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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh074
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received October 16, 2003; accepted January 9, 2004
© 2004 Society of Toxicology

Immunotoxicology

Evaluation of the Use of Reporter Antigens in an Auricular Lymph Node Assay to Assess the Immunosensitizing Potential of Drugs

Stefan Nierkens 1*, Leonie Nieuwenhuijsen 1, Mieke Thomas 1, and Raymond Pieters 1

1 Institute for Risk Assessment Sciences, Immunotoxicology, Utrecht University, Utrecht, The Netherlands

* To whom correspondence should be addressed. E-mail: s.nierkens{at}iras.uu.nl.


  Abstract

Immune-mediated idiosyncratic drug reactions are a major problem for susceptible patients, physicians and pharmaceutical industries. Validated screening tools to assess the immune sensitizing capacity of orally or intravenously administered pharmaceuticals are currently not available. To date, the popliteal lymph node assay (PLNA) seems the most promising tool for this purpose. The PLNA has recently been extended with the use of reporter antigens (RA) that are coinjected together with the drug of interest. The measurement of isotypes of RA-specific antibody secreting cells (ASC) enables the distinction of sensitizing chemicals and (non-sensitizing) irritants without radio-isotopic endpoints. However, the use of footpad injections raises ethical concerns. Therefore, we examined the use of RA after intradermal injection of the ear of BALB/c mice and measured RA-specific ASC in the draining auricular lymph node (ALN).

We show that RA-specific IgG isotype ASC numbers are very useful and sensitive parameters to identify drug-induced hypersensitivity in both PLN and ALN. However, the type-1 associated parameters (CD8+ cells, macrophages, IFN-{gamma}, TNF-{alpha} and IL-1{beta}) that are induced in the PLN by STZ were less pronounced in the ALN. Thus, the PLNA may provide more immunologically relevant information on the mechanisms of certain chemical-induced hypersensitivity reactions.

In conclusion, the RA-ALN assay may provide an alternative for the RA-PLNA as both assays can be used to distinguish sensitizing compounds from non-sensitizers.


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