Local delivery of adenoviral vectors encoding murine interleukin 10 induces colonic interleukin 10 production and is therapeutic for murine colitis
- 1Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, UK
- 2Fourth Department of Surgery, University of Helsinki Central Hospital, Kasarmikatu 11-13, FIN-00130 Helsinki, Finland
- 3Department of Hepatology, Royal Free and University College Medical School, Royal Free Campus, London, UK
- Correspondence to:
Dr J O Lindsay, Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, London W6 8LH, UK;
- Accepted 18 September 2002
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 5×108 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 5×108 PFU AdvmuIL-10 entered clinical and histological remission whereas empty cassette adenovirus (Adv0) 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 Adv0 (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-1β over the four week experiment was significantly higher in mice treated with saline or Adv0 than in those treated with AdvmuIL-10 (p<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.
- IL-10, interleukin 10
- AdvmuIL-10, adenoviral vector encoding murine IL-10
- Advβgal, adenoviral vector encoding β-galactosidase
- Adv0, empty cassette adenoviral vector
- TNF-α, tumour necrosis factor α
- IFN-γ, interferon γ
- LPS, lipopolysaccharide
- FCS, fetal calf serum
- PBS, phosphate buffered saline
- DMEM, Dulbecco’s modified Eagle’s medium
- CAR, Coxsackie virus and adenovirus receptor
- LPMN, lamina propria mononuclear cell
- MOI, multiplicity of infection