THE EFFECT OF A SELECTIVE ESTROGEN-RECEPTOR MODULATOR ON THE PROGRESSION OF SPONTANEOUS AUTOIMMUNE-DISEASE IN MRL LPR LPR MICE/

The MRL lpr/lpr mouse strain is an animal model for the autoimmune dis order systemic lupus erythematosus (SLE). Pathologic changes in the mi ce include a severe proliferative glomerulonephritis, lymph node and s pleen enlargement, increase in autoantibody titers, and shortened life spans. In the present investigation, female MRL lpr/lpr mice have bee n dosed po daily for 7 months with the selective estrogen receptor mod ulator (SERM) LY139478 (4 mg/kg) or 17 alpha-ethinylestradiol (EE2, 1 mg/kg) and compared to vehicle control animals. The LY139478 group had an increase in survival (73% survival at 7 months, P = 0.02) but the EE2-treated animals did not (53% survival at 7 months, P = 0.4) when c ompared to the control group (32% survival at 7 months). Although ther e were no reductions in autoantibody levels as determined by anti-DNA antibody ELISA, histological analysis of kidney tissue indicated that both LY139478 and EE2 mitigated the progression of glomerular nephriti s which was evident in the controls. In contrast, there were no signif icant differences in lymph node size although the LY139478 and EE2 gro ups retained a well-defined sinusoidal region. Finally, flow cytometri c analysis documented that thymuses from animals treated for 7 months with LY139478 but not with EE2 contained predominantly CD4(+)/CD+ T ce lls consistent with a normal thymic phenotype observed in non-MRL lpr/ lpr mouse strains. These studies demonstrate that SERMs may be potenti ally useful for the treatment of autoimmune disorders. (C) 1996 Academ ic Press, Inc.