Screening tests for autoimmune-related immunotoxicity.

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Abstract
A large number of chemicals induce or exacerbate autoimmune-like diseases in man. Because of the complexity of processes involved, these adverse effects are often if not always missed in standard toxicity testing. To date no validated and generally applicable predictive animal model exists and only a few chemicals have actually been shown to induce adverse autoimmune effects in certain animals. The popliteal lymph node assay (PLNA) is a very promising animal test to (pre)screen for systemic immunosensitizing, including autoimmunogenic potential. This review describes the essentials of the various PLNAs against the background of current understanding of chemically induced systemic immunostimulation. The most simple primary PLNA measures enlargement of the popliteal lymph node 6-8 days after subcutaneous injection of a chemical into the footpad. The primary PLNA can distinguish between immunostimulating (both sensitizers and irritants) and innocent chemicals but does not assess the involvement of T cells or immunosensitization. For this, but also for elucidation of relevant mechanisms, detection of anamnestic responses in secondary PLNAs or responses to reporter antigens in the modified PLNA are suitable. To date over 100 compounds (drugs and environmental pollutants) have been tested, and results show a good correlation with reported immunostimulating (both autoimmunogenic and allergic) potential. Importantly, no false-negative chemicals were detected if metabolism was considered. The various types of the PLNA, but in particular the secondary and modified PLNAs, await extensive validation before they can be recommended as a standard test for autoimmunogenic potential.

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