Targeting TGF-beta1 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-beta1 (TGF-beta1), 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-beta1 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-beta1-specific immunoglobulin G (IgG), which inhibited TGF-beta1-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 semiquantitative scoring indicated that vaccination even ameliorated colonic inflammation. Cytokine profile analysis revealed that levels of TGF-beta1, 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-beta1 peptide-based vaccine, which suppressed excessive TGF-beta1 bioactivity, may prevent the development of intestinal fibrosis and associated complications, presenting a novel approach in the treatment of IBD.
Ma
Yanbing
Y
Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
Guan
Qingdong
Q
Bai
Aiping
A
Weiss
Carolyn R
CR
Hillman
China-Li
CL
Ma
Allan
A
Zhou
Gang
G
Qing
Gefei
G
Peng
Zhikang
Z
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D005260:Female; D005355:Fibrosis; D007074:Immunoglobulin G / Q000097:blood; D020381:Interleukin-17 / Q000032:analysis; D053759:Interleukin-23 / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008643:Mesentery / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000276:immunology; D051900:Smad3 Protein / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use*
D007074:Immunoglobulin G; D020381:Interleukin-17; D053759:Interleukin-23; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D014614:Vaccines, Synthetic; D014302:Trinitrobenzenesulfonic Acid