The new Cancer Inflammation Program has inspired two new projects in colon cancer that diverge from our previous focus on IL-7. One project involves IL-17A , IL-17 F and IL-25. These are T cell cytokines that are produced by cells that strongly promote the intestinal inflammation that leads to colon cancer. It has not been determined where IL-17 and 25 are produced during this inflammatory response. We have developed knockin reporter mice for the two IL-17 genes using two colors and for IL-25. This will enable us to visualize cells producing these critical inflammatory cytokines during bowel inflammation leading to colon cancer. A second project aims to inhibit the bowel inflammation leading to colon cancer. IL-27 and IL-35 are suppressive cytokines that we have cloned into the food bacterium, Lactococcus lactis. These engineered bacteria were given orally to mice with experimentally-induced fatal IBD. IL-27 rescued all mice from IBD and death and therefore is an extremely promising therapeutic. The mechanism appears to be through secondary induction of the suppressive cytokine IL-10, and subsequent inhibition of many inflammatory cytokines such as IL-23 and IL-6. We have now extended the L.lactis-IL-27 therapy to three very different mouse models of IBD, and potent therapeutic efficacy is seen in all three, greatly encouraging the development of a human trial. Currently we are characterizing a new L.lactis-IL-27 construct that is designed for human therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011150-05
Application #
8763366
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$636,846
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Hanson, Miranda L; Hixon, Julie A; Li, Wenqing et al. (2014) Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology 146:210-221.e13
McLean, Mairi H; Neurath, Markus F; Durum, Scott K (2014) Targeting interleukins for the treatment of inflammatory bowel disease-what lies beyond anti-TNF therapy? Inflamm Bowel Dis 20:389-97