Mucosal Lymphokines in Inflammatory Bowel Disease

Fiocchi, Claudio

Abstract

This project proposes to evalute the role of lymphokines, soluble products of immunologically activated cells, as modulators of the function of intestinal mucosa mononuclear cells from patients with inflammatory bowel disease (IBD). The rationale of this investigation is based on four basic points: 1) the assumption that IBD may be caused by immunoregulatory abnormalities; 2) evidence for the increasingly important role of lymphokines in the process of immunomodulation; 3) lack of information as to whether such abnormalities in IBD are cell- or lymphokine-dependent; and 4) the concept that utilization of gut-derived immune cells is more representative and, therefore, more revealing of defective immunoregulatory events responsible for IBD. Lamina propria mononuclear cells (LPMC), enzymatically isolated from surgically resected segments of IBD and control intestine, will be used in vitro to investigate: 1) the mechanism(s) responsible for the recently described decreased interleukin 2 (IL2) activity of IBD LPMC, by identifying the cell subsets responsible for IL2 production, determining the relative capacity of LPMC for producing and absorbing IL2, and determining if prostaglandins contribute to the low IL2 levels in IBD; 2) the mechanisms of generation of lymphokine-activated killer (LAK) cells from IL2-cultured LPMC, identifying the precursor and effector cell(s), defining the role of interferon (IFN) in the induction of LAK cells, and assessing whether IBD LPMC exhibit deficient LAK cell function in the presence of autologous IL2; 3) the role of IFN in mucosal immunity by confirming that IBD LPMC produce less IL2-induced IFN than controls, identifying the cell(s) type responsible for IFN production, and measuring the activity of an IFN-induced enzyme; and 4) the role of interleukin 1 (IL1) as a mediator of immunoregulation and inflammation in IBD, by confirming that intestinal mucosa macrophages spontaneously produce high levels of IL1 in culture, investigating whether antigen-specific stimulated T cells can activate macrophages to produce IL1, and if such activation is mediated by IFN-gamma. This proposal will test the hypothesis that investigation of the production of and response to various lymphokines may reveal fundamental defects of mucosal immunoregulation contributing to the pathogenesis of IBD.