Title:Administration of DNA Plasmid Coding Protein Aggregating Domain Induces Inflammatory Bone Loss
Volume: 16
Issue: 2
Author(s): Dimitrios Agas, Fabio Concetti, Melania Capitani, Giovanna Lacava, Antonio Concetti, Luigi Marchetti, Fulvio Laus, Andrea Marchegiani, Vasco Azevedo, Maria Giovanna Sabbieti and Franco Maria Venanzi
Affiliation:
Keywords:
DNA vaccines, Adjuvants, Protein aggregates, Chronic inflammation, Bone remodeling, Osteoporosis.
Abstract: Background: Plasmids coding protein aggregation polypeptides from different
sources have been proposed as genetic adjuvants for DNA vaccines. We reported
that a plasmid (pATRex), encompassing the DNA sequence for the von Willebrand A
(vWA/A) domain of the Anthrax Toxin Receptor-1 (ANTXR-1, alias TEM8, Tumor
Endothelial Marker 8), acts as strong immune adjuvant by inducing formation of insoluble
intracellular aggregates and subsequent cell death. Objective: In the present study we addressed the question of
whether there is any substantial immunotoxicity associated with the use of self-aggregating proteins as genetic adjuvants.
Methods & Results: Here we report, by mean of histology, X-ray and molecular examinations of bone specimens, the unexpected
finding that intramuscular injection of pATRex in mice triggers, per se, severe bone loss (osteoporosis) independently
from the sex and genotype of the treated animals. Conclusion: Even though the study suggests that proteinaceous
“sticky “ adjuvants are unlikely to find their way into practical vaccination, the information gained is of value as
ATRex injections could provide an additional, simplified, mouse model of osteoporosis. Moreover, our results provide
experimental support to the hypothesis that proteotoxic aggregates chronically activate the innate immune system in amyloid
and aggregosome associated disorders.
