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*
Kennedy Institute of Rheumatology Division, and
Division of Medicine (Medicine A), Imperial College School of Medicine, London, United Kingdom;
Fourth Department of Surgery, University of Helsinki Central Hospital, Helsinki, Finland; and
Department of Hepatology, Royal Free and University College Medical School, London, United Kingdom
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 and are unable to induce complete remission in
IL-10-/- mice with established disease. In this paper, we
investigate the duration, potency, and immunogenicity of gene therapy
using an adenoviral vector encoding murine IL-10 (AdvmuIL-10). A single
systemic injection of AdvmuIL-10 was sufficient not only to prevent the
onset of colitis for at least 10 wk but also to induce clinical and
histological remission in mice with established disease. In addition,
AdvmuIL-10 diminished the systemic manifestations of disease, including
elevated acute-phase proteins, as well as the local consequences of
inflammation such as raised stool IL-1
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-
, IFN-
, and RANTES release from stimulated splenocyte
cultures, and also by a change in the proportion of
CD45RBhigh/low lymphocytes in the spleen compared with
control mice. The delivery of AdvmuIL-10 resulted in a significantly
diminished host antiadenoviral response compared with control
adenoviral vectors. Thus, gene therapy strategies using adenoviral
vectors encoding immunoregulatory and antiinflammatory cytokines may
prove to be a potent approach for the treatment of chronic inflammatory
disease. Antiinflammatory cytokine expression protects against immune
responses directed at gene vectors.
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