Delay in the onset of systemic lupus erythematosus following treatment with the immunomodulator AS101: Association with IL-10 inhibition and increase in TNF-α levels

Yona Kalechman, Uzi Gafter, Ji Ping Da, Michael Albeck, Donate Alarcon-Segovia, Benjamin Sredni

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76 Scopus citations

Abstract

It has recently been found that in systemic lupus erythematosus (SLE), a multisystem inflammatory disorder characterized by autoantibody production and decreased cellular immune response, increased spontaneous production of IL-10 occurs. The immunomodulator AS101 (ammonium trichloro(dioxoethylene-0,0′)tellurate) was previously shown to significantly decrease IL-10 levels in cancer patients and in murine models. This study shows that AS101 inhibits the development of SLE-related autoimmune pathological manifestations. AS101 decreased the spontaneous IL-10 production by mononuclear cells from SLE patients in vitro. In vivo, systemic injection of AS101 to SCID mice transplanted with mononuclear cells from SLE patients significantly decreased serum human IL-10 levels. There was also a decrease in all serum human Ig isotypes, in anti-dsDNA, and in anti-Sm Igs. In the New Zealand Black/New Zealand White/F 1 model, AS101 significantly increased serum TNF-α and IFN-γ while decreasing IL-10 levels; these changes were accompanied by a rapid decrease in anti-dsDNA and anti-ssDNA Igs. More importantly, continuous treatment of New Zealand Black/New Zealand White/F 1 mice with AS101 for 6 mo led to the development of proteinuria in 30% of the treated mice compared with 100% in PBS-treated mice (p < 0.001). AS101 treatment reduced the level of immmune complex deposition in the glomeruli, prevented glomerular hypercellularity and mesangial expansion and led to a much smaller mean glomerular volume in treated mice (185 ± 6 vs 428 ± 47.103 μm 3; p < 0.01). We suggest that treatment with a nontoxic immunomodulator such as AS101, previously used in phase II trials on cancer patients, may be an effective therapeutic approach for controlling SLE.

Original languageEnglish
Pages (from-to)2658-2667
Number of pages10
JournalJournal of Immunology
Volume159
Issue number6
StatePublished - 15 Sep 1997

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