C. De Salvo

P.05.2 PATHOGENIC ROLE OF IL-33-MEDIATED EOS INFILTRATION AND FUNCTION IN EXPERIMENTAL INFLAMMATORY BOWEL DISEASE

Background and aim: IL-33, a new member of the IL-1 family, is linked to several immune and inflammatory disorders, such as IBD. Eosinophils (EOS) are found in active inflammatory lesions of IBD patients and can secrete proinflammatory molecules, alter epithelial barrier function and initiate mucosal immune responses leading to chronic gut inflammation. Recent evidence show that IL-33 can regulate EOS infiltration and function. The aim of this study is to determine IL-33-mediated EOS activation and ileal inflammation in the SAMP1/YitFc (SAMP) murine model of chronic enteritis. Material and methods: EOS were detected by IHC for major basic protein (MBP). IL-33 and EOS-associated cytokines, IL-5 and eotaxin-1,-2,-3, were measured by qPCR in a timecourse study of SAMP and AKR (parental control) ilea. Th2 cytokines were measured by ELISA in mesenteric lymph nodes (MLN) of SAMP treated daily with rIL-33 (33 ug/kg, ip for 1wk). EOS depletion and IL-33 neutralization studies were performed by ip administration (2X/wk for 6 wks) of Abs against IL-5/CCR3 and anti-ST2 (all 5mg/kg), respectively, on inflamed SAMP, and ileitis and cytokine expression evaluated. Results: Ileal IL-33, IL-5, and eotaxin-1 & -2 mRNA transcripts increased according to disease severity in SAMP (4vs. 20-wk-old, p<0.01) and were elevated vs. age-matched AKR controls (p<0.05). EOS infiltration showed a similar trend with more abundant and intense MBP staining in cells morphologically resembling EOS during disease progression in SAMP, and was virtually absent in AKR. Administration of rIL-33 induced an increase in the Th2 cytokines, IL-4, -5, &-10, levels in MLN of treated vs. vehicle-treated mice (p<0.05). Lastly, administration of either anti-IL-5/anti-CCR3 or antiST2 to inflamed SAMP resulted in a marked decrease in ileal inflammation (p<0.01), EOS infiltration, and Th2 cytokine/eotaxin-1&-2 mRNA expression (p<0.01) vs. IgG control-treated mice. Conclusions: Taken together, these data demonstrate a pathogenic role of IL33-mediated EOS infiltration and function in chronic intestinal inflammation, and that blockade of IL-33 and/or downstream EOS activation may represent a novel therapeutic modality to treat patients with IBD.