Transforming growth factor-beta gene therapy ameliorates experimental colitis in rats

Objective: To modulate experimental colitis by the direct intramuscular injection of cDNA expression vector encoding transforming growth factor-beta₁. Methods: Colitis was induced in rats by the intracolonic administration of 0.25 ml 50% ethanol containing 30 mg trinitrobenzene sulfonic acid. Three and 10 days later the rats were injected intramuscularly with 200 μg transforming growth factor-beta₁ cDNA subcloned to the pRSV expression vector (pRSVTGF-β₁). Control rats were injected with pRSVP₂. The rats were sacrificed 2 weeks after trinitrobenzene sulfonic acid treatment and a 10 cm long distal colonic segment was resected, weighed, the lesion area measured, sections obtained for histology and the mucosa extracted for determination of myeloperoxidase activity and leukotriene generation. Results: In pRSVP₂-treated rats (n = 17) the colon was inflamed and ulcerated with many adhesions to adjacent structures; the pRSVTGF-β₁-treated rats (n = 21) had minimal swelling and inflammation in the colon. On histological examination 50% of the pRSVTGF-β₁-treated rats had minimal or no ulceration, whereas 83% of the pRSVP₂-treated rats had a maximal damage score. In pRSVTGF-β₁-treated rats the lesion area and wet weight were 21 and 52.5%, respectively, of the values for pRSVP₂-treated rats (P < 0.05). The amelioration of tissue injury was accompanied by a significant decrease in mucosal leukotriene C₄ generation. Conclusions: Direct intramuscular transforming growth factor-beta₁ gene delivery effectively ameliorates trinitrobenzene sulfonic acid-induced colitis, suggesting that gene therapy with immunosuppressive cytokines may be a novel approach for the treatment of inflammatory bowel disease.