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ToxSci Advance Access published online on October 27, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi021
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received August 18, 2004
Accepted October 24, 2004

Immunotoxiocology

Development of an Oral Exposure Mouse Model to Predict Drug-Induced Hypersensitivity Reactions by Using Reporter Antigens

Stefan Nierkens 1*, Marloes Aalbers 1, Marianne Bol 1, Femke van Wijk 1, Ine Hassing 1, and Raymond Pieters 1

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

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


  Abstract

The capability of certain drugs to cause immune-mediated drug hypersensitivity reactions in susceptible individuals has initiated a search for pre-clinical screening tools to identify immunosensitizing drugs. Since most drugs are taken orally, hazard assessment of their immunosensitizing potential should include oral exposure models. In this study, the predictive value of the reporter antigen (RA) approach was investigated in combination with oral or intraperitoneal (i.p.) exposure to a selection of allergenic drugs, i.e. D-penicillamine (D-Pen), Diclofenac (DF), or Nevirapine (Nevi). The RA trinitrophenyl-Ovalbumin (TNP-OVA) was used to assess the capacity of the drugs to stimulate systemic immune responses to a bystander antigen, whereas the RA TNP-Ficoll was used to indicate whether the drugs were able to induce specific anamnestic T cell responses.

TNP-OVA was injected (i.p.) in C3H/HeOuJ mice that were subsequently exposed (orally or i.p.) to one of the drugs via different exposure protocols. All three model drugs used resulted in delayed type hypersensitivity reactions to TNP-OVA after i.p and oral exposure. In addition, TNP-specific serum antibody levels were increased after i.p. exposure to Nevi, and after both oral and i.p. exposure to D-Pen and DF. These data indicate that the present drugs are able to stimulate immune responses to bystander antigens.

Responses to TNP-Ficoll were measured in the popliteal lymph node of BALB/c mice 3 weeks after they received a single oral dose of D-Pen or DF. Results of this approach show that orally pre-treated mice responded with enhanced responses (TNP-specific IgG1 and IFN-{gamma} production) to sub-optimal doses of D-Pen or DF in a drug-specific manner. Data with TNP-Ficoll indicate that these drugs stimulate systemic formation of specific T cells.

Together, the RA-approach allows assessment of systemic sensitization upon oral and/or i.p. exposure to the selected drugs. To further evaluate the utility of these models, more drugs, including non-allergenic drugs and those that require metabolic conversion to become allergenic need to be studied in the present models.

Keywords: drug-induced hypersensitivity; reporter antigen; mouse model; oral; relevant route; antibodies.
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