Detection of autoimmunity by pharmaceuticals.
Despite the important health and economic impact of autoimmunogenicity or allergenicity by pharmaceuticals models to detect such adverse effects are not available yet. The most important reason for this is the related complex interplay of multiple factors, for which reason these adverse effects are also referred to as idiosyncratic in nature. Moreover, clinical effects are quite diverse, and involve both organ-specific and systemic effects, including a diversity of skin diseases. Because of its complexity on the one hand and the fundamental knowledge on certain particular mechanistic effects it may be more relevant to design a rationalistic toolbox of test models from which a predictive strategy can be composed. Since one mechanistic aspect centers around T cell sensitization a straightforward lymph node assay such as the reporter antigen-popliteal lymph node assay (RA-PLNA) would fit in such a toolbox. This RA-PLNA holds a strong promise to distinguish sensitizing and/or neoantigen-forming capacity of low molecular weight pharmaceuticals. In addition, from the pharmacokinetic point of view a rationalistic toolbox should also contain oral exposure models with immunological read out parameters in normal or in genetically predisposed animal strains. This review focuses on these two categories of candidate test methods, PLNA and oral exposure models, and proposes to use these in tandem in order to predict the hazard of induction of allergy or autoimmune phenomena by new pharmaceutical candidates.
Pieters
Raymond
R
Institute for Risk Assessment Sciences, Immunotoxicology, Utrecht University, The Netherlands. r.pieters@iras.uu.nl
D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions / Q000276:immunology*; D023441:Local Lymph Node Assay; D051381:Rats; D011914:Rats, Inbred BN