Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis.
Steroidal estrogens can regulate inflammatory immune responses and may be involved in the suppression of multiple sclerosis (MS) during pregnancy. However, the risks and side effects associated with steroidal estrogens may limit their usefulness for long-term MS therapy. Selective estrogen receptor modulators (SERMs) could provide an alternative therapeutic strategy, because they behave as estrogen agonists in some tissues, but are either inert or behave like estrogen antagonists in other tissues. In this study, we investigated the ability of two commercially available SERMs (tamoxifen and raloxifene) to regulate myelin specific immunity and experimental autoimmune encephalomyelitis (EAE) in mice. Both tamoxifen and raloxifene suppressed myelin antigen specific T-cell proliferation. However, tamoxifen was more effective in this regard. Tamoxifen treatment reduced the induction of major histocompatibility complex II by lipopolysaccharide stimulated dendritic cells and decreased their ability to activate myelin specific T-cells. At lower doses, tamoxifen was found to increase the levels of Th2 transcription factors and induce a Th2 bias in cultures of myelin-specific splenocytes. EAE symptoms and the degree of demyelination were less severe in mice treated with tamoxifen than in control mice. These findings support the notion that tamoxifen or related SERMs are potential agents that could be used in the treatment of inflammatory autoimmune disorders that affect the central nervous system.
Bebo
Bruce F
BF
Neurological Sciences Institute, Oregon Health & Science University, Beaverton, Oregon, USA.
Dehghani
Babak
B
Foster
Scott
S
Kurniawan
Astrid
A
Lopez
Francisco J
FJ
Sherman
Larry S
LS
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000188:drug therapy; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005802:Genes, MHC Class II / Q000502:physiology; D007111:Immunity, Cellular / Q000187:drug effects; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000276:immunology*; D009186:Myelin Sheath / Q000276:immunology; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D013629:Tamoxifen / Q000627:therapeutic use
D047628:Estrogen Receptor alpha; D008070:Lipopolysaccharides; D009185:Myelin Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride