Local delivery of adenoviral vectors encoding murine interleukin 10 induces colonic interleukin 10 production and is therapeutic for murine colitis.
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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 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-1 beta 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
|Title:||Local delivery of adenoviral vectors encoding murine interleukin 10 induces colonic interleukin 10 production and is therapeutic for murine colitis|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||DA - 20030213 IS - 0017-5749 LA - eng PT - Journal Article RN - 0 (Antibodies, Viral) RN - 0 (Genetic Vectors) RN - 0 (Lipopolysaccharides) RN - 0 (Tumor Necrosis Factor) RN - 130068-27-8 (Interleukin-10) SB - AIM SB - IM|
|Keywords:||Adenoviridae, ADENOVIRUS, Administration, administration & dosage, Administration, Rectal, Animals, antibodies, Antibodies, Viral, Antibody, As, beta, biosynthesis, cell, Cells, Cultured, clinical, colitis, Concentration, control, Crohn Disease, Crohn's disease, cytokine, Cytokines, DELIVERY, DEVELOPED, disease, Diseases, effects, EFFICACY, Epithelial Cells, expression, GENE, Gene Therapy, Gene Transfer Techniques, GENE-THERAPY, genetic, Genetic Vectors, genetics, Hepatic, IL-1, IM, immune, immunology, inflammatory diseases, INFUSION, Injections, interleukin 10, Interleukin-10, intestinal mucosa, INTRAVENOUS, knockout, LA, LEVEL, Lipopolysaccharide, Lipopolysaccharides, local, Local delivery, LONG, LONG-TERM, May, metabolism, Methods, mice, Mice, Inbred C57BL, Mice, Knockout, murine, necrosis, pathology, phosphate, POTENT, release, REMISSION, Result, Saline, SINGLE, Spleen, stool, strategies, strategy, Support, Non-U.S.Gov't, SUPPRESSION, SYSTEMIC, T cell, T-CELL, TERM, Th1, therapeutic, therapy, treatment, Tumor, tumor necrosis, Tumor Necrosis Factor, TUMOR-NECROSIS-FACTOR, VECTOR, VECTORS, viral, virology|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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