Peptide-based vaccination against OPN integrin binding sites does not improve cardio-metabolic disease in mice

Abstract

Obesity causes insulin resistance via a chronic low-grade inflammation. This inflammation is characterized by elevated pro-inflammatory markers and macrophage accumulation in the adipose tissue (AT). AT inflammation is a key factor causing insulin resistance and thus type 2 diabetes, both linked to atherosclerotic cardiovascular disease. Osteopontin (OPN), a well-known inflammatory cytokine, is involved in obesity-linked complications including AT inflammation, insulin resistance, atherosclerosis and CVD. During inflammation, OPN is proteolytically cleaved by matrix metalloproteinases or thrombin leading to increased OPN activity. Therefore, OPN provides a new interesting target for immunological prevention and treatment of obesity-associated diseases. The aim of our study was to evaluate peptide-based vaccines against integrin binding sites of OPN and to examine whether these active immunotherapies are functional in reducing metabolic tissue inflammation, insulin resistance, and atherosclerosis in a cardio-metabolic (Ldlr mice) and a diet-induced obesity model (WT mice). However, atherosclerosis, insulin resistance and AT inflammation were not diminished after treatment with OPN-derived peptides in murine models. Lack of efficacy was based on a failure to induce antibodies capable to bind epitopes in the context of functional OPN protein. In conclusion, our data point to unexpected challenges in the immunotherapeutic targeting of adhesive motives, such as RGD containing sequences, on endogenous proteins.

Antibody-mediated targeting of cleavage-specific OPN-T cell interactions

“…With an active vaccination approach presented here, antisera can be produced containing antibodies that specifically recognize the cleaved forms of OPN without binding to FL-OPN. An initial attempt using murine OPN-peptide-KLH conjugates, however, failed to induce OPN-specific antibodies[40]. In the work described in this paper, human OPN sequences were used and their human in vivo effects have not been elucidated yet.…”

Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue

“…Intriguingly, OPN inflammatory activity could be modulated by thrombin-mediated proteolytic cleavage at a highly conserved cleavage sites, which likely occurs in the tumor microenvironment. This cleavage exposes an integrin-binding motif that is thought to promote OPN biological activities [ 399 ]. Deletion of the thrombin-cleavable site of OPN in breast cancer cells resulted in reduced in vitro cellular adhesion and enhanced in vivo tumor growth and lymph node metastasis [ 400 ].…”