Active Vaccination With EMMPRIN-Derived Multiple Antigenic Peptide (161-MAP) Reduces Angiogenesis in a Dextran Sodium Sulfate (DSS)-Induced Colitis Model

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.

CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression

“… 22 The results of this study show that CD147 is indispensable for TFF3-induced cell migration, invasion, and proliferation of CRC cells, and this is supported by previous findings regarding the roles of CD147 in inflammation. 23 , 24 as well as promotion of proliferation, survival, angiogenesis, and the invasive properties of tumor cells. 25 , 26 …”

Targeting Angiogenesis With Peptide Vaccines

“…While cancer diseases are one form of chronic inflammation, angiogenesis is also essential to the progression of autoimmune and inflammatory diseases (79, 80). However, with the exception of our previously mentioned study on a DSS-induced colitis model (66), other studies on peptide vaccination targeting angiogenic proteins in autoimmune disease models were not found. Therefore, examining the potential of targeting angiogenesis in such conditions is strongly indicated.…”

“…Additionally, the vaccination reduced tumor cell proliferation, increased macrophages and CTL infiltration into the tumor, and shifted the TME to allow more cytotoxicity toward the tumor cells, thereby reducing tumor size and the number of metastatic lung foci (59). In a DSS-induced colitis model that simulates the human autoimmune disease ulcerative colitis, we show that a similar effect occurs, where angiogenesis is reduced and infiltration of macrophages and CTLs to the colon tissue is increased, ultimately leading to improvement in the clinical score of the vaccinated mice relative to their controls (66).…”

Role of sphingosine‐1‐phosphate receptors in vascular injury of inflammatory bowel disease

“…There are several important mechanisms governing angiogenic disorders, including oxidative stress, endoplasmic reticulum (ER) stress, abnormal glycolysis and activated VEGF signalling. In intestinal mucosa of patients with IBD, significantly increased ROS levels were seen 54 . Under basic conditions, low levels of reactive oxygen species (ROS) act as messenger molecules to promote angiogenesis; however, high levels of ROS inhibit angiogenesis 55 .…”

“…In intestinal mucosa of patients with IBD, significantly increased ROS levels were seen. 54 Under basic conditions, low levels of reactive oxygen species (ROS) act as messenger molecules to promote angiogenesis; however, high levels of ROS inhibit angiogenesis. 55 ER stress levels were also increased significantly in inflammatory state.…”