Progress in understanding adjuvant immunotoxicity mechanisms

Over the last twenty years research has provided an important insight into the mechanisms responsible for the immunotoxicity of both local and systemic adverse reactions following the use of immunostimulating drugs and adjuvants. In this article we provide an update of the present knowledge relating to the various parameters and reactants of the immune system at the cellular as well as molecular level that are believed to play a key role in reactogenicity. We discuss evidence obtained from observations in vitro, in vivo in animal models and from clinical applications, including adjuvants used in large scale vaccination today. The data discussed are mainly taken from animal models following hyperstimulation of the immune system; either by the use of very powerful adjuvants, like Freund's that are too toxic for use in practical vaccination, by deliberate high dose application of adjuvants or by the in vivo application of cytokines. Although such hyperstimulating regimens are unlikely to find their way into practical vaccination of humans, this information is of great value as it may facilitate the understanding of the toxicity mechanisms, aid the design of standardised models for the assessment of adjuvant safety and the possible application of new adjuvants in vaccines for humans.