P106. Active macrophage migration inhibitory factor (MIF) is a previously unrecognized isoform of MIF and a potential new biomarker for inflammatory bowel diseases
D. Völkel1, M. Thiele1, P. Douillard1, R. Kerschbaumer1, F. Scheiflinger1, H. Ehrlich1, H. Tilg2, A. Moschen2, 1Baxter Innovations GmbH, Vienna, Austria, 2Medical University Innsbruck, Department of Medicine, Innsbruck, Austria
Macrophage migration inhibitory factor is a proinflammatory cytokine and exerts a multitude of regulatory actions on innate and adaptive immunity. It has been shown that MIF plays an essential role in the pathogenesis of IBD. Some features of MIF are different from those of other pro-inflammatory cytokines. MIF is constitutively expressed, stored in the cytoplasm of many different cell types and constantly present in the circulation of healthy subjects. We have discovered a novel, previously unrecognized conformational isoform of MIF (designated ‘active MIF’) that is produced in diseases and cannot be detected in healthy subjects. Active MIF is specifically recognized by a set of phage display derived human monoclonal anti-MIF antibodies showing beneficial effects in acute and chronic mouse models of IBD.
New ELISA was established that allow the determination of active MIF. Plasma samples from ulcerative colitis and Crohn's disease patients have been analyzed. Colonic biopsies for whole tissue cultures were taken from UC and CD patients from areas showing endoscopic signs of high inflammatory activity and from endoscopically normal-appearing, non-inflamed mucosa. Controls were obtained from patients without any signs of intestinal inflammation.
In plasma of healthy subjects we determined a baseline level of MIF (median 5810 pg/ml, n = 19) as expected. However, our analysis revealed that this represents the non-active isoform of MIF. Active MIF, in turn, could not be detected in the plasma from healthy controls (median 0pg/mL, n = 19), but concentrations of active MIF were significantly increased in plasma of UC patients (median 4267pg/mL, n = 15, p = 0.04 vs controls) and of CD patients (median 6378pg/mL, n = 21, p = 0.01 vs controls). To address the presence of active MIF in the colon of IBD patients, we analyzed supernatants from WTC. For both UC and CD, significant amounts of active MIF were released from biopsies taken from lesional sites (UC: median 598pg/mg/d; CD: median 768pg/mg/d). Biopsies from non-lesional sites of UC or CD patients did not release significant amounts of active MIF compared to control biopsies.
The absence of active MIF in plasma from healthy controls allows a clear distinction between disease and non-disease state. Detection of active MIF levels in WTC confirmed the production of this novel form of MIF in the diseased tissue. Our data demonstrate the suitability of active MIF as a marker for disease activity or disease progression in IBD.