title: 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.
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Grün
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Strohmeier
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Veronica
authors.initials: V
authors.lastname: Moreno-Viedma
authors.affiliation: AFFiRiS AG, Vienna, Austria.
authors.forename: Marie
authors.initials: M
authors.lastname: Le Bras
authors.affiliation: AFFiRiS AG, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Landlinger
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria; FH Campus Wien, University of Applied Sciences, Department Health, Section Biomedical Science, Vienna, Austria.
authors.forename: Karina
authors.initials: K
authors.lastname: Zeyda
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Wanko
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Leitner
authors.affiliation: AFFiRiS AG, Vienna, Austria.
authors.forename: Günther
authors.initials: G
authors.lastname: Staffler
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Department of Pediatrics and Adolescent Medicine, Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Medical University of Vienna, Vienna, Austria.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Zeyda
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: thomas.stulnig@meduniwien.ac.at.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites / Q000276:immunology*; D015415:Biomarkers; D003429:Cross Reactions / Q000276:immunology; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000097:blood / Q000209:etiology / Q000378:metabolism* / Q000628:therapy; D007114:Immunization; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007333:Insulin Resistance; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008659:Metabolic Diseases / Q000097:blood / Q000209:etiology / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism; D053495:Osteopontin / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D011485:Protein Binding; D011973:Receptors, LDL / Q000172:deficiency
chemical_list: D000906:Antibodies; D015415:Biomarkers; D016023:Integrins; D010446:Peptide Fragments; D011973:Receptors, LDL; D053495:Osteopontin
keywords: Atherosclerosis; Cardio-metabolic disease; Cytokine; Immunization; Osteopontin; Rodent