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

Paolo Fagone, Karuppiah Muthumani, Katia Mangano, Gaetano Magro, Pier Luigi Meroni, Joseph J. Kim, Niranjan Y. Sardesai, David B. Weiner, Ferdinando Nicoletti

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)594-602
Number of pages9
JournalImmunology
Volume142
Issue number4
DOIs
Publication statusPublished - 2014

Fingerprint

Toll-Like Receptor 4
Systemic Lupus Erythematosus
Lipopolysaccharides
Antigen Presentation
Genes
Pleurisy
Oligonucleotide Array Sequence Analysis
Type 1 Diabetes Mellitus
Inflammatory Bowel Diseases
Acetic Acid
Autoimmune Diseases
3-phenyl-4,5-dihydro-5-isoxazole acetic acid
Immunity
Rheumatoid Arthritis
Animal Models
Genome
Gene Expression
Antigens

Keywords

  • Autoimmunity
  • Bioinformatics
  • Cell activation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

VGX-1027 modulates genes involved in lipopolysaccharide-induced Toll-like receptor 4 activation and in a murine model of systemic lupus erythematosus. / Fagone, Paolo; Muthumani, Karuppiah; Mangano, Katia; Magro, Gaetano; Meroni, Pier Luigi; Kim, Joseph J.; Sardesai, Niranjan Y.; Weiner, David B.; Nicoletti, Ferdinando.

In: Immunology, Vol. 142, No. 4, 2014, p. 594-602.

Research output: Contribution to journalArticle

Fagone, P, Muthumani, K, Mangano, K, Magro, G, Meroni, PL, Kim, JJ, Sardesai, NY, Weiner, DB & Nicoletti, F 2014, 'VGX-1027 modulates genes involved in lipopolysaccharide-induced Toll-like receptor 4 activation and in a murine model of systemic lupus erythematosus', Immunology, vol. 142, no. 4, pp. 594-602. https://doi.org/10.1111/imm.12267
Fagone, Paolo ; Muthumani, Karuppiah ; Mangano, Katia ; Magro, Gaetano ; Meroni, Pier Luigi ; Kim, Joseph J. ; Sardesai, Niranjan Y. ; Weiner, David B. ; Nicoletti, Ferdinando. / VGX-1027 modulates genes involved in lipopolysaccharide-induced Toll-like receptor 4 activation and in a murine model of systemic lupus erythematosus. In: Immunology. 2014 ; Vol. 142, No. 4. pp. 594-602.
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