Targeting TCF-β1 by Employing a Vaccine Ameliorates Fibrosis in a Mouse Model of Chronic Colitis

Background: Intestinal fibrosis and stricture formation are major complications of inflammatory bowel disease (IBD), for which there are currently few effective treatments. We sought to investigate whether targeting transforming growth factor-beta l (TGF-beta 1), a key profibrotic mediator, with a peptide-based virus-like particle vaccine would be effective in suppressing intestinal fibrosis by using a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis. Methods: The vaccine was prepared by inserting a peptide derived from mouse TGF-beta 1 into a carrier hepatitis B core antigen using gene recombination methods. Chronic colitis was induced in BALB/c mice by 8 weekly TNBS administrations. Mice were subcutaneously injected with vaccine, carrier, or phosphate-buffered saline (PBS) in 2 separate studies: either before or after acute inflammatory responses commenced. Results: Sera from vaccinated mice exhibited significantly elevated levels of TGF-beta 1-specific immunoglobulin G (IgG), which inhibited TGF-beta 1-induced luciferase production in mink lung epithelial cells. In the chronic colitis model, mice receiving vaccine showed improved body weight gain and significantly reduced colonic collagen deposition. Hematoxylin and eosin staining and semi-quantitative scoring indicated that vaccination even ameliorated colonic inflammation. Cytokine profile analysis revealed that levels of TGF-beta 1, interleukin (IL)-17, and IL-23 in vaccinated mouse colon tissues were decreased, and that percentages of IL-17-expressing CD4(+) lymphocytes in mesenteric lymph node cells were reduced. Furthermore, Smad3 phosphorylation, a key event in TGF-beta signaling, was decreased in colonic tissue in vaccinated mice. Conclusions: This TGF-beta 1 peptide-based vaccine, which suppressed excessive TGF-beta 1 bioactivity, may prevent the development of intestinal fibrosis and associated complications, presenting a novel approach in the treatment of IBD.