Abstract

This project proposes to evaluate the role of cytokines, soluble products of immunologically activated cells, as modulators of the function of intestinal mucosal mononuclear cells from patients with inflammatory bowel disease (IBD). The rationale of this investigation is based on the assumption that IBD may be caused by immunoregulatory abnormalities, evidence for a fundamental role of cytokines in the process of immunoregulation, previous reports of cytokine abnormalities in IBD, and the concept that utilization of gut-derived immune cells better reflects immunoregulatory defects that may be present in the diseased bowel. Lamina propria mononuclear cells (LPMC) enzymatically isolated from surgically resected bowel segments, will be used in cellular immunology and molecular biology assays to investigate: 1) the role of interleukin 1 and tumor necrosis factor as mediators of immunoregulation and inflammation in IBD, by identifying their producer cells, their ability to induce inflammatory mediators, and explore their direct cytotoxic potential; 2) whether cellular and soluble interleukin 2 receptors (IL2R) better reflect the in vivo state of activation of LPMC, by measuring levels of soluble IL2R in plasma and culture supernatants and correlating them with number of IL2R positive cells and IL2 activity; 3) the role of interleukin 4 (IL4) as a modulator of LPMC, by measuring production of ad response to IL4 by mucosal T cells, investigation the relationship of IL4 to other cytokines, and the potential for IL4 to induce cytotoxicity from LPMC; 4) whether the technique of limiting dilution assay (LDA) may provide new insights into functional differences between IBD and control LPMC that are not detectable in conventional bulk culture conditions; and 5) production of cytokines by LPMC by quantitative and qualitative determination of their messenger RNA in fresh and cultured cells. This proposal is pursuing the hypothesis that study of cytokine relevant to intestinal mucosal immunity may reveal fundamental abnormalities of immunoregulation contributing to the patho-genesis of IBD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK030399-09
Application #
3229433
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1982-08-01
Project End
1992-12-31
Budget Start
1991-07-01
Budget End
1992-12-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195

  Publications

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

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