Considering Fas ligand as a target for therapy

About a decade ago, the death factor Fas ligand (FasL) was identified as the natural trigger of Fas/CD95-dependent apoptosis and as an inducer of Fas-dependent activation-induced cell death. Meanwhile, it is known that this molecule not only contributes to target cell lysis in the immune system but also to the establishment of immune privilege and tumour survival. Because delivering a specific antiproliferative signal to T lymphocytes is of major biomedical interest, the FasL/Fas system has gained much attention over the last few years. However, only recently it became evident that the biology of FasL is more complex than initially anticipated. FasL displays a complex pattern of inducible and constitutive expression associated with a number of different functions as a death factor or a co-stimulatory/accessory molecule in lymphocyte activation. Thus, side effects are likely to occur following systemic administration of, for example, anti-FasL medication, not only because of the constitutive FasL expression on cells within immune privileged tissues and vascular endothelium. In addition, FasL comes in different forms: as a surface molecule, as a protease-shed soluble variant or secreted in vesicles. Because increased levels of soluble FasL (sFasL) have been determined in various immunological and non-immunological diseases, it has been suggested that sFasL might serve as a prognostic or diagnostic marker even though the pathophysiological cause for its enhanced production is hardly known in most cases. This review summarises the current facts and ideas about the clinical and pharmacological potential of FasL and sFasL as targets for therapeutic interventions.