The regulation of macrophage and dendritic cell (DC) responses to ingested antigens and luminal microorganisms is a critical component of homeostasis in the intestinal muosa. We have reported that resident macrophages in normal human intestine are profoundly down-regulated for inflammatory responses due to exposure to mucosal stromal cell products, particularly TGF-beta (Smythies, et al. J. Clin. Invest. 115:66, '05). This down-regulation likely contributes to the near absence of inflammation in normal small intestine. Regarding intestinal DCs, our preliminary results suggest that resident DCs in normal human small intestinal mucosa are less prevalent, express lower levels of maturation and activation markers, and release lower levels of cytokines than DCs in the non-inflamed mucosa of patients with Crohn's disease. Thus, DCs in normal intestinal mucosa, like intestinal macrophages, may be down-regulated for inflammatory activity, suggesting that intestinal DCs also contribute to the low level of inflammation in normal intestinal mucosa, DCs in non-inflamed intestinal mucosa of patients with Crohn's disease may be less stringently downregulated and thus able to promote inflammation. Our preliminary results suggest that intestinal lamina propria stroma releases factors that down-regulate the maturity and inflammatory potential of monocyte-derived DCs (M-DCs), indicating a possible mechanism by which intestinal DCs, which likely are derived from the circulation, become down-regulated for inflammatory activity in normal intestinal mucosa. Therefore, to confirm and extend our preliminary results, we propose in this application to test the following two hypotheses: (1) Primary human intestinal DCs from patients with Crohn's disease are more prevalent, more mature and more activated than DCs from normal intestine and (2) The reduced level of maturity and activation of DCs in normal intestinal mucosa compared to that of DCs in Crohn's disease intestinal mucosa is due to intestinal stromal factors on DCs recruited from the circulation into the lamina propria. Using homologous primary intestinal DCs and M-DCs, we propose to test the above hypotheses with the following two Specific Aims: 1. Determine whether small intestinal DCs from patients with Crohn's disease are more prevalent, more mature and more activated than DCs from normal intestine, enabling DCs from Crohn's disease tissue to present antigen more efficiently than DCs from normal intestinal tissue. 2. Determine whether the reduced level of maturity and activation of DCs from normal intestinal mucosa compared to DCs from Crohn's disease mucosa is due to the effects of intestinal stromal factors on DCs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK074033-01
Application #
7023429
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2005-09-30
Project End
2007-08-31
Budget Start
2005-09-30
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$181,875
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Smythies, Lesley E; Shen, Ruizhong; Bimczok, Diane et al. (2010) Inflammation anergy in human intestinal macrophages is due to Smad-induced IkappaBalpha expression and NF-kappaB inactivation. J Biol Chem 285:19593-604
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Maheshwari, Akhil; Smythies, Lesley E; Wu, Xiaoyun et al. (2006) Cytomegalovirus blocks intestinal stroma-induced down-regulation of macrophage HIV-1 infection. J Leukoc Biol 80:1111-7
Smythies, Lesley E; Maheshwari, Akhil; Clements, Ronald et al. (2006) Mucosal IL-8 and TGF-beta recruit blood monocytes: evidence for cross-talk between the lamina propria stroma and myeloid cells. J Leukoc Biol 80:492-9
Wahl, Larry M; Wahl, Sharon M; Smythies, Lesley E et al. (2006) Isolation of human monocyte populations. Curr Protoc Immunol Chapter 7:Unit 7.6A
Smythies, Lesley E; Wahl, Larry M; Smith, Philip D (2006) Isolation and purification of human intestinal macrophages. Curr Protoc Immunol Chapter 7:Unit 7.6B