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* = Presenting author

P078. Efficacy of human anti-macrophage migration inhibitory factor antibodies in mouse models of inflammatory bowel disease

M. Thiele1, E. Magelky2, A. Schinagl1, D. Völkel1, P. Douillard1, H. Ehrlich1, F. Scheiflinger1, R. Kerschbaumer1, C. Terhorst2, 1Baxter Innovations GmbH, Vienna, Austria, 2Beth Israel Deaconess Medical Center, Harvard Medical School, Division of Immunology, United States

Background

The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that regulates adaptive an innate immune responses, e.g. in the pathogenesis of inflammatory bowel diseases (IBD). We recently discovered a novel conformational isoform of MIF (designated ‘active MIF’), which is produced in several disease states and which is not detectable in healthy individuals. As active MIF is specifically recognized by a set of phage display derived monoclonal anti-MIF antibodies, we assessed whether these antibodies mitigate either acute or chronic enterocolitis in mice.

Methods

To induce acute colitis an agonistic monoclonal antibody directed against mouse CD40 or an isotype control were injected intraperitoneally into Rag-1−/− mice on day 0. Monoclonal antibodies directed against active MIF (or isotype control) were administered on Day 0 and Day 1, and mice were sacrificed on day 7.

Spontaneous chronic enterocolitis of IL-10−/− mice was synchronized by placing the mice on an NSAID [piroxicam] containing diet for two weeks followed by a piroxicam-free diet for two additional weeks. On Day −1 and twice per week for four weeks, mice were injected intraperitoneally with our monoclonal antibodies directed against active MIF. All mice were sacrificed for tissue harvest after four weeks.

Disease activity indices (DAI) and histology index (HI) were assessed by established scoring systems; DAI parameters: hunching, wasting, stool consistency, colon thickening; HI parameters: inflammation, hyperplasia/goblet cell depletion, epithelial damage/crypt destruction, crypt abscess.

Results

Administering our novel anti-MIF antibodies ameliorates both acute and chronic enterocolitis in the mouse – as judged by prevention of weight loss, DAI and HI. The highest efficacy was observed at a dosage of 1 mg antibody/mouse (approx. 40 mg/kg). Moreover, in the IL10−/− piroxicam model, Th1-like cytokines (IL-6, TNF-α, MCP-1) were reduced in colon homogenates upon neutralization of active MIF.

Conclusion

Our studies show that human monoclonal antibodies directed against active MIF ameliorated acute and chronic murine enterocolitis. These observed immunosuppressive effects in mice strongly support the therapeutic potential of targeting active MIF in IBD patients.