Central nervous system toxicity of interferons and other cytokines

Prolonged administration of interferons, interleukins and tumor necrosis factor are accompanied by a range of toxic effects of which central nervous system toxicity may be an important dose-limiting factor. While symptoms are widely reported, practically nothing is known about mechanisms of action. This review attempts to distinguish between a direct effect of cytokines upon circumventricular organs and an indirect effect mediated by factors released by endothelial-glial cells of the blood-brain barrier normally impermeable to cytokines. In order to reduce the toxicity of biological response modifiers the definition of the minimum effective dose, the use of the lymphatic route and the observance of the chronobiological rules may help to improve the therapeutic index of these hormone-like compounds. It appears however, that the relationship between cytokine: dose: route: schedule: timing on one side and efficacy: toxicity on the other is complex, and so far no general rule has clearly emerged so that at the moment it appears necessary to find out the optimal therapeutic index for each particular disease.