The inflammatory bowel diseases (i.e. ulcerative colitis (UC) and Crohn's disease (CD)) are associated with accumulation of dendritic cells (DC) into the inflamed intestine and draining lymph nodes. These chronic inflammatory conditions may in part be due to failure by DC to induce T cell tolerance in a retinoic acid-dependent manner. To explore whether this is the case we will utilize spontaneous models of chronic murine ileitis to longitudinally examine the role of DC in inducing, perpetuating and regulating Intestinal inflammation. Furthermore, these studies will also examine the sources of retinoic acid (RA) in the terminal ileum of TNF-overproducing (i.e. TNF ARE) and SAMP1/YitFc mice, which spontaneously develop Crohn's-like ileitis and the effect of RA and growth factors that promote expansion of tolerogenic DC on chronic Inflammation. Our preliminary data demonstrates that pro-regulatory CD103POS DC subset and their RA synthetic machinery is decreased in TNF ARE ileal lamina propria at 20-weeks-of-age resulting in a decrease in regulatory CD4+/CD25+/FoxP3+ regulatory T cells, despite upregulation of the RA synthetic machinery of intestinal epithelial cells (IEC). Supplementation with all-trans retinoic acid and administration of fms-like tyrosine ligand (FLT3L) significantly attenuated Ileitis, suggesting that IEC-derived RA was insufficient to sustain intestinal RA concentrations. However, the mechanism of RA- and FLT3L-mediated attenuation of ileitis remains unclear. As a result, the proposed studies will 1) elucidate the mechanisms of regulatory T cell deficiency in models of ileitis 2) examine the mechanism of action of all-trans RA as a therapeutic agent in chronic ileitis. 3) Explore the mechanisms of action of growth factors such as FLT3L and GMCSF behind the attenuation of chronic ileitis. Given the therapeutic effect of RA supplementation and FLT3L administration in clinically relevant models of ileitis, these studies may provide feasibility for the evaluation of dendritic cell-based manipulation as a novel therapeutic strategy in CD.

Public Health Relevance

Inflammatory Bowel Disease (IBD) accounted for 13,468 admissions to VA hospitals from 1986 to 1989. Crohn's disease in particular affects predominantly young Americans (peak incidence age = 24 years), thus it disproportionately affects U.S. military service personnel. Although anti-TNF therapies are effective in up to 70% of patients, this leaves one third of patients with limited therapeutic options. Therefore, alternative biological therapies must be evaluated in IBD. Modulation of proinflammatory responses by tilting the balance towards regulation is an attractive strategy. We show that increasing anti-inflammatory cells and their products attenuates inflammation in mouse models of Crohn's-like IBD with high translational value. These studies aim at understanding how these compounds work, with an ultimate goal to find new drugs to treat the numerous veterans that suffer from IBD.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
7I01BX001051-02
Application #
8413327
Study Section
Gastroenterology (GAST)
Project Start
2011-04-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2013
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161