Abstract
Background & Aims: Treatment of inflammatory bowel disease would benefit from specific targeting of therapeutics to the intestine. We developed a strategy for localized delivery of the immunosuppressive cytokine interleukin (IL)-27, which is synthesized actively in situ by the food-grade bacterium Lactococcus lactis (LL-IL-27), and tested its ability to reduce colitis in mice.
Methods: The 2 genes encoding mouse IL-27 were synthesized with optimal codon use for L lactis and joined with a linker; a signal sequence was added to allow for product secretion. The construct was introduced into L lactis. Colitis was induced via transfer of CD4+CD45RBhi T cells into Rag -/- mice to induce colitis; 7.5 weeks later, LL-IL-27 was administered to mice via gavage. Intestinal tissues were collected and analyzed.
Results: LL-IL-27 administration protected mice from T-cell transfer-induced enterocolitis and death. LL-IL-27 reduced disease activity scores, pathology features of large and small bowel, and levels of inflammatory cytokines in colonic tissue. LL-IL-27 also reduced the numbers of CD4+ and IL-17+ T cells in gut-associated lymphoid tissue. The effects of LL-IL-27 required production of IL-10 by the transferred T cells. LL-IL-27 was more effective than either LL-IL-10 or systemic administration of recombinant IL-27 in reducing colitis in mice. LL-IL-27 also reduced colitis in mice after administration of dextran sodium sulfate.
Conclusions: LL-IL-27 reduces colitis in mice by increasing the production of IL-10. Mucosal delivery of LL-IL-27 could be a more effective and safer therapy for inflammatory bowel disease.
Original language | English |
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Pages (from-to) | 210-221.e13 |
Number of pages | 25 |
Journal | Gastroenterology |
Volume | 146 |
Issue number | 1 |
Early online date | 11 Oct 2013 |
DOIs | |
Publication status | Published - 1 Jan 2014 |
Keywords
- Crohn's Disease
- Immune Regulation
- Mouse Model
- Ulcerative Colitis
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
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McLean, Mairi H
- Respiratory Medicine and Gastroenterology - Clinical Reader (Teaching and Research)
Person: Academic