The induction of antigen-specific immunological tolerance and attenuation of inflammation via cytokine antigen fusion protein therapy in a mouse model of pulmonary inflammation

Abstract

Allergic asthma is a significant medical issue, affecting more than 300 million individuals and causing approximately 250,000 deaths each year. Current asthma therapies temporarily minimize discomfort and manage symptoms, but there are no effective long-term, preventative, or curative agents available. Recent studies have indicated that targeting immunogens to specific immune cells via fusion with cytokines increases the effectiveness of immunotherapy in animal models for asthma as well as other immune-mediated disease models such as experimental autoimmune encephalomyelitis. This study tested the hypothesis that fusion proteins comprised of granulocyte macrophage colony stimulating factor (GM-CSF) and OVA 323-339 epitopes potentiate antigen-specific immunological tolerance and attenuate development of pulmonary inflammation. Fusion products were generated through combining OVA 323-339 and GM-CSF sequences, and biological activity of fusion protein cytokine and antigenic domains was assessed. A successful model of ovalbumin-induced inflammation in mice was then established for verification of cytokine fusion protein vaccine efficacy. In the model, pre-treatment with the cytokine fusion protein vaccine was tested for ability to attenuate OVA-induced increases in inflammation. GMCSF-OVA 323-339-treated mice showed significantly decreased numbers of pro-inflammatory eosinophils, neutrophils, and lymphocytes, and cellular infiltration in perivascular, peribronchial, peribronchiolar, and parenchymal spaces were visibly lessened. In addition, small airway mucus deposition was reduced in mice given the fusion protein. In this study, it was found that pre-treatment of mice with GMCSF-OVA 323-339 fusion proteins reduced pulmonary inflammation when compared to mice given saline treatment, demonstrating that GMCSF-OVA 323-339 fusion proteins have the capability of influencing immune responses within a murine model of pulmonary inflammation. Data from this study suggests potential for cytokine-fusion proteins as a therapeutic tool in pathological pulmonary inflammation as well as in other fields involving immune system-mediated pathologies.