Clinical Potential of <i>Lactococcus lactis</i> Mediated Delivery of Human Interleukin-10 and Trefoil Factors

Abstract

Systemic treatment with infliximab, a monoclonal antibody that binds TNFa is among the most potent therapies for Crohn's disease. Despite initial successes with intravenous addition of IL-10, this treatment was abandoned in later trials. Both treatments suffered a serious drawback from the fact that they had to be administered systemically and thus caused potentially serious side effects. We used two mouse models for IBD to evaluate the efficacy of L. lactis mediated topical delivery of IL-10. In the Dextran Sulphate Sodium (DSS)-induced chronic colitis intragastric administration of mIL-10-secreting L. lactis led to a 50% reduction in inflammation. Also, daily administration of the engineered strain prevented the onset of colitis, normally associated with the IL-10 knockout genotype. In both models, the effect was strictly dependent on delivery of live bacteria. We engineered a strain exhibiting biological containment. To this end, the thymidilate synthase (thy A) gene of L. lactis was replaced with a synthetic human IL-10 gene. ThyA-deficient bacteria are suicidal in the absence of thymine or thymidine and therefore cannot accumulate in the environment. A limited clinical trail in Crohn's patients under physical containment proved that the treatment was safe, the biological containment strategy was effective and the results obtained suggested a clinical effect. In contrast to oral administration of purified protein, intragastric administration of Trefoil factor-secreting L. lactis was very effective in prevention and healing of acute DSS colitis. In addition this approach was successful in improving established chronic colitis in IL-10 knockout mice.