Choi et al.  have exploited the finding that increased production of IFN-γ is the hallmark of in vivo anti-4-1BB administration  https://www.selleckchem.com/GSK-3.html to treat EAU: treatment of C57BL/6 mice with IRBP peptide (an EAU-inducing agent) and anti-4-1BB led to expansion of IFN-γ+ CD11c+CD8+ T cells and indoleamine 2,3-dioxygenase (IDO)+ DCs and these, in combination, led to deletion of autoreactive CD4+ T cells . Taken together, these various findings indicate that targeting CD137 is an attractive strategy for preventing the symptoms associated with various autoimmune diseases (Table 1, Fig. 1e). The Fas (Apo-1/CD95) and Fas ligand (FasL) are one of the extensively studied TNF superfamily members. The
Fas was described originally as a cell surface molecule capable of inducing apoptosis when stimulated by Fas ligand (FasL) or agonistic
anti-Fas mAb [104–106]. However, there are reports that ligation of Fas on freshly isolated T cells co-stimulates cellular activation and proliferation , an attribute that is somewhat conflicting with its proposed role in apoptosis. The Fas is expressed in most tissues  and is up-regulated further during inflammation [109,110]. selleck At the cellular level, Fas expression is low on freshly isolated lymphocytes but is up-regulated on activated T cells . Also, proportions of Fas-positive cells in peripheral T and B cells have been reported to increase in humans with Etofibrate advancing age . Conversely, the expression of FasL is governed tightly and is expressed, among others, by activated T cells . The Fas and FasL have been shown to play critical roles in various diseases including fulminant hepatitis [114,115], graft-versus-host disease  and tissue-specific autoimmune disease . Fas–FasL interactions also are important in T cell-mediated cytotoxicity , immune privilege tissues [119–121], activation-induced cell death (AICD) [122,123] and transplant tolerance . The Fas- and FasL-deficient mice develop autoimmune diseases and lymphadenopathy
due to the inability to delete the autoreactive T and B lymphocytes [125,126]. The importance of the Fas–FasL pathway has been underscored in a number of autoimmune diseases, including lupus , SLE , autoimmune lymphoproliferative syndrome (ALPS) [128,129], Canale–Smith syndrome , type 2 autoimmune hepatitis , Hashimoto’s syndrome , insulin-dependent diabetes mellitus [133,134], MS , Sjögren’s syndrome , myasthenia gravis , EAE  and RA . Increased Fas+ and FasL+ cells were observed on the glial cells, macrophages and infiltrating lymphocytes in the white matter of MS brains [135,140]. Also, acinar cells of salivary glands of Sjögren’s syndrome patients show high expression of Fas and FasL and were shown to die by apoptosis . While patients with Hashimoto’s disease showed decreased sFas, increased levels were noted in Graves’ thyroiditis and SLE patients [142,143].