Most current theories suggest that Crohn's disease is caused by an abnormal immune response to commensal bacteria In a genetically susceptible host. Defective recruitment of and faulty cytokine secretion by dendritic cells and macrophages is an attractive alternative hypothesis. We propose to test this by studying myeloid cells in the SAMPI/YitFc mouse model of chronic ileitis with a focus on dendritic cells (DCs) and macrophages. Over the past 10 years, with a focus on T cells, we have found important roles for leukocyte adhesion molecules in chronic ileitis development in SAMPI/YitFc mice. We now have preliminary data showing altered composition of the DC compartment in mesenteric lymph nodes (MLN) and lamina propria (LP) of SAMPI/YitFc mice. Many DCs and macrophages of the LP and MLN express CX3CR1, a chemokine receptor of central importance for monocyte, macrophage and dendritic cell development, homing, differentiation and survival.
Aim 1 is to test the role of the intestinal dendritic cell compartment in chronic ileifis. Based on our preliminary findings of a severe defect in CD103+ DCs and a virtual absence of retinoic acid-producing DCs in the MLN of SAMPI/YitFc mice, we will conduct reconstitution studies after selective DC depletion using CD1 IcDTR mice treated with diphtheria toxin. Multiphoton imaging in CD1 IcYFP mice will reveal the dynamics of DC migration and interactions with T cells and other cells.
Aim 2 is to test how E-cadherin-expressing DCs influence disease outcome in SAMPI/YitFc mice. These cells were recently shown to exacerbate colitis in an adoptive transfer model.
Aim 3 is to test the role of CX3CR1 in chronic ileitis by crossing existing Cx3cr1GFP mice into the SAMPI/YitFc and AKR backgrounds. DC-depleted mice will be reconstituted with monocytes or monocyte-DC precursors (MDPs) from Cx3cr1GFP/+ (heterozygous) and Cx3cr1GFP/GFP (knockout) mice. This project is designed to understand the molecular mechanisms of myeloid cell recruitment, differentiation and function in the context of chronic ileitis, which may inspire potential new therapies for Crohn's disease, directed at modulating the myeloid compartment. This is expected to impact disease management, outcome and quality of life of Crohn's patients.

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 #
8716739
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
$249,479
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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