Offner reported that estrogen and its derivatives exert neuroimmunoprotective effects against EAE and that E2 upregulates the expression of Foxp3 and Ctla4, which contribute to the activity of Tregs, suggesting the therapeutic application of estrogen to MS [157] . Papenfuss et al. also demonstrated that estriol (E3), a pregnancy-specific estrogen, has therapeutic efficacy in MS and EAE and they confirmed that E3 protects mice against EAE by inducing DCs to increase their expression of inhibitory costimulatory markers (PD-L1, PD-L2, B7-H3) and deviate towards a Th2 phenotype [158] .