Attenuation of autoimmune disease in Fas-deficient mice by treatment with a cytotoxic benzodiazepine

Jeffrey J. Bednarski, Roscoe E. Warner, Tharaknath Rao, Francesco Leonetti, Raymond Yung, Bruce C. Richardson, Kent J. Johnson, Jonathan A. Ellman, Anthony W. Opipari, Gary D. Glick

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Objective. Elimination of autoreactive cells relies on Fas-dependent activation-induced cell death mechanisms, an important component of peripheral tolerance. Defects in Fas or its cognate ligand lead to inefficient activation-induced cell death and are specific causes of lymphoproliferative and autoimmune diseases. The present study was undertaken to investigate a novel 1,4-benzodiazepine (Bz-423) that induces apoptosis and limits autoimmune disease in NZB/NZW mice, to determine its activity against lupus-like disease associated with defective Fas expression. We investigated the Fas-dependence of its cytotoxic actions, its therapeutic potential in mice deficient in Fas, and its therapeutic mechanism of action. Methods. Primary lymphocytes isolated from Fas-deficient MRL/MpJ-Faslpr (MRL-lpr) mice were tested for sensitivity to Bz-423. Bz-423 was administered to MRL-lpr mice for short (1-week) or long (14-week) periods, and its effects on cell survival were determined along with measures of nephritis, arthritis, antibody titers, and Th subpopulations. BALB/c mice were similarly treated to determine if Bz-423 alters normal immune functions in vivo. Results. Administration of Bz-423 to MRL-lpr mice significantly reduced autoimmune disease including glomerulonephritis and arthritis. Treatment was associated with decreases in CD4+ T cells and an alteration in the Th1/Th2 balance. At the therapeutic dosage, Bz-423 did not interfere with normal T and B cell responses in BALB/c mice, suggesting that this agent is not globally immunosuppressive. Conclusion. Bz-423 is a novel immunomodulatory agent that is active against disease even in the context of defective Fas signaling. It is a leading compound for further investigation into the development of selective therapies for lupus.

Original languageEnglish
Pages (from-to)757-766
Number of pages10
JournalArthritis and rheumatism
Volume48
Issue number3
DOIs
StatePublished - Mar 1 2003

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