A39 TARGETING IL-4 TO TREAT CROHN’S DISEASE ASSOCIATED INTESTINAL FIBROSIS IN SHIP DEFICIENT MICE

Abstract

Abstract Background Crohn’s disease (CD) is an immune-mediated disease characterized by chronic, relapsing, or progressive inflammation along the gastrointestinal tract. One in 3 people with CD will develop intestinal fibrosis requiring surgery within 10 years of diagnosis. Biological therapy is very effective at reducing inflammation in CD; however, biologics do not reduce the incidence of fibrosis or surgery in people with CD, suggesting that a distinct mechanism(s) may exist that drives intestinal fibrosis. Treatments for intestinal fibrosis are urgently needed as currently, no treatment exists that target intestinal fibrosis directly. Mice deficient in the Src homology 2 domain-containing inositolphosphate 5’-phosphatase (SHIP-/-) develop spontaneous CD-like ileal inflammation and fibrosis. Fibrosis is dependent on PI3Kp110δ activation, which leads to induction of the enzyme arginase I (argI). Genetic ablation or pharmacologic inhibition of PI3Kp110δ or inhibition of arginase activity blocked the development of intestinal fibrosis in SHIP-/- mice. Both IL-4 and IL-13 can activate PI3Kp110δ but intestinal pathology in SHIP-/- mice is characterized by high levels of IL-4. Thus, we hypothesize that SHIP-/- mice develop CD-like intestinal fibrosis due to increased IL-4 signalling. Aims Aim 1: To determine whether genetic ablation of IL-4 prevents ileal fibrosis in SHIP-/- mice Aim 2 To determine whether inhibition of IL-4 activity can block or reverse ileal fibrosis in SHIP-/- mice Methods SHIP-/- mice were crossed with mice deficient in IL-4 (IL-4-/-) to generate wild type, SHIP+/+IL-4-/- SHIP-/-IL-4+/+, and SHIP-/-IL4-/- mice. Fibrosis was assessed in mice at 8 weeks of age. SHIP-/- mice (8-week-old) were treated with an anti-IL-4 antibody, IgG isotype control or PBS (injection control), for 2 weeks. Ileal fibrosis was assessed in SHIP-/- mice and compared to mice treated with anti-IL-4 antibody or controls. Measurements of ileal fibrosis include muscle thickening, and collagen accumulation by Masson’s trichrome staining. Results SHIP-/-IL4-/- mice do not have less ileal fibrosis than their SHIP-/- littermates. Inhibition of IL-4 signalling in SHIP-/- mice did not reduce ileal fibrosis. Conclusions Blocking IL-4 is not sufficient to block the development of ileal fibrosis in SHIP-/- mice. In future experiments, we will examine whether blocking IL-13, alone or in combination with IL-4, can ameliorate the development of intestinal fibrosis in SHIP-/- mice. Funding Agencies CIHR