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. 2015 Dec;22(12):1269-75.
doi: 10.1128/CVI.00331-15. Epub 2015 Oct 14.

Development of a Recombinant Xenogeneic Tumor Necrosis Factor Alpha Protein Vaccine To Protect Mice from Experimental Colitis

Yang Wan  1 , Meng Li  2 , Hailong Zhang  3 , Xiuran Zheng  2 , Chaoheng Yu  2 , Gu He  2 , Yan Luo  2 , Li Yang  4 , Yuquan Wei  2
Affiliations

Development of a Recombinant Xenogeneic Tumor Necrosis Factor Alpha Protein Vaccine To Protect Mice from Experimental Colitis

Yang Wan et al. Clin Vaccine Immunol. 2015 Dec.

Abstract

Previous studies have highlighted the efficacy of tumor necrosis factor alpha (TNF-α) inhibitors, including monoclonal antibodies and soluble receptors, in the treatment and management of intestinal bowel disease (IBD). However, because of the immunogenicity of xenogeneic TNF-α inhibitors, antidrug antibodies (ADAs) can be triggered after repeated administration. An alternative way to target TNF-α is active immunization to elicit the production of high titers of neutralizing antibodies. In this study, we prepared a xenogeneic TNF-α protein vaccine and studied the protective effects in experimental colitis models. The xenogeneic TNF-α protein vaccine could overcome self-tolerance and induce TNF-α-specific neutralizing antibody. Moreover, the xenogeneic TNF-α protein vaccine could protect mice from acute and chronic colitis induced by dextran sodium sulfate (DSS). One possible explanation for this protective effect is the production of TNF-α-specific neutralizing antibody, which absorbed the biological activity of mouse TNF-α (mTNF-α) and failed to induce T lymphocyte apoptosis. In summary, use of the xenogeneic TNF-α protein vaccine may be a potent therapeutic strategy for IBD.

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Figures

FIG 1
FIG 1
Characterization of recombinant hTNF-α and mTNF-α proteins. (A and B) The purified proteins were analyzed by SDS-PAGE (A) and HPLC (B). (C) Western blot showing that the recombinant proteins were recognized specifically by the anti-TNF-α antibodies. AU, arbitrary units.
FIG 2
FIG 2
mTNF-α-specific IgG responses after TNF-α protein vaccination. C57BL/6 mice were immunized subcutaneously with mTNF-α or hTNF-α proteins in combination with 2% Alhydrogel as the adjuvant 6 times at 1-week intervals. Sera were collected 5 days after immunization and at death. Data represent geometric mean antigen-specific IgG titers ± standard deviations (SD) for n = 6 mice/group. *, P < 0.05; ***, P < 0.001 (compared with the results from the PB control group).
FIG 3
FIG 3
Protective effect of TNF-α vaccine in acute colitis model. One week after the last immunization, mice were fed 2.5% DSS for 7 days to induce acute colitis. (A) The DAI score was recorded every 2 days. Data represent mean DAI scores ± SD for n = 6 mice/group. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (compared with the results from the PB control group). (B) Photomicrographs of representative H&E-stained colon sections. The colon section photographs are representative of 6 mice for each group (magnification, ×100). (C) Histological scoring was performed by two experienced pathologists in a blind fashion. Data represent mean histological scores ± SD for n = 6 mice/group. *, P < 0.05 (compared with the results from the PB control group). (D) The effect of hTNF-α vaccination on serum TNF-α concentrations. Data represent mean serum TNF-α concentrations ± SD for n = 3 mice/group. ***, P < 0.001 (compared with the results from the PB control group).
FIG 4
FIG 4
Protective effect of TNF-α vaccine in chronic colitis model. One week after the last immunization, mice were fed by three cycles of administration of 2% DSS in drinking water for 5 days, alternating with 5-day periods of recovery. (A) Photomicrographs of representative H&E-stained colon sections. The colon section photographs are representative of 6 mice for each group (magnification, ×100). (B) Histological scoring was performed by two experienced pathologists in a blind fashion. Data represent mean histological scores ± SD for n = 6 mice/group. **, P < 0.01 (compared with the results from the PB control group).
FIG 5
FIG 5
Neutralizing effects of TNF-α-specific antibodies. (A) L929 cells were treated with mTNF-α and serially diluted sera, and protective rates were calculated. Data represent mean protective rates ± SD for n = 3 mice/group. ***, P < 0.001 (compared with the results from the PB control group). (B and C) Mice were treated with DSS to induce acute colitis and administered sera from hTNF-α- or mTNF-α-vaccinated mice. Mice were sacrificed on day 7 after DSS treatment, and colons were collected for histological examination. (B) Data represent mean DAI scores ± SD for n = 6 mice/group. *, P < 0.05; **, P < 0.01 (compared with the results from the PB control group). (C) Data represent mean histological scores ± SD for n = 6 mice/group. **, P < 0.01 (compared with the results from the PB control group).
FIG 6
FIG 6
The effect of TNF-α-specific antiserum on activated T lymphocyte apoptosis. Activated T lymphocytes were treated with antiserum at a dilution of 1:100 for 24 h, and then cells were doubly stained with annexin V and propidium iodide (PI) to detect apoptosis. Data shown are representative of the results of 3 independent experiments.
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