Project 4, headed by Dr. Theresa Pizarro, will focus on epithelial-immune cell interactions, specifically the interplay between the intestinal epithelium, DCs and T cells. The central hypothesis is that intestinal DCs prematurely exposed to luminal antigens as a direct consequence of an inherent defect in intestinal epithelial barrier function leads to aberrant innate DC activation that drives dysregulated adaptive immunoregulatory processes, resulting in uncontrolled chronic gut inflammation similar to that observed in CD.
Specific Aim 1 will characterize epithelial-DC interactions leading to activation of the intestinal lamina propria (LP) DC population. DCs will be purified from the LP and mesenteric lymph nodes (MLNs) of SAMP, SAMP-ChrX*B6, as well as control AKR and 86 mice. Epithelial-DC interactions will be investigated by a variety of techniques, including cytokine and chemokine measurement, FACS and in vitro cell culture analysis and static confocal and dynamic 2-photon microscopy. Finally, the impact of the bacterial flora on epithelial-DC interactions will be evaluated in germ-free (GF), compared to specific pathogen-free (SPF) SAMP mice.
In Aim 2, we will determine how inherent epithelial barrier dysfunction results in loss of intestinal resident DC anergy/tolerance and consequently drives dysregulated T regulatory cell (Treg) function. The ability of DCs from the SAMP, SAMP-ChrX*B6, and controls to polarize Teff/Treg cell populations will be assessed by multiple techniques, both in vitro and in vivo to precisely define DC/Treg interaction in this model.
Aim 3 will evaluate the precise genetic contribution of ChrX-linked genes to the development of chronic ileitis in the SAMP strain. B6-ChrX*SAMP will be generated and fine gene mapping will be performed to identify and potentially confirm candidate disease susceptibility genes on ChrX (i.e., claudin-2, TLR cluster, FoxP3) previously shown to be dysregulated in SAMP mice. The overall goal of this project is to further elucidate the mechanism(s) of chronic intestinal inflammation characteristic of CD, and identify potential, early disease pathways that can lead to targeted therapeutic strategies to treat patients suffering from this devastating disease.

Public Health Relevance

CD affects more than 500,000 individuals in the US and incurs significant costs to society. Understanding the precise mechanisms and immune defects that cause the disease will allow us to develop better therapies and begin to develop a cure for this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK091222-04
Application #
8716740
Study Section
Special Emphasis Panel (ZDK1-GRB-6)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$195,314
Indirect Cost
$81,272
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ray, Shuvra; De Salvo, Carlo; Pizarro, Theresa T (2014) Central role of IL-17/Th17 immune responses and the gut microbiota in the pathogenesis of intestinal fibrosis. Curr Opin Gastroenterol 30:531-8
Ryan, Sean O; Leal Jr, Sixto M; Abbott, Derek W et al. (2014) Mgat2 ablation in the myeloid lineage leads to defective glycoantigen T cell responses. Glycobiology 24:262-71
Goodman, W A; Garg, R R; Reuter, B K et al. (2014) Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol 7:1255-65
Bamias, Giorgos; Arseneau, Kristen O; Cominelli, Fabio (2014) Cytokines and mucosal immunity. Curr Opin Gastroenterol 30:547-52
Tigno-Aranjuez, Justine T; Benderitter, Pascal; Rombouts, Frederik et al. (2014) In vivo inhibition of RIPK2 kinase alleviates inflammatory disease. J Biol Chem 289:29651-64
Corridoni, Daniele; Arseneau, Kristen O; Cominelli, Fabio (2014) Functional defects in NOD2 signaling in experimental and human Crohn disease. Gut Microbes 5:340-4
Corridoni, Daniele; Arseneau, Kristen O; Cominelli, Fabio (2014) Inflammatory bowel disease. Immunol Lett 161:231-5
Cavalcanti, Elisabetta; Vadrucci, Elisa; Delvecchio, Francesca Romana et al. (2014) Administration of reconstituted polyphenol oil bodies efficiently suppresses dendritic cell inflammatory pathways and acute intestinal inflammation. PLoS One 9:e88898
Goodman, Wendy A; Pizarro, Theresa T (2013) Regulatory cell populations in the intestinal mucosa. Curr Opin Gastroenterol 29:614-20
Pastorelli, Luca; De Salvo, Carlo; Vecchi, Maurizio et al. (2013) The role of IL-33 in gut mucosal inflammation. Mediators Inflamm 2013:608187

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