of diabetes mellitus, insulin, leptin, and ghrelin with gastroesophageal reflux and Barrett's esophagus. Gastroenterology 145:1237-44.e1-5|
|Yang, Jyh-Chin; Yang, Hung-Chih; Shun, Chia-Tung et al. (2013) Catechins and Sialic Acid Attenuate Helicobacter pylori-Triggered Epithelial Caspase-1 Activity and Eradicate Helicobacter pylori Infection. Evid Based Complement Alternat Med 2013:248585|
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