title: Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Miranda L
authors.initials: ML
authors.lastname: Hanson
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hixon
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Li
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Felber
authors.affiliation: Laboratory Animal Services Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland.
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Anver
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Stewart
authors.affiliation: Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Janelsins
authors.affiliation: Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Datta
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Mairi H
authors.initials: MH
authors.lastname: McLean
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland. Electronic address: durums@mail.nih.gov.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Durum
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D004760:Enterocolitis / Q000276:immunology*; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases; D016753:Interleukin-10 / Q000276:immunology*; D007378:Interleukins / Q000008:administration & dosage* / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology*; D013294:Lactococcus lactis; D051379:Mice; D013601:T-Lymphocytes; D014169:Transformation, Bacterial
chemical_list: C556062:IL10 protein, mouse; C486767:Il27 protein, mouse; D007155:Immunologic Factors; D007378:Interleukins; D016753:Interleukin-10
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