Attenuation of autoimmune disease in Fas-deficient mice by treatment with a cytotoxic benzodiazepine.
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-Fas(lpr) (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.


CONCLUSIONS
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.
Bednarski
Jeffrey J
JJ
University of Michigan, Ann Arbor, 48109, USA.
Warner
Roscoe E
RE
Rao
Tharaknath
T
Leonetti
Francesco
F
Yung
Raymond
R
Richardson
Bruce C
BC
Johnson
Kent J
KJ
Ellman
Jonathan A
JA
Opipari
Anthony W
AW
Glick
Gary D
GD
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001569:Benzodiazepines / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy / Q000473:pathology; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D019014:fas Receptor / Q000235:genetics
D000276:Adjuvants, Immunologic; D000974:Antibodies, Antinuclear; D019014:fas Receptor; D001569:Benzodiazepines; C468549:Bz-423