title: Local delivery of adenoviral vectors encoding murine interleukin 10 induces colonic interleukin 10 production and is therapeutic for murine colitis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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 x 10(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 5 x 10(8) 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-1beta 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, London W6 8LH, UK. j.lindsay@doctors.org.uk
authors.forename: J O
authors.initials: JO
authors.lastname: Lindsay
authors.forename: C J
authors.initials: CJ
authors.lastname: Ciesielski
authors.forename: T
authors.initials: T
authors.lastname: Scheinin
authors.forename: F M
authors.initials: FM
authors.lastname: Brennan
authors.forename: H J
authors.initials: HJ
authors.lastname: Hodgson
mesh_terms: D000256:Adenoviridae; D000818:Animals; D002460:Cell Line; D003106:Colon / Q000378:metabolism; D003424:Crohn Disease / Q000276:immunology* / Q000628:therapy; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10