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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Cleveland Clinic Lerner
United States
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