Abstract
Ulcerative colitis (UC) is an autoimmune disease that affects the colon and shares many clinical and histological features with the dextran sulfate sodium (DSS)-induced colitis model in mice. Angiogenesis is a critical component in many autoimmune diseases, as well as in the DSS-induced colitis model, and is it partially mediated by EMMPRIN, a multifunctional protein that can induce the expression of both the potent pro-angiogenic vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). We asked whether targeting EMMPRIN by active vaccination, using a novel, specific epitope in the protein, synthesized as a multiple antigenic peptide (MAP), could trigger beneficial effects in the DSS-induced colitic C57BL/6J mice. Mice were vaccinated with four boost injections (50 μg each) of either 161-MAP coding for the EMMPRIN epitope or the scrambled control peptide (Scr-MAP) emulsified in Freund's adjuvant. We show that male mice that were vaccinated with 161-MAP lost less weight, demonstrated improved disease activity indices (DAI), had reduced colitis histological score, and their colons were longer in comparison to mice vaccinated with the Scr-MAP. The 161-MAP vaccination also reduced serum and colon levels of EMMPRIN, colon concentrations of VEGF, MMP-9, and TGFβ, and vessel density assessed by CD31 staining. A similar effect was observed in female mice vaccinated with 161-MAP, including weight loss, colitis histological score, colon length, colon levels of EMMPRIN and colon concentrations of VEGF. However, for female mice, the changes in DAI values, EMMPRIN serum levels, and MMP-9 and TGFβ colon concentrations did not reach significance. We conclude that our strategy of alleviating autoimmunity in this model through targeting angiogenesis by actively vaccinating against EMMPRIN was successful and efficient in reducing angiogenesis.
Highlights
Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases, with the two major diseases being Crohn’s disease (CD) and ulcerative colitis (UC)
We have recently identified a novel epitope in the EMMPRIN protein extracellular domain I, which is responsible for the induction of both vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs)-9 [19]
EMMPRIN is highly expressed in the colon, FIGURE 2 | 161-multiple antigenic peptide (MAP) active vaccination prevents damage and extends colon length
Summary
Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases, with the two major diseases being Crohn’s disease (CD) and ulcerative colitis (UC). Matrix metalloproteinases (MMPs) can remodel the ECM to facilitate endothelial cell migration, release VEGF that is bound to the ECM, or degrade collagen XVIII to produce the anti-angiogenic factor endostatin [9]. We have recently identified a novel epitope in the EMMPRIN protein extracellular domain I, which is responsible for the induction of both VEGF and MMP-9 [19] We have synthesized this epitope as an octa-branched multiple antigenic peptide (designated 161-MAP), and used it either in a therapeutic or a prophylactic manner to vaccinate mice that were implanted with the CT26 colon carcinoma tumors subcutaneously, or that were intravenously injected with this cell line to generate an experimental metastasis model. In view of the importance of angiogenesis in colitis, we ask whether the same vaccination against EMMPRIN could affect chronic inflammation in a mouse DSS-induced colitis model
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