BLyS antagonists and peptide tolerance induction

The major impediment to drug development for systemic lupus erythematosus (SLE) is its heterogeneity. The unpredictable manner in which lupus targets different organs at varying intensity makes the study of new drugs and the optimization of their administration extremely difficult. With the advent of novel, targeted biologic agents for SLE, it can be hoped that more strategic, lupus-relevant immune modulation will lead to safer and more effective treatments. Two alternative new approaches to lupus treatment are reviewed. The first involves selective inhibition of a single protein (BLyS), which may play a central role in host defense and in the pathogenesis of SLE. Although this approach is finely targeted to the inhibition of a single protein which is known to be upregulated in SLE patients, the positioning of BLyS at a critical hub in the immune response suggests that more global adverse repercussions on immunity might still occur. The second strategy is the use of peptides designed to specifically induce tolerance in limited autoreactive immune responses. Immune repercussions might, at least in theory, be almost nonexistent with this kind of approach. Concerns that limited induction of tolerance might have equally limited impact on the complex immune disorder of SLE are not borne out in preliminary murine data. Specific development programs are ongoing using both of these strategies and have recently entered human trials.