Background: DNA vaccines provide high tolerability and safety but commonly suffer from suboptimal immunogenicity. We previously reported that a plasmid vector (pATRex), encoding for the extracellular domain of the Tumor Endothelial Marker-8, when given in combination with plasmid-encoded tumor antigens acted as a powerful molecular adjuvant enhancing immunity against various tumors. Aims: the present study has been developed to determine whether the adjuvant action of pATRex can also extend to vaccines against infectious diseases such as malaria, to identify which is the mechanism of action that underlies pATRex adjuvancy and, finally, to deeply investigate the potential side effects. Results: here we show that co-administration of pATRex potentiates antibody production elicited by an intramuscular injection of plasmid encoding for malaria plasmodium antigens. Cells were transfected with pATRex and this resulted in formation of insoluble intracellular aggregates (as confirmed by 3D molecular modeling) and apoptotic cell death, thus explaining that adjuvancy mechanism is mediated by immunogenic cell death. Besides, histological examination of pATRex-injected mice organs, we have uncovered that proteotoxic aggregates profoundly disrupt the bone and bone marrow architecture and influenced the molecular network and the cytokine interchanges through the skeletal and hematopoietic marrow components. We also discovered that a similar scenario occurs when mice were injected with a plasmid DNA encoding for the mutant Huntington, a well-known aggregating-protein responsible for Huntington's disease in humans. Finally, we provided the first evidence that the impaired bone deposition and the enfeeble bone homeostasis is also present in the transgenic mouse model for human Spinocerebellar Ataxia 1 carrying the mutant aggregating protein Ataxin 1. Conclusions and Perspectives: in the present work we found that plasmids encoding aggregating proteins behave as adjuvants for DNA vaccines but they also controvert the delicate steady-state bone and bone marrow physiology ultimately driving to impaired bone formation in conjunction with bone marrow niche disruption. These findings drew the attention of further investigation in reference to the side effects associated with the use of aggregating proteins as adjuvants. We have also unveiled, for the first time, that the osteoporotic phenotype, which is often present in the neurodegenerative diseases, is a coherent fall-out of the protein aggregates observed in human and animal carriers of the mentioned diseases

Aggregating Proteins Affect Immunity and Bone Homeostasis in Vivo

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2014-06-24

Abstract

Background: DNA vaccines provide high tolerability and safety but commonly suffer from suboptimal immunogenicity. We previously reported that a plasmid vector (pATRex), encoding for the extracellular domain of the Tumor Endothelial Marker-8, when given in combination with plasmid-encoded tumor antigens acted as a powerful molecular adjuvant enhancing immunity against various tumors. Aims: the present study has been developed to determine whether the adjuvant action of pATRex can also extend to vaccines against infectious diseases such as malaria, to identify which is the mechanism of action that underlies pATRex adjuvancy and, finally, to deeply investigate the potential side effects. Results: here we show that co-administration of pATRex potentiates antibody production elicited by an intramuscular injection of plasmid encoding for malaria plasmodium antigens. Cells were transfected with pATRex and this resulted in formation of insoluble intracellular aggregates (as confirmed by 3D molecular modeling) and apoptotic cell death, thus explaining that adjuvancy mechanism is mediated by immunogenic cell death. Besides, histological examination of pATRex-injected mice organs, we have uncovered that proteotoxic aggregates profoundly disrupt the bone and bone marrow architecture and influenced the molecular network and the cytokine interchanges through the skeletal and hematopoietic marrow components. We also discovered that a similar scenario occurs when mice were injected with a plasmid DNA encoding for the mutant Huntington, a well-known aggregating-protein responsible for Huntington's disease in humans. Finally, we provided the first evidence that the impaired bone deposition and the enfeeble bone homeostasis is also present in the transgenic mouse model for human Spinocerebellar Ataxia 1 carrying the mutant aggregating protein Ataxin 1. Conclusions and Perspectives: in the present work we found that plasmids encoding aggregating proteins behave as adjuvants for DNA vaccines but they also controvert the delicate steady-state bone and bone marrow physiology ultimately driving to impaired bone formation in conjunction with bone marrow niche disruption. These findings drew the attention of further investigation in reference to the side effects associated with the use of aggregating proteins as adjuvants. We have also unveiled, for the first time, that the osteoporotic phenotype, which is often present in the neurodegenerative diseases, is a coherent fall-out of the protein aggregates observed in human and animal carriers of the mentioned diseases
24-giu-2014
Concetti, Fabio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/401744
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