PTU-103 Intra-luminal Interleukin (il)-27 Is A Potential Future Therapeutic For Inflammatory Bowel Disease

Introduction Oral Lactococcus lactis engineered to express the immunoregulatory cytokine IL-27 (LL-IL27) is therapeutically active in chronic murine enterocolitis. Here, efficacy in acute colitis was examined. Methods 2 mg 2,4,6-trinitrobenzene sulfonic acid (TNBS) was delivered intra-rectally in 45% ethanol or 45% ethanol alone into 6–8 week old male SJL mice. L. lactis control (LLC) or LL-IL-27 was delivered by oral gavage on 4 occasions, 24 h apart, commencing at colitis induction. Therapeutic effect was assessed clinically and histologically. Potential mechanisms of action were investigated. Results TNBS induced an acute severe distal colitis. LL-IL-27 led to a significant reduction in disease activity index compared to LLC (4.9 vs. 8.7/12 on day 2 (p = 0.001); 3.6 vs. 7.7/12 on day 3 (p = 0.001), improved macroscopic colitis score (p Il6, Il1β, Tnf , and Il10 , assessed by RT-PCR, with no differential effect seen with LL-IL-27. However, LL-IL-27 led to a significant reduction in IL-6 (p = 0.002), IL-1β (p = 0.001) and TNF (p = 0.014) protein assessed by ELISA. A significant reduction in colonic mucosal myeloperoxidase + neutrophil infiltrate was seen in the LL-IL-27 group (p = 0.004), along with a significant decrease in the neutrophil chemoattractant CXCL2 (p in vitro , suggesting an indirect mechanism in vivo . Peri-ulceration distal colonic mucosa was isolated by laser capture microdissection and RNA applied to mouse Genome 430 2.0 Affymetrix microarray. Principal component analysis grouped mice by treatment. 285 genes were differentially expressed (>/ + B cell infiltrate (p = 0.02). Up-regulated genes include those involved with anti-microbial defense ( RegIIIb , Clec7A, ligp1 ) and innate immune response ( cxcl10, cxcl9 ). Conclusion Intra-luminal IL-27 represents a potential therapy for human inflammatory bowel disease and acute colitis of differing aetiologies. Disclosure of Interest M. McLean: None Declared, M. Hanson: None Declared, B. Gold: None Declared, Y. Golubeva: None Declared, M. Anver: None Declared, X. Wu: None Declared, D. Sun: None Declared, L. Steidler Employee of: ActoGenix, S. Durum: None Declared.