VGX-1027 modulates genes involved in lipopolysaccharide-induced Toll-like receptor 4 activation and in a murine model of systemic lupus erythematosus.

Abstract

VGX-1027 [(S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid] is a small molecule compound with immunomodulatory properties, which favourably influences the development of immuno-inflammatory and autoimmune diseases in different animal models such as type 1 diabetes mellitus, pleurisy, rheumatoid arthritis and inflammatory bowel disease. However, the precise mechanism of action of VGX-1027 remains to be ascertained. With this aim, we have studied the immunomodulatory effects of VGX-1027 in vitro, using a genome-wide oligonucleotide microarray approach, and in vivo, using the NZB/NZW F1 model of systemic lupus erythematosus. Microarray data revealed that the administration of VGX-1027 profoundly affected the immune response to exogenous antigens, by modulating the expression of genes that are primarily involved in antigen processing and presentation as well as genes that regulate immune activation. When administered in vivo VGX-1027 ameliorated the course of the disease in the NZB/NZW F1 mice, which correlated with higher per cent survival and improved clinical and histopathological signs. The data presented herein support the theory that VGX-1027 modulates immunity, probably by inhibiting inflammatory antigen presentation and so limiting immune cell expansion.

• Authors: Paolo Fagone, Karuppiah Muthumani, Katia Mangano, Gaetano Magro, Pier Luigi Meroni, Joseph J Kim, Niranjan Y Sardesai, David B Weiner, Ferdinando Nicoletti
• Journal: Immunology (Immunology) Vol. 142 Issue 4 Pg. 594-602 (Aug 2014) ISSN: 1365-2567 [Electronic] England
• PMID: 24527796 (Publication Type: Journal Article)
• Copyright: © 2014 John Wiley & Sons Ltd.

Chemical References

• 3-phenyl-4,5-dihydro-5-isoxazole acetic acid
• Acetates
• Immunologic Factors
• Lipopolysaccharides
• Oxazoles
• TLR4 protein, human
• Tlr4 protein, mouse
• Toll-Like Receptor 4

Topics

• Acetates (pharmacology)
• Animals
• Disease Models, Animal
• Female
• Humans
• Immunologic Factors (pharmacology)
• Lipopolysaccharides (toxicity)
• Lupus Erythematosus, Systemic (chemically induced, drug therapy, immunology, pathology)
• Male
• Mice
• Oxazoles (pharmacology)
• Toll-Like Receptor 4 (immunology)