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 disorder systemic lupus erythematosus (SLE). Pathologic changes in the mice include a severe proliferative glomerulonephritis, lymph node and spleen enlargement, increase in autoantibody titers, and shortened life spans. In the present investigation, female MRL lpr/lpr mice have been dosed po daily for 7 months with the selective estrogen receptor modulator (SERM) LY139478 (4 mg/kg) or 17alpha-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 compared to the control group (32% survival at 7 months). Although there 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 nephritis which was evident in the controls. In contrast, there were no significant differences in lymph node size although the LY139478 and EE2 groups retained a well-defined sinusoidal region. Finally, flow cytometric analysis documented that thymuses from animals treated for 7 months with LY139478 but not with EE2 contained predominantly CD4+/CD+ T cells consistent with a normal thymic phenotype observed in non-MRL lpr/lpr mouse strains. These studies demonstrate that SERMs may be potentially useful for the treatment of autoimmune disorders.
Apelgren
L D
LD
Division of Cardiovascular Research, Lilly Research Labs, Indianapolis, Indiana 46285, USA.
Bailey
D L
DL
Fouts
R L
RL
Short
L
L
Bryan
N
N
Evans
G F
GF
Sandusky
G E
GE
Zuckerman
S H
SH
Glasebrook
A
A
Bumol
T F
TF
D000818:Animals; D001327:Autoimmune Diseases; D015496:CD4-Positive T-Lymphocytes / Q000145:classification; D018414:CD8-Positive T-Lymphocytes / Q000145:classification; D004195:Disease Models, Animal; D018450:Disease Progression; D045166:Estradiol Congeners / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000276:immunology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013950:Thymus Gland / Q000166:cytology
D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D013876:Thiophenes; D004997:Ethinyl Estradiol; C025430:LY 117018