The prevention and treatment of murine colitis using gene therapy with adenoviral vectors encoding IL-10

IL-10-deficient (IL-10(-/-)) mice develop colitis with many similarities to Crohn's disease. Daily IL-10 injections have a short systemic half-life an d are unable to induce complete remission in IL-10(-/-) mice with establish ed disease. In this paper, we investigate the duration, potency, and immuno genicity of gene therapy using an adenoviral vector encoding murine IL-10 ( AdvmuIL-10). A single systemic injection of AdvmuIL-10 was sufficient not o nly to prevent the onset of colitis for at least 10 wk but also to induce c linical and histological remission in mice with established disease. In add ition, AdvmuIL-10 diminished the systemic manifestations of disease, includ ing elevated acute-phase proteins, as well as the local consequences of inf lammation such as raised stool IL-1 beta concentrations. Both IL-10 protein and the effects of secreted IL-10 were detectable for 10 wk after AdvmuIL- 10 injection. Furthermore, the immunoregulatory effect of a single AdvmuIL- 10 injection was manifest both by a reduction in TNF-alpha, IFN-gamma, and RANTES release from stimulated splenocyte cultures, and also by a change in the proportion of CD45RB(high/low) lymphocytes in the spleen compared with control mice. The delivery of AdvmuIL-10 resulted in a significantly dimin ished host antiadenoviral response compared with control adenoviral vectors . Thus, gene therapy strategies using adenoviral vectors encoding immunoreg ulatory and antiinflammatory cytokines may prove to be a potent approach fo r the treatment of chronic inflammatory disease. Antiinflammatory cytokine expression protects against immune responses directed at gene vectors.