Local delivery of adenoviral vectors encoding murine interleukin 10 induces colonic interleukin 10 production and is therapeutic for murine colitis

Introduction: Interleukin 10 knockout (IL-10-/-)mice spontaneously develop a Th1 T cell mediated colitis with many similarities to Crohn's disease. Daily injections of IL-10 are unable to induce remission in mice with established disease. In contrast, we have shown previously that intravenous administration of adenoviral vectors encoding IL-10 (AdvmuIL-10) induces hepatic IL-10 release and leads to long term disease suppression with profound systemic immunoregulatory changes. Aims: To determine whether rectal delivery of AdvmuIL-10 induces localised colonic IL-10 expression without systemic immune suppression, and assess its therapeutic efficacy in IL-10-/- mice with established colitis. Results: A single rectal infusion of 5x10(8) PFU AdvmuIL-10 to 10 week IL-10-/- mice resulted in a median level of 27.3 pg/mg IL-10 in colonic homogenates harvested one week later. IL-10-/- mice. with established colitis treated with an enema of 5x10(8) PFU AdvmuIL-10 entered clinical and histological remission whereas empty cassette adenovirus (AdvO) or phosphate buffered saline (PBS) treated mice developed progressive disease. After four weeks, the histological score of AdvmuIL-10 treated mice (4.4 (1.5) was significantly lower than that of AdvO (11.1 (1.1); p<0.001) and PBS (10.9 (1.0); p<0.01 treated controls. In addition, the stool concentration of IL-13 over the four week experiment was significantly higher in mice treated with saline or AdvO than in those treated with AdvmuIL-10 IP<0.01). Conclusion: Local AdvmuIL-10 therapy reverses colitis in IL-10-/- mice without the systemic effects seen after intravenous administration. Gene therapy strategies using adenoviral vectors encoding immunoregulatory cytokines may prove to be a potent approach to the treatment of chronic inflammatory diseases such as Crohn's disease.