2. Academic Validation
  3. Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice

Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice

  • Gastroenterology. 2014 Jan;146(1):210-221.e13. doi: 10.1053/j.gastro.2013.09.060.
Miranda L Hanson 1,  Julie A Hixon 1,  Wenqing Li 1,  Barbara K Felber 2,  Miriam R Anver 3,  C Andrew Stewart 1,  Brian M Janelsins 4,  Sandip K Datta 4,  Wei Shen 1,  Mairi H McLean 1,  Scott K Durum 5
Affiliations

Affiliations

  • 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
  • 2 Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
  • 3 Laboratory Animal Services Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland.
  • 4 Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
  • 5 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland. Electronic address: durums@mail.nih.gov.
PMID: 24120477 DOI: 10.1053/j.gastro.2013.09.060
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.

Keywords

Crohn's Disease; DAI; DP; DSS; Ebi3; Epstein–Barr virus–induced protein 3; GI; IBD; IEL; IFN; IL; Immune Regulation; LAL; LL; LPS; Lactococcus lactis; MLN; Mouse Model; PBS; SI; T-helper cell; Th; Ulcerative Colitis; dextran sulfate sodium; disease activity index; double positive; gastrointestinal; inflammatory bowel disease; interferon; interleukin; intraepithelial lymphocyte; limulus amebocyte lysate; lipopolysaccharide; mRNA; mesenteric lymph node; messenger RNA; phosphate-buffered saline; recombinant mouse; rm; small intestine.

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