Mucosal cytokines are key components of inflammatory bowel disease (IBD) pathogenesis. This proposal will further define the role of cytokines in IBD by focusing on immunoregulatory molecules originated from two distinct CD4+ T helper cell subsets: Th1 and Th2. Th1-and Th2- cytokines exhibit activities that are likely to be relevant to early disregulation in IBD, as opposed to late tissue-damaging events. To reach our goals we have developed new tissue culture and molecular biology techniques, including isolation and characterization of mucosal T cells from endoscopic biopsies, establishment of T cell lines, clones and hybridomas, Northern blot analysis, PCR, and in situ hybridization. The central hypothesis of this proposal is that a balance between Th1- and Th2-like cells in the gut results in specific cytokine patterns that maintain local immune homeostasis, whereas an imbalance of Th1- vs Th2- like cytokines is present in IBD. This will be tested by four specific aims: 1) Characterization of CD4+ T cells and cytokines in human intestinal mucosa. This will include the isolation of T cells, their phenotypic characterization, the establishment of CD4+ T cell lines, clones and hybridomas, and assessment of their cytokine production; 2) Investigation of Th1- and Th2-like cytokine profiles in normal intestinal mucosa. This will determine which cytokines are produced, if production varies along the gastrointestinal tract, and whether Th1, Th2 or intermediate patterns are present; 3) Investigation of Th1- and Th2-like cytokine profiles in IBD-involved intestinal mucosa. This will determine which cytokines are produced in IBD, whether Th1, Th2 or intermediate patterns predominate, and define the chronic or acute nature of the inflammatory response. 4) Prospective evaluation of Th1- and Th2-like cytokine profiles in IBD. This will provide a dynamic perspective of mucosal cytokines in IBD, improve the detection of specific cytokine patterns, and determine how cytokine profiles vary with clinical status. The identification of mediators responsible for abnormal mucosal immunoregulation in IBD will facilitate searching for inhibitors to control inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK030399-10
Application #
3229428
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1982-08-01
Project End
1997-11-30
Budget Start
1993-01-01
Budget End
1993-11-30
Support Year
10
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Angulo, Sandra; Morales, Albert; Danese, Silvio et al. (2011) Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase. PLoS One 6:e16953
Sturm, Andreas; de Souza, Heitor S P; Fiocchi, Claudio (2008) Mucosal T cell proliferation and apoptosis in inflammatory bowel disease. Curr Drug Targets 9:381-7
Danese, Silvio; Sans, Miquel; Spencer, David M et al. (2007) Angiogenesis blockade as a new therapeutic approach to experimental colitis. Gut 56:855-62
Kugathasan, S; Saubermann, L J; Smith, L et al. (2007) Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut 56:1696-705
Rieder, Florian; Cheng, Ling; Harnett, Karen M et al. (2007) Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities. Gastroenterology 132:154-65
Danese, Silvio; Dejana, Elisabetta; Fiocchi, Claudio (2007) Immune regulation by microvascular endothelial cells: directing innate and adaptive immunity, coagulation, and inflammation. J Immunol 178:6017-22
Danese, Silvio; Sans, Miquel; de la Motte, Carol et al. (2006) Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology 130:2060-73
Musso, Alessandro; Dentelli, Patrizia; Carlino, Alessandra et al. (2005) Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis 11:91-8
Reyes, Brenda M Rivera; Danese, Silvio; Sans, Miquel et al. (2005) Redox equilibrium in mucosal T cells tunes the intestinal TCR signaling threshold. J Immunol 175:2158-66
Danese, Silvio; Fiocchi, Claudio (2005) Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease. Crit Rev Immunol 25:103-21

Showing the most recent 10 out of 59 publications