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-beta 1.


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 micrograms transforming growth factor-beta 1 cDNA subcloned to the pRSV expression vector (pRSVTGF-beta 1). 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, weighted, 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-beta 1-treated rats (n = 21) had minimal swelling and inflammation in the colon. On histological examination 50% of the pRSVTGF-beta 1-treated rats had minimal or no ulceration, whereas 83% of the pRSVP2-treated rats had a maximal damage score. In pRSVTG-beta 1-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-beta 1 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.
Giladi
E
E
Department of Medicine, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel.
Raz
E
E
Karmeli
F
F
Okon
E
E
Rachmilewitz
D
D
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000628:therapy*; D018076:DNA, Complementary; D015316:Genetic Therapy; D005822:Genetic Vectors; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014302:Trinitrobenzenesulfonic Acid
D018076:DNA, Complementary; D016212:Transforming Growth Factor beta; D014302:Trinitrobenzenesulfonic Acid