VGX-1027 modulates genes involved in the LPS-induced TLR-4 activation and in a murine model of Systemic Lupus Erythematosus

VGX-1027 [(S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid] is a small molecule compound with immunomodulatory properties which favorably influences the development of immunoinflammatory 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. To 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 (SLE). Microarray data revealed that the administration of VGX-1027 profoundly affected the immune response to exogenous antigens, by modulating the expression of genes which are primarily involved in the antigen processing and presentation as well as genes which 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 percent survival and improved clinical and histopathological signs. The data presented herein support that VGX-1027 modulates immunity likely by inhibiting inflammatory antigen presentation and thus limiting immune cell expansion. This article is protected by copyright. All rights reserved.