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

TY - JOUR

T1 - Oral delivery of il-27 recombinant bacteria attenuates immune colitis in mice

AU - Hanson, Miranda L.

AU - Hixon, Julie A.

AU - Li, Wenqing

AU - Felber, Barbara K.

AU - Anver, Miriam R.

AU - Stewart, C. Andrew

AU - Janelsins, Brian M.

AU - Datta, Sandip K.

AU - Shen, Wei

AU - McLean, Mairi H.

AU - Durum, Scott K.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Crohn's Disease

KW - Immune Regulation

KW - Mouse Model

KW - Ulcerative Colitis

UR - https://www.scopus.com/pages/publications/84890608517

U2 - 10.1053/j.gastro.2013.09.060

DO - 10.1053/j.gastro.2013.09.060

M3 - Article

AN - SCOPUS:84890608517

SN - 0016-5085

VL - 146

SP - 210-221.e13

JO - Gastroenterology

JF - Gastroenterology

IS - 1

ER -