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(+)CD45RB(hi) 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 |
|---|---|
| Pages (from-to) | 210-221.e13 |
| Number of pages | 25 |
| Journal | Gastroenterology |
| Volume | 146 |
| Issue number | 1 |
| Early online date | 9 Oct 2013 |
| DOIs | |
| Publication status | Published - Jan 2014 |
Bibliographical note
The authors thank Kelli Czarra and Megan Karwan for animal technicalassistance, Kathleen Noer, Roberta Matthai, and Guity Mohammadi for flow
cytometry assistance, Christopher Karp for use of Vert-X mice, and Giorgio
Trinchieri for use of interleukin-10-/- mice. The authors are also grateful to
Joost J. Oppenheim for critical review of the manuscript.
This research was supported in part by grants from the Crohn’s and Colitis
Foundation of America and the Eli and Edythe Broad Foundation, the
Intramural Research Program of the National Institutes of Health, and with
federal funds from the National Cancer Institute, National Institutes of Health
(contract HHSN261200800001E).
Keywords
- Mouse Model
- Crohn's Disease
- Ulcerative Colitis
- Immune Regulation