Convincing studies have shown that CD137/CD137L interactions may play an important role in the pathogenesis of autoimmune disease. The serum levels of sCD137 and sCD137L in patients may help the diagnosis of certain autoimmune diseases, and CD137 targeted immunotherapy regimes especially CD137 agonists hold lots of promise in treating inflammatory diseases.
From the therapeutic point of view, the agonistic anti-CD137 mAbs stands out for following reasons. First, they are both prophylactic and therapeutic. Anti-CD137 treatment not just prevents the development of autoimmune disease, but also reverses the disease severity in afflicted mice, and it generates immunoregu-latory mechanism protecting the mice from subsequent disease induction. Second, they allow for selective depletion or anergy induction of activated autoreactive lymphocytes without inducing global immunosuppression. Agonistic anti-CD137 treatment inhibits autoimmunity without overt interference with the normal immune response to exogenous antigens after the termination of treatment (Foell et al., 2003; Sun et al., 2002a). Third, Agonistic anti-CD137 treatment abrogates antibody production against itself due to its potential inhibition of T-dependent humoral immune responses, thereby making repeated administration possible (Foell etal.,2003; Mittler etal., 1999). The above feature ofCD137 agonist allows short-term therapy; therefore the treatment is cost-effective and beneficial to patients. So a therapeutic approach based on triggering CD137 is very attractive in clinical application of autoimmune and inflammatory disease treatment.
However, CD137 crosslinking in vivo does not attenuate all autoimmune diseases. Experiments performed by Sytwu et al. (2003) showed that transgenic non-obese diabetic (NOD) mice, which overexpress membrane-bound agonistic single-chain anti-CD137 Fv (scFv) in pancreatic beta cells, developed earlier onset and more aggressive diabetes than their non-transgenic littermates with enhanced GAD-specific T-cell responses and higher mortality. NOD mice have been widely used as animal model for human type I autoimmune diabetes (T1D). Both CD4+ and CD8+ T cells are implicated in the pathogenesis of T1D. Since CD137 provides potent costimulatory signaling to CD8+ T cells and prolongs their survival, CD8+ T cell-involved autoimmune diseases may not be good targets of anti-CD137-based immunotherapy. Combinatorial treatment with CD8+ T cell inhibitors may be necessary. Anti-CD137 based immunotherapy may be more effective in CD4+ T cell-dominant inflammatory diseases. When used properly, CD137-targeted im-munotherapy strategy may provide an effective novel therapeutic avenue in the treatment of various autoimmune diseases.
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