112 : Lactococcus lactis expressing IL-27: A potential therapeutic for inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) affects approximately 1.4 million individuals in the United States and greatly predisposes to colon cancer. Developing precise targeting of therapeutics to the intestine would advance IBD treatment. Thus, we aimed to develop a localized delivery of the immuno- suppressive cytokine IL-27 that is actively synthesized in situ by the food-grade bacterium, Lactococcus lactis (LL-IL-27) to treat chronic IBD. LL-IL-27 showed a substantial therapeutic benefit in T cell transfer induced enterocolitis, DSS colitis and TNBS colitis. LL-IL-27 improved survival, decreased disease activity, and reduced inflammatory cytokine levels in the colonic tissue of diseased mice. LL-IL-27 mice had normal colon and small intestine histology, while control mice had extensive inflammation, crypt abscesses, goblet cell loss, and intraepithelial neoplasia. In addition, LL-IL-27 decreased CD4+ and IL-17+ T cells and increased CD4+CD8αα+ T cells in the intraepithelium of the small intestine. In the T cell transfer model of enterocolitis, the therapeutic benefit required induction of IL-10 in the transferred T cell population. Furthermore, LL-IL-27 was more effective in reducing disease activity and colon pathology than either LL-IL-10 or systemic administration of recombinant mouse IL-27. LL-IL-27 treatment was not associated with any pathology nor did it affect intestinal barrier function or exacerbate infection with the enteric pathogen Citrobacter rodentium. These results suggest that mucosal delivery of LL-IL-27 offers promise as a more effective and safer management of IBD in humans.