Abstract
Background: Interleukin-10 knockout (IL-10 -/-) mice spontaneously develop Th1 T cell mediated colitis with many similarities to Crohn's disease. Daily injections of IL-10 are able to prevent disease onset but do not induce remission in established disease. Aims: To investigate the therapeutic efficacy and mechanism of action of gene therapy using adenoviral vectors encoding IL-10 (AdvmuIL-10) in the IL-10 -/- mouse model of colitis. Results: A single systemic injection of AdvmuIL-10 was able to prevent the onset of colitis for at least 10 weeks, but was also sufficient to induce remission in IL-10 -/- mice with established disease (p<0.001 by ANOVA compared to saline or empty vector (Adv0) treated controls). Histological scores were significantly lower in AdvmuIL-10 treated mice than controls (p<0.05). In addition, AdvmuIL-10 therapy reduced the elevated serum amyloid protein levels and stool IL-1β concentrations characteristic of this disease (p<0.05). IL-10 protein was present in colonic homogenates of AdvmuIL-10 treated IL-10 -/- mice, and the effects of secreted IL-10 were detectable by a sensitive bioassay for at least 10 weeks after injection. The immunoregulatory effect of a single AdvmuIL-10 injection was manifest both by a reduction in TNF-α, IFN-γ and RANTES release from stimulated spleen cell cultures (p<0.005 compared to saline treated controls) and also by a change in the proportion of CD45RBhigh/low lymphocytes in the spleen compared to control mice (p<0.05 compared to saline treated controls). The delivery of IL-10 appeared to diminish the host anti adenoviral response as serum from IL-10 -/- mice treated with AdvmuIL-10 contained significantly lower titres of neutralising anti-adenoviral antibodies than mice that had received either empty vector or a virus encoding an irrelevant protein - Advβgal (p<0.05). Conclusion: Gene therapy strategies using adenoviral vectors encoding immunoregulatory cytokines may prove to be a potent approach for the treatment of chronic inflammatory …
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